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Sketchy Pharmacology Contents Sketchy Pharmacology ........................................................................................................................................................... 1 Autonomic Pharmacology ....................................................................................................................................................... 5 1. Parasympathetics ............................................................................................................................................................ 5 2. Sympathetics ................................................................................................................................................................... 5 1.1 – “I’d Like to Buy the World an Acetyl-Cola”: Cholinomimetics ......................................................................... 5 1.2 – “Stigmata Gravis”: Cholinesterase inhibitors (neostigmine, pyridostigmine, edrophonium, physostigmine, organophosphates, galantamine, rivastigmine, donepezil) ............................................................................................ 6 2.1 – “Atropine in Wonderland”: Muscarinic Antagonists (atropine, ipratropium, tiotropium, oxybutynin, tolterodine, scopolamine, benztropine, trihexyphenidyl) .............................................................................................. 8 2.1 – “One Epic Summer Band Camp”: Direct Sympathomimetics (norepinephrine, phenylephrine, epinephrine, dobutamine, isoproterenol) ............................................................................................................................................ 9 2.2 – “Catecholamine Catch & Release”: Indirect sympathomimetics (cocaine, ephedrine, amphetamine, methylphenidate, modafinil, atomoxetine) .................................................................................................................. 12 2.3 – “The Phantom of the Alpha”: α-adrenergic drugs (α2 agonists: clonidine, α-methyldopa tizanidine; α antagonists: phentolamine, phenoxybenzamine, prazosin, mirtazapine) ........................................................................................ 13 2.4 – “Brahms’s LOL Lullaby”: β blockers ...................................................................................................................... 13 Circulatory (CV & Renal)........................................................................................................................................................ 15 1.

Heart Failure ............................................................................................................................................................. 15

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Diuretics .................................................................................................................................................................... 15

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Anti-hypertensives .................................................................................................................................................... 15

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Antiarrhythmics......................................................................................................................................................... 15

1.1 – “Pretty in Yellow”: Digoxin, milrinone, nesiritide .......................................................................................... 15 1.2 – “The House Always Wins”: ACE-inhibitors, ARBs, aliskiren ................................................................................. 17 2.1 – “Pro Cart Track”: Acetazolamide, mannitol ......................................................................................................... 19 2.2 – “Loop-de-loop of Henle”: Loop Diuretics (furosemide, ethacrynic acid) ............................................................. 20 2.3 – “Distal Convoluted Tube Slide”: Thiazide diuretics .............................................................................................. 21 2.4 – “Salty Mineral Food Court”: Potassium Sparing Diuretics (amiloride, triamterene, eplerenone, spironolactone) 22 3.1 – “We All Scream for Calci-YUM!” Calcium Channel Blockers ................................................................................ 24 3.2 – “High Tension on the High Seas”: Primary HTN & Hypertensive crisis ................................................................ 26 4.1 – “Soloist at the Heartbreak Hotel”: Class I (A, B, C) Antiarrhythmics – Na-channel blockers ............................... 27 4.2 – “β Brass Quartet”: Class II Antiarrhythmics - β .................................................................................................... 29 4.3 – “Tres Amigos”: Class III Antiarrhythmics – K+ channel blockers .......................................................................... 30 4.4 – “Calci-YUM quartet”: Class IV antiarrhythmics .................................................................................................... 31 4.5 – “DJ Foxglove Discotheque”: Class V antiarrhythmics (basically everything else) ................................................ 32 Blood & Inflammation ........................................................................................................................................................... 33 1

Anticoagulants and thrombolytics ............................................................................................................................ 33

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Dyslipidemia .............................................................................................................................................................. 33

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Anti-inflammatory drugs ........................................................................................................................................... 33

2 1.1 – “Heparin Season”: Heparin & direct Factor X inhibitors ................................................................................ 33 1.2 – “Warfarin, what is it good for?” ........................................................................................................................... 35 1.3 – “Bad News Platelets”: Antiplatelet Agents .......................................................................................................... 36 1.4 – “Warning: Bleeding Hazard”. Thrombolytics ................................................................................................. 38 2.1 – “Statin Steampunks”: Statins ............................................................................................................................... 39 2.2 – “Twenty Thousand Lipids Under the Sea”: Cholestyramine, ezetimibe .............................................................. 41 2.3 – “Loch Niacin Monster”: Fibrates & Niacin ........................................................................................................... 41 3.1 – “NSAIDs in the outfield” ....................................................................................................................................... 43 3.2 – “Confessions of a knit-wit”: Gout drugs (allopurinol, febuxostat, probenecid, pegloticase) .............................. 46 Smooth Muscle ..................................................................................................................................................................... 48 1. Vasoactive drugs ........................................................................................................................................................... 48 2. Allergy & Pulmonary drugs ........................................................................................................................................... 48 1.1 – “The Ballad of Johnny Nitro”: Nitrates ................................................................................................................. 48 1.2 – “Pounding at the Sumo Festival”: Triptans & migraines ...................................................................................... 50 1.3 – “Pro-Slugger Sporting Goods”: Prostaglandins, prostacyclin, bosentan, PDE-5 inhibitors.................................. 51 2.1 – “A Midsummer Night’s Diphenhydramine”: Antihistamines ............................................................................... 53 2.2 – “Fant-asthmic Parade”: Asthma treatment (β-2 selective agonists, leukotriene inhibitors, methylxanthines, cromolyn, sulfate omalizumab) .................................................................................................................................... 54 GI & Endocrine ...................................................................................................................................................................... 56 1. Gastrointestinal ............................................................................................................................................................. 56 2. Diabetes ........................................................................................................................................................................ 56 3. Thyroid, parathyroid, & adrenals .................................................................................................................................. 56 4. Hypothalamic & Pituitary .............................................................................................................................................. 56 1.1 – “Stadium Vomitorium”: Anti-emetics – Ondansetron, metoclopramide, H1 receptor antagonists, scopolamine, aprepitant ............................................................................................................................................... 56 1.2 – “Gastroesophageal Refund”: Acid control therapy with H2 receptor blockers & PPIs........................................ 58 1.3 – “Relaxatives”: Laxative agents (lactulose, magnesium, polyethylene glycol, docusate, Senna, psyllium, loperamide, diphenoxylate) & antidiarrheals ............................................................................................................... 60 2.1 – “Langerhansel & Gretel”: Insulin, sulfonylureas, meglitinides, GLP-1 agonists, DPP-4 inhibitors ....................... 61 2.2 – “Rosiglitazones are Red, Pioglitazones are Blue…”: Metformin, Thiazolidinediones, Pramlintide, SGLT2 inhibitors 63 3.1 – “Iodine is Forever”: Propylthiouracil, methimazole, levothyroxine..................................................................... 65 3.2 – “The Natural h/o Osteoporosis”: Bisphosphonate, raloxifene, calcitonin, denosumab ...................................... 67 3.3 - "PthD in Paleontology": Teriparatide, Vitamin D, Cinacalcet, Sevelamer ............................................................ 68 3.4 – “The Court of Sone Henge”: Glucocorticoids ....................................................................................................... 70 4.1 - "JAK Stat and the Beanstalk": Growth Hormone, Mecasermin, Octreotide, Pegvisomant .................................. 71 4.2 - "Water Hazard": Posterior pituitary regulation (ADH, DDAVP, ADH Receptor Antagonists) ............................... 72 Neuro & psych Drugs ............................................................................................................................................................ 73 1.

Sedatives & hypnotics ............................................................................................................................................... 73

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Anesthetics & analgesics ........................................................................................................................................... 73

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Antidepressants & anxiolytics ................................................................................................................................... 73

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Mood stabilizers; antiepileptics ................................................................................................................................ 73

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Antipsychotics, Parkinson’s disease .......................................................................................................................... 73

3 1.1 – “L’eggo my Benzo!” Benzodiazepines, flumazenil ......................................................................................... 73 1.2 – “Catching some Zs”: Non-benzo hypnotics, melatonin, ramelteon ..................................................................... 75 1.3 – “Barber Shop”: Barbiturates ................................................................................................................................ 76 2.1 – “You’re getting sleepy…” IV anesthetics (Propofol, etomidate, ketamine) ......................................................... 77 2.2 – “Laughing gas”: inhaled anesthetics, dantrolene ................................................................................................ 78 2.3 – “Utopia resort”: Opiates, naloxone, naltrexone .................................................................................................. 79 3.1 – “Serotonin sitcom”: SSRIs, SNRIs, cyproheptadine .............................................................................................. 81 3.2 – “I want to ride my tricycle”: Tricyclic antidepressants ........................................................................................ 83 3.3 – “Of Mice & MAOIs” .............................................................................................................................................. 84 3.4 – “March Sadness”: Atypical antidepressants (Bupropion, mirtazapine, trazadone) ............................................ 85 4.1 – “Ski Mania”: Lithium ............................................................................................................................................ 86 4.2 – “Seize the land”: Broad spectrum anti-epileptics (valproate, topiramate, lamotrigine, levetiracetam) ............. 87 4.3 – “Seize the night”: Narrow spectrum anti-epileptics (Carbamazepine, phenytoin, gabapentin, tiagabine, vigabatrin) ..................................................................................................................................................................... 89 4.4 – “Seize the daydream”: Ethosuximide................................................................................................................... 91 5.1 – “The Typical Impressionist”: First generation antipsychotics (haloperidol, trifluoperazine, fluphenazine, chlorpromazine, thioridazine) ....................................................................................................................................... 92 5.2 – “The Atypical surrealist”: Second generation antipsychotics (olanzapine, quetiapine, aripiprazole, ziprasidone, risperidone, clozapine).................................................................................................................................................. 94 5.3 – “Money for Old Rope”: Parkinson management (Levodopa, carbidopa, entacapone, tolcapone, selegiline, ropinirole, pramipexole, amantadine) .......................................................................................................................... 96 Antimicrobials ....................................................................................................................................................................... 98 1. Cell wall & membrane active antibiotics (β-lactams, vancomycin, daptomycin) ......................................................... 98 2. Inhibitors of bacterial protein synthesis ....................................................................................................................... 98 3. Antimycobacterial ......................................................................................................................................................... 98 4. Other antibacterials ...................................................................................................................................................... 98 5. Antifungals .................................................................................................................................................................... 98 6. Antivirals: HIV ................................................................................................................................................................ 98 7. Antivirals: Hepatitis ....................................................................................................................................................... 98 8. Antivirals: others ........................................................................................................................................................... 98 1.1 – “Princess Ellen’s New Hope”: Penicillins .............................................................................................................. 98 1.2 – “The Staphylococci Strike Back”: Nafcillin, oxacillin, dicloxacillin ...................................................................... 100 1.3 – “Amped up at the Cantina”: Extended spectrum penicillins (Ampicillin, amoxicillin, piperacillin, ticarcillin) & βlactamase inhibitors (clavulanate, tazobactam, sulbactam) ...................................................................................... 101 1.4 – “Revenge of the Ceph”: Cephalosporins ............................................................................................................ 103 1.5 – “The coverage is strong with this one”: monobactams & carbapenems........................................................... 105 1.6 – “MRSA… why did it have to be MRSA?”: Vancomycin ....................................................................................... 106 1.7 – “Let my chickens go”: Daptomycin .................................................................................................................... 107 2.1 – “Le Tour de Cyclines”: Tetracyclines .................................................................................................................. 108 2.2 – “The Crow”: Macrolide antibiotics ..................................................................................................................... 109 2.3 – “Keeping it Clean at the Anaerobic Gym”: Clindamycin! ................................................................................... 110 2.4 – “A Splash of Gray”: Chloramphenicol ................................................................................................................ 111 2.5 – “Do Not Cross”: Linezolid ................................................................................................................................... 112 2.6 – “Feudal assassins”: aminoglycosides ................................................................................................................. 113

4 3.1 – “The Magnificent Four” ...................................................................................................................................... 114 3.2 – “For a Few Mycobacteria more”: Rifampin, rifabutin, ethambutol, clofazimine .............................................. 115 4.2 – “Trick or Treat, Smell my Drugs”: Sulfa drugs (TMP/SMX, pyrimethamine/sulfadiazine) ................................. 116 4.2 – “A Nordic Spring”: Fluoroquinolones ................................................................................................................. 117 4.3 – “Murder on the Metro Express” ........................................................................................................................ 118 5.1 – “Bio 101 meets Music 101”: amphotericin, flucytosine, nystatin ..................................................................... 119 5.2 – “We’re not in Candida Anymore”: azole antifungals ......................................................................................... 120 5.3 – “There’s no place like Canada”: Griseofulvin, terbinafine, echinocandins ........................................................ 121 6.1 – “Le Morte d’HIV”: NRTIs (abacavir, diadnosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine) 122 6.2 – “The Council of Elfavir”: NNRTIs (Nevirapine, efavirenz, delavirdine) ............................................................... 123 6.3 – “Lady Guinevere and the Sword in the Stone”: Protease inhibitors .................................................................. 124 6.4 – “How HIV was thwarted at the Gates of Camelot”: Entry inhibitors, fusion inhibitors, integrase inhibitors .... 125 7.1 – “Insert Cytocoin to Continue”: Interferon α, IFN-β, IFN-γ ................................................................................. 126 7.2 – “Dr Liver-stone, I presume?”: Hep-C treatment (Ribavirin, sofosbuvir, simeprevir) ......................................... 127 8.1 – “You are Now Free to move about the Ganglia”: Acyclovir, valacyclovir, famciclovir, cidofovir, foscarnet ..... 128 8.2 – “Clean up on Aisle HHV-5”: CMV treatment (Ganciclovir, valganciclovir, cidofovir, foscarnet, probenecid) ... 129 Antineoplastic Drugs ........................................................................................................................................................... 130 1. Antimetabolites........................................................................................................................................................... 130 2. DNA & Cellular division ............................................................................................................................................... 130 3. Kinase inhibitors, monoclonal antibodies ................................................................................................................... 130 1.1 – “Imitation folate”: methotrexate, leucovorin, 5-Fluorouracil, hydroxyurea ..................................................... 130 1.2 – “Hunchback of Notre DNA”: Azathioprine, 6-MP, mycophenolate mofetil....................................................... 132 1.3 – “Neolithic antineoplastics”: cladribine, cytarabine, gemcitabine ...................................................................... 133 2.1 – “Alkylating Odyssey”: Cyclophosphamide, Ifosfamide, Busulfan, Nitrosoureas ................................................ 134 2.2 – “Breakfast at Cisplatin’s”: Cisplatin, carboplatin, amifostine ............................................................................ 135 2.3 – “Doxorubicin’s Locker”: Bleomycin, anthracyclines, doxorubicin...................................................................... 136 2.4 – “Untangled”: Topoisomerase inhibitors ............................................................................................................ 137 2.5 – “Me taxane, You Christine”: Microtubule inhibitors ......................................................................................... 138 3.1 – “Revolutionary Kinase inhibitors”: imatinib, erlotinib, sorafenib, sunitinib, vemurafenib ............................... 139 3.2 – “The MAB who would be king”: Rituximab, cetuximab, bevacizumab, alemtuzumab, trastuzumab ............... 140

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Autonomic Pharmacology 1. Parasympathetics 2. Sympathetics 1.1 – “I’d Like to Buy the World an Acetyl-Cola”: Cholinomimetics • acetylcholine (ACh) is the primary signal molecule of parasympathetic nervous system (PNS). Cholinomimetic agents mimic effects of ACh by acting as ACh-receptor agonists or directly modifying ACh (Acetyl-cola mime = ACh mimetic). None of the cholinomimetics are especially specific, so when using clinically, monitor for negative effects. • There are two types of ACh receptors: o Nicotinic receptors (nAChR) (smoker) are ion channels (smoker has his eye on tv channel in storefront). Found in ANS ganglia (electric transformers connected wire-to-wire, like ganglia), NMJ endplate (outlet plate), & adrenal glands (beanie hat) ▪ ANS nerve typically synapse onto a ganglion before reaching target organs. The adrenal glands are an exception to this. o Muscarinic receptors (mAChR) (motorcycle parking spots) are found generally in autonomic effector tissues (heart, SM, some tissues, but not ANS ganglia). All are GPCRs (QIQ market for M1-M2-M3 inducers). In general, Muscarinic agents increase glandular secretion & smooth muscle activity. ▪ M1: Gq → IP3-DAG cascade (3 dogs) →↑intracellular Ca (dog has bone). Found in CNS & enteric nervous system (brain helmet) ▪ M2: Gi → ↓ intracellular cAMP (a rolled-up tent & packs with ↓↓arrows). Found in cardiac atria, SA & AV nodes (jacket with nodal jewels) →↓atrial contraction, ↓sinoatrial HR, ↓AV conduction velocity. Note that cardiac ventricles are controlled primarily by SNS, not PNS (cardiac jacket doesn’t show ventricles) ▪ M3: Gq → IP3-DAG cascade (3 dogs). Found in glands, including bladder & eye, & smooth muscles (SM) (glandular sponge & muscle-like paint job of 3rd biker). In healthy vasculature, IV M3 agonists stimulate NO release → ↑cGMP release →→ vasodilation; with atherosclerosis NO interacts directly with mAChR → vasoconstriction. Cholinomimetic drugs • Bethanechol (Beth the construction worker). Primarily muscarinic. Indications: o Used in neurogenic ileus, non-obstructive GI dysmotility, & congenital megacolon (cement coming from colon spout), d/t stimulation of GI secretion & motor activity ▪ contraindicated in obstructive processes (“DO Not Obstruct” sign). o Used to treat urinary retention from non-obstructive urinary retention, e.g. post-operatively or spinal injury (bladdershaped hose) • Pilocarpine (pile of carp). Primarily muscarinic. Indications: o Used to treat dry mouth, e.g. from Sjogren’s, nerve damage, prescription adverse effects d/t ↑salivary excretion (seawater around carp looks like drool) o Glaucoma. Stimulation of mAChR reduces IOP by contraction of ciliary body → relaxation of zonula fibers → outflow of aqueous humor (SM crane with zonula-like net fibers). Ciliary contraction also results in lens accommodation (round glass floats on top of net) o Activations sphincter pupillary muscle → pupillary constriction → miosis (dock worker with hoodie cinched all the way up – looks like miotic eyeball). Used in acute closed angle glaucoma • Carbachol (person on upper story with drawn hoodie). Nicotinic & muscarinic activity (dude is standing above smoker & looking at cyclists) o Pupillary constriction, used in acute angle closure glaucoma • Methacholine o Contracts bronchiolar SM. Used in pharmacological asthma challenge (marathon challenge = methacholine challenge). Will exacerbate existing obstructive pulmonary processes, such as asthma & COPD (wheezing runner in back) • Varenicline. Nicotinic partial agonists. (1-800-VERY-CLEAN smoking cessation) o Used for smoking cessation • Common adverse effects o COPD, asthma exacerbation o Peptic ulcer exacerbation

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1.2 – “Stigmata Gravis”: Cholinesterase inhibitors (neostigmine, pyridostigmine, edrophonium, physostigmine, organophosphates, galantamine, rivastigmine, donepezil) • Acetylcholinesterase (AChE) hydrolyzes ACh in post synaptic cleft, decreasing its availability for signaling (dumpster full of acetyl-cola bottles; anti-establishment graffiti). • Indirect cholinomimetics reversibly or irreversibly bind AChE, blocking ACh degradation →↑ availability for signaling in synaptic cleft (“Acetyl-Cola” billboard visible indistinctly, or indirectly, in the distance; acetyl-cola bottles spill out of knocked over dumpster, suggesting ↑ACh availability in synaptic cleft). Most end in -stigma drug suffix (stigma graffiti). Effect is similar to that of cholinomimetics in eye, GI tract, respiratory tract, & urinary tract. Specifically: o Enhances effects of ACh at NMJ endplate by acting on nicotinic ACh receptors (brick wall looks like skeletal muscle, with electrical outlet). Results in increased contraction strength, used in treatment of myasthenia gravis (Gravis graffiti with a grave marker). ▪ Myasthenia gravis is an autoimmune disorder with production of antibodies against NMJ nicotinic receptors. Presents with progressive proximal weakness, ptosis, diplopia, difficulty swallowing. Cholinesterase inhibitors are used for symptomatic relief; immunosuppression is used for autoimmune disease. • Endogenous & exogenous tertiary amines can cross BBB. Synthetic quaternary amines class do not, because of charge. Drugs: General • Pyridostigmine (volunteer with “Pride” jacket cleaning graffiti) o Used in long term treatment of myasthenia gravis o Quaternary amine (“Quarters only” sign on phone booth) • Neostigmine (neon sign) o Not used as commonly as pyridostigmine in treatment of MG. o Treats urinary retention d/t muscarinic activity (bladder hose) o Can be used to reverse nondepolarizing neuromuscular blockade o Quaternary amine (“Quarters only” sign on phone booth) • Edrophonium (phone both) o Very short action, ~5 minutes, allows use for tensilon test to determine whether exacerbation of MG symptoms is d/t overtreatment or undertreatment. MG overtreatment → ACh receptor overstimulation & refractory receptors = cholinergic crisis; looks similar to MG symptomatology. If signs & symptoms improve with edrophonium, suggest undertreatment (tense phone wire for ⊕ tensilon test) . (Phone booth in working order to remind of edrophonium reversing muscle weakness in undertreated. Busted up phone booth with slack wire suggests edrophonium fails to reverse muscle weakness = ⊖ test) o Quaternary amine (“Quarters only” sign on phone booth) • Physostigmine (phys-ed center) o Reverses atropine OD in the CNS by increasing ACh concentration at synapse to overcome competitive inhibition (Alice graffiti; phys ed teacher reprimanding atropine graffiti artist). Also used in cases of belladonna (deadly nightshade) or Jimson weed toxicity (flower in Alice’s hand, weeds in front of gym). o Crosses BBB, which can cause central cholinergic effects (“Your brain on drugs” poster). Toxicity remembered as “DUMBBELSS” (guy working out in gym, unable to lift weights) ▪ Diarrhea ▪ Urination ▪ Miosis/muscle weakness ▪ Bronchorrhea ▪ Bradycardia ▪ Emesis ▪ Lacrimation ▪ Salivation/sweating o Weak nAChR effects, such that toxicity includes flaccid paralysis (limp kid) Drugs: NMJ blockade • NMJ blockade used in, e.g., surgery. • Nondepolarizing agents o Curare compounds include tubocurarine, pancuronium, cisatracurium ▪ Inhibit nAChRs at NMJ endplate (CURARE brand crayons stuck in electrical outlet) • Depolarizing agents

7 o Succinylcholine (“Sucks” graffiti) ▪ Overstimulate nAChRs at NMJ endplate, causing a prolong refractory period (Volunteer is getting a shock; he is overstimulated). ▪ Two phase block • Phase 1 of depolarizing blockade is irreversible (phase 1 clean-up crew getting shocked). Na channels surrounding motor end plate are inactivated & cannot reopen until the end plate is repolarized; results in flaccid paralysis. AChE inhibitors have no reversal effect in this phase. • Phase 2 With continued administration, nAChR become desensitized and gradual repolarization occurs. This is similar to a non-depolarizing blockade, & AChE inhibitors may help reverse. ▪ Hydrolyzed in the cytoplasm by pseudocholinesterase, such that typically only 10% of administered succinylcholine actually reaches NMJ. • In patients with a pseudocholinesterase deficiency, an autosomal recessive disorder caused by polymorphism in the BCHE gene, use of succinylcholine as an anesthetic can cause prolonged paralysis of respiratory musculature, and prolonged post-op apnea. Little risk of harm to patient if mechanical ventilation is maintained. Otherwise, this is a benign condition. ▪ Adverse effects: • Malignant hyperthermia in genetically susceptible patients, especially with halothane • Severe hyperkalemia in patients with burns, myopathies, crush injuries, & denervation. Occurs because the nAChR is a nonselective cation channel, and opening allows both Na influx & K efflux. Seen in these specific patient populations d/t upregulation of muscular nAChRs. • Bradycardia from PNS stimulation or tachycardia d/t SNS effects Alzheimer’s treatments • Galantamine (Alzheimer's gala), rivastigmine (release stigma), donepezil (done with puzzle) o All cross BBB o Benefits modest. Must be balanced against risk of major adverse effects d/t ↑ AChE activity. AChE inhibitor OD • Seen with exposure to organophosphates, used commonly in insecticides, like parathion, malathion, echothiopate, as well as nerve agents & herbicides (dude spraying “THIOL” herbicide outside gym) Can cause thiosulfate toxicity, & major cause of acute cholinergic toxicity (green fumes causing weightlifter’s weakness). • Toxicity must be recognized immediately. Organophosphates bind covalently to AChE; left too long, aging of organophosphatecholinesterase complex leads to irreversible binding (older pest control man has irreversibly damaged AChE dumpster). o DUMBBELSS toxicity • Pralidoxime reverses peripheral toxicity (toxic dumpster with lid open) o increasing hydrolysis of covalent bond → regenerates AChE at peripheral muscarinic & nicotinic receptors, reversing cholinergic toxicity including flaccid paralysis (new AChE dumpsters). o Does not cross BBB, so will not reverse CNS muscarinic effects. • Atropine reverses muscarinic toxicity (Alice’s head on toxic waste dumpster) o Crosses CNS. Reverses muscarinic toxicity in both peripheral & central nervous systems.

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2.1 – “Atropine in Wonderland”: Muscarinic Antagonists (atropine, ipratropium, tiotropium, oxybutynin, tolterodine, scopolamine, benztropine, trihexyphenidyl) • Muscarinic antagonists reversibly inhibit muscarinic receptors (mouse’s car reversing into muscarinic parking place). Block effects of cholinomimetic agents, including toxicity (Tweedledum with dumbbells & Tweedledee with Acetyl-cola are blocked from parking) • Note that any of these will have desired effects in one system but undesirable effects in another. Elevated heart rate is a particularly common side effect. • Atropine (Alice) o Jimson weed & Belladonna flowers are naturally occurring alkaloids. May be of clinical relevance in gardeners and children (Alice’s flowers, Jim's tea) ▪ Side note: The name Belladonna derived from Italian for beautiful woman. During the Renaissance, large pupils were perceived as beautiful & so women used a tincture of Belladonna flowers to dilate their eyes o Non-selective antagonist of M1, M2, & M3 receptors, causing effects in many systems ▪ Mydriasis & cycloplegia (walrus with telescope & very large pupil) ▪ CV effects: • PNS activation of M2 receptors in SA & AV nodes →↓HR (queen of hearts with stars for SA & AV nodes on her staff) • Reverses depressed SA & AV node action in MI or shock →↑HR, ↑AV conduction. (rabbit rushing toward antimuscarinic table with elevated heart watch) • Used in heart block to ↑conduction through AV node (rabbit pushing over heart shield) ▪ Block M1 receptors in CNS • Scopolamine o M1 specificity o used to treat motion sickness (walrus in a sailor costume) • Ipratropium & tiotropium (Uncle Caterpillar) o inhaled M3 antagonists used as bronchodilators in management of COPD (caterpillar inhaling off hookah; is a blue bloater on a pink puffer) ▪ Inhibit vagal nerve stimulation of M3 receptor, which causes bronchial airway constriction. o ↓mucosal secretions. o Tiotropium dissociates more slowly from M3 receptor, so has longer-lasting bronchodilator action. (Tioooooo smoke) • Oxybutynin & tolterodine (Fox & turtle butlers) o M3 antagonists. Relax smooth muscle of bladder & ureters, o Relieve urinary incontinence d/t spasm (turning off bladder shape spigots) • Trihexyphenidyl & benztropine (mouse car with 3 hexagons, and Benz) o Central acting M1 antagonists (in parking space M1; parking center sign over space M1) o Used in Parkinson’s to reduce tremor and rigidity (tremor: shaking antennae; cogwheel rigidity: cogwheels on old car) ▪ Tremors may be d/t excess acetylcholine activity in absence of dopaminergic activity. o Used to treat extrapyramidal adverse effects of antipsychotic medications by re-establishing dopaminergic/cholinergic balance (extra parking pyramid cone) ▪ Side effects d/t increased transmission of dopamine at nigra striatal tract ▪ Include dystonia, akathisia, drug-induced parkinsonism Anticholinergic Toxicity • “Hot as a hare, red as a beet, blind as a bat, dry as a bone, mad as a Hatter, full as a flask, fast as a fiddle” (many of these are represented by the guests at the table) o Hyperthermia results from antimuscarinic inhibition of sweat gland M3 receptors →↓ sweating. o Flushing results from ↓sweating & hyperthermia o Blurred vision d/t mydriasis & cycloplegia o Dry mouth & eyes d/t decreased salivation & lacrimation d/t M3 receptors o CNS effects: sedation, agitation, amnesia, up to hallucination & coma, especially in elderly patients. o ↓ smooth muscle contraction in the balder & intestine → urinary retention and constipation o Tachycardia d/t ↓vagal tone at the sinoatrial node o Acute closed angle glaucoma d/t mydriasis & consequent decreased outflow of aqueous humor (high-pressure tea kettle with a lid shaped like a dilated pupil).

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2.1 – “One Epic Summer Band Camp”: Direct Sympathomimetics (norepinephrine, phenylephrine, epinephrine, dobutamine, isoproterenol) • Direct sympathomimetics work predominately on sympathetic nervous system (SNS) (all the nervous energy of adolescent summer camp!). Adrenergic receptors respond to norepinephrine (NE) or epinephrine (E); norepinephrine acts as a neurotransmitter on postsynaptic adrenergic receptors, while epinephrine is produced in adrenal medulla & acts as a circulating hormone on targets. Particularly key in regulating BP. • Sympathomimetic drugs stimulate some aspect of this system (mimetic mime fleeing bear in “fight or flight” mode) Adrenergic receptors • Four main adrenergic receptors: α1, α2, β1, β2. All are GPCRs – Gq, Gi, Gs, Gs respectively (misspelled “KISS”). Each represented by a cabin. • Alpha receptors (α camp) o α1 (single candle): Gq → IP3-DAG cascade → ↑intracellular calcium in smooth muscle cells (3-dog teams, carrying a bone) ▪ ↑peripheral resistance via vasoconstriction at small arteries, arterioles, precapillary sphincters. Dose dependent (α1 scout with dogs on artery-like red leashes. More dogs would pull leads tighter.) ▪ ↑ mean arterial pressure (MAP) (Map) ▪ Venoconstriction →↑ venous return & ↓ venous capacitance (Scout with dogs on blue leashes) ▪ Pupillary dilatory muscles → mydriasis (wide-eyed binoculars) ▪ Urethral sphincter & prostatic smooth muscle contraction → urinary retention (scouts tight belt & full canteen) o α2 (two candles): sympatholytic; Gi →↓cAMP (falling tent) ▪ act centrally to decrease SNS tone (“No Sympathy” sign). Activity in presynaptic neuron → localized negative feedback (α2 scout rolling in presynaptic cord). ▪ Activity at pancreatic islet cells →↓insulin release (rolled up “welcome inside” mat) ▪ ↓lipolysis & fatty acid release (dousing fat roasting pig) ▪ α2 activation at ciliary body →↓aqueous humor production (emptying water from eyeball hat) • Brimonidine is an α2-agonist used to treat chronic open angle glaucoma (water draining over brim of hat) ▪ Decreased cAMP → ↑platelet aggregation (plates aggregated on steps of α2 cabin) • β receptors → ↑cAMP (band camp sign) o β1 (bugle) ▪ Found in heart tissue (I α agonist with dose dependent effects ▪ At LOW dose, β effects dominant (β side of raft is lower, probably because of the tuba) • β2 → bronchodilation (nervous girl on inhaler) • β2 → Vasodilation → ↓SVR → ↓DBP (diamond falling off raft)

11 • β1 → ↑HR (heart watch) • β1 → ↑contractility ( ) ▪ At HIGH doses, α effects dominate • Pressure tracing. Note increased pulse pressure o α1 arteriolar constriction → ↑SBP o α1 ↑SVR → ↑MAP o β2 arteriolar dilation →↓DBP. This is partly outweighed by α1 activity o Used in anaphylaxis: α1 counteracts vasodilation, β1 improves tissue blood flow, β2 opens airways. (Anna + Phil with bolt. “Love can feel a lot like anaphylaxis”) o Inotropic & chronotropic effects make useful in resuscitation attempts

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2.2 – “Catecholamine Catch & Release”: Indirect sympathomimetics (cocaine, ephedrine, amphetamine, methylphenidate, modafinil, atomoxetine) • Indirect sympathomimetics enhance catecholamines by displacing them from nn ending or by inhibiting reuptake or metabolism (same scene, indirect perspective. Mime for mimetics. Catecholamine catfish). All act to ↑catecholamine concentration at adrenergic nerve terminals (dock = nerve terminals) • Adrenergic transmission at the synapse: o Tyrosine precursor to catecholamines is transported to nn terminals (tire being drawn to dock). o Once at terminal, tyrosine → L-dopa→ dopamine (tyrosine tire, L-shaped winch handle, dopamine dope rope). • In dopaminergic neurons, here ends the process. • In most sympathetic presynaptic nn, dopamine in vesicles is converted to E & norepinephrine (vessel) o Dopamine is converted to norepinephrine by dopamine β-hydroxylase (navigator with North oriented compass) o Dopamine is then release from the vesicle in response to intracellular ↑Ca o Synaptic transmission is discontinued by diffusion of dopamine or reuptake into the cell o NE Transporter (NET) transports catecholamines back into the presynaptic neuron; DAT is specific to dopamine (hauling in a net of catfish on presynaptic dock; “NET DAT Catfish!”) o Can be recycled into vesicles by vesicular monoamine transporter (VMAT) (catfish being hauled in on mat with Vs) Dopamine Receptor activation • D1 is a GsPCR, D2 is Gi (Dope Rope Swing – for D1 & D2 respectively) o D1 ▪ GsPCR→↑cAMP → PKA activation → smooth muscle relaxation • Renal vasculature stimulation → ↑ RBF, GFR, Na excretion. This is in contrast to norepinephrine & E α1-mediated constriction of renal afferents (Dope Rope 1 has a kidney on the end) ▪ DBA • Dopamine activates dopamine Receptors at low doses, β-adrenergic receptors ad higher doses, & α-adrenergic receptors at high doses. (bugler higher than kidney & scout with single candle highest up) o D2 (swing with 2 ropes) ▪ Important in CNS • Metyrosine (counselor claiming, “my tire!”) o a tyrosine analog o inhibits conversion of tyrosine to L-dopa • Cocaine o Inhibits NET & DAT → accumulation of NTs in synapse (scouts with hot cocoa not taking up net). Results in a variety of effects: ▪ Peripherally: HTN, tachycardia, mydriasis (flushed scout); coronary vasospasm, angina, a/o MI (crown on mug; angina anvil; clutching chest) ▪ Central DAT inhibition →↑dopamine in CNS → arousal, addiction, seizures o May see nasal mucosal atrophy or septal perforation d/t vasoconstriction (scout with bloody nose) o Management is supportive. NEVER give β-blockers; will → unopposed α1 action & HTN crisis (β1 bugle causing excessive head pressures) • Atomoxetine inhibits NET o Treats ADHD (kid distracted by AD channel in HD next to net) • Reserpine (serpent blocking catfish storage) o Inhibits VMAT o Not used clinically • Amphetamines (Friend of Mine shirt on ichthyophile) o CNS stimulated via norepinephrine > dopamine release. Mood elevating effect. Improved attention to repetitive tasks, & stimulating effects o Appetite suppression effects (untouched plate of dinner) o Methylphenidate for ADHD (distracted kid watching “Friend Date” on HDTV) o Modafinil used for narcolepsy (clock in sleep mode) ▪ Fewer adverse effects than straight amphetamines

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2.3 – “The Phantom of the Alpha”: α-adrenergic drugs (α2 agonists: clonidine, αmethyldopa tizanidine; α antagonists: phentolamine, phenoxybenzamine, prazosin, mirtazapine) • Most of these bind to α1 & α2 receptors in periphery, preventing catecholamine & other agonists • α2 agonists • When given systemically reduce SNS outflow directly at the level of the brainstem → systemic BP (brain-shaped platform for CNS action) o Clonidine (Raoul with 2 claw weapons) ▪ Centrally acting α2 agonist – i.e. sympatholytic (2 lit candles; “sympathy” crossed out by claw marks) ▪ Indications • Used to treat HTN, including HTN crisis (High pressure pipes under stage, marked “urgent”) • Extended release effective in refractory ADHD (Raoul is distracted by HD mirror screen) • Tourette’s – α2 agonists preferred over neuroleptic agents d/t decreased risks of extrapyramidal adverse effects (Tourette’s marionette) o α-methyldopa (α-shaped noose) ▪ L-dopa analog (rope noose). Converted to α-methyldopamine & α-methyl-NE, which can act on central α2 receptors, similar to clonidine (2 lit α candles held near brain rug) ▪ Historically, used for HTN (high pressure pipes). Now, used mainly in gestational HTN (Christine is pregnant) ▪ Side effects: • Lupus-like syndrome (rare) (lupus wolf) • Autoimmune hemolytic anemia; may be d/t production of autoantibodies o Tizanidine (Letter to X-tine) ▪ Centrally acting α2 receptor. Muscle relaxant (recliner chair) • α antagonists (on stage, α-candles have been extinguished) o Phentolamine ▪ Reversible α1 & α2 receptor blocker (single & paired candles extinguished) ▪ Causes vasodilation (dilated sleeves). Can prevent pressor effects of sympathomimetics ▪ Can be used to treat cocaine induced HTN crisis, avoiding β-blocker effects (spilling mug of hot cocoa) ▪ Can be used intraoperatively in case of HTN crisis o Phenoxybenzamine (phoenix tattoo) ▪ Irreversible α1 & α2 receptor blocker (tattoos are permanent; single & paired candles extinguished) ▪ May take several days for new receptors to be synthesized. ▪ Normalize BP prior to pheochromocytoma removal (kidney-and-adrenal shaped ice cream) – causes intermittent headache, HTN, palpitation, sweating (scared looking manager holding head). o α agonists may be used to reverse widespread catecholamine-induced vasoconstriction, as in the case of cocaine toxicity (spilling mug of hot cocoa); tyramine-induced HTN crisis in patients on MAO-Is (tyramine found in aged wine & cheese) (wine & cheese table). o Side effects: ▪ Orthostatic HTN d/t ↓α1 effects (tilt table) accompanied by Reflex tachycardia (heart shaped reflex hammer). First dose is especially high risk • α1 selective antagonists o include prazosin, terazosin, doxazosin, tamsulosin (opera singer for -osin suffix holding 1 extinguished α candle) o Relax smooth muscle in urethra & prostrate (sitting on banner). Used for symptomatic control of BPH o Cause vasodilation (dilated sleeves) o Prazosin has CNS effects, including helping with sleep regulation. Used in PTSD (dog tags held by praying opera singer • Mirtazapine (misery & mirth masks) o Atypical antidepressant with antagonistic effects at α2 & other receptors (2 extinguished α candles)

2.4 – “Brahms’s LOL Lullaby”: β blockers • β-receptor antagonists (blocked β1 bugle & β2 tubas). Mostly end in -lol suffix (Brahms’ lullaby). o Decrease cardiac contractility d/t antagonism of β1 receptor (heart-shaped music stand weak arms) o β1: Inhibit SA node activity → bradycardia (low handing heart watch; SA & AV nodal notes)

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o β1: Slowed AV conduction. Contraindicated in AV block (“Door to remain unblocked” on shield shaped sign – recurring symbol for AV) Indications o Used in management of chronic stable angina(xylophone on anvil). ↓Cardiac contractility & HR → ↓oxygen demand (oxygen cannula flying off) o β1 → ↓renin levels & JGA (blocked bugle in hand of rain jacket wearing player) o All have antihypertensive properties with mild to moderate HTN, but rarely used as initial monotherapy d/t risk for adverse CV outcomes (high pressure steam pipes on pipe organ). Especially helpful in CHF & MI. o Useful in management of hypertrophic obstructive cardiomyopathy, especially when acute hemodynamic collapse d/t obstruction (bagpiper with filled heart-shaped bags is blowing against an obstruction). o Metoprolol, propranolol, timolol can be used as episodic Migraine prophylaxis (pounding unilaterally on head-shaped bell). o Treatment of thyroid storm: catecholamine surge → agitation, delirium, fever, tachyarrhythmia, death (thyroid shaped bowtie with lightning bolts); treatment: propranolol, propylthiouracil, & prednisolone (3 Ps). β-blockers are used for symptomatic relief of thyroid overactivity as e.g. in Graves’ disease, thyroid toxicity o Essential tremor (conductor tremor while holding baton) o Type 1 antiarrhythmics. Effective in Ventricular and supraventricular arrhythmias (rhythmic record player in background) o Glaucoma. Topical administration of β blockers (timolol) inhibits β2 receptors at ciliary epithelium →↓aqueous humor production (Tim the tuba player with the eye-shaped block) Common adverse effects o Exacerbates asthma & COPD by non-selective β blockers (huffing blue bloated tuba player) o Impotence in men (floppy trombone) o Toxicity: glucagon administration (glucagon packets in conductor’s podium) β1 selective antagonists o include atenolol, betaxolol, esmolol, acebutolol, metoprolol (A-BEAM spotlight on β1 bugler). o Cardioselectivity (second A-BeaM spotlight). o Indications: ▪ β blocker reduces MI mortality if given within short order (MI = broken harp string; strings broken acutely for acute treatment). ▪ Used on CHF (sad heart balloon). Reduce structural remodeling and the effect of chronic exposure to catecholamines in CHF resulting in ↓mortality & morbidity (harpist in angle get-up, for ↓mortality; building is remodeling). May worsen acute HF, as catecholamines acutely help with cardiac contractility & maintaining sufficient function. o Carvedilol is nonselective β-antagonist with some α1 effects (carved candleholder with single snuffed α-candle). Used in conjunction with other β-blockers Laβlol o α1 & nonselective β activity (organ stops with snuffed α candle). o Vasodilation → ↓SVR (dilated sleeves). o Safe for pregnancy; may preserve utero-placental blood flow better than other blockers (pregnant organist). o Rapid onset makes useful in HTN crisis (“emergency stop” with ivy =IV). o Used in aortic dissection, where want to rapidly bring down BP (unlike other HTN crises where want to decrease, but more gradually) (dissecting pipe on organ) Partial agonists o Should not be used in HF & MI, as lack the protective effect of complete blockers (holes in failing heart balloon in audience) o Acebutolol – β1-selective with partial antagonist activity (plastic bugle). o Pindolol – Nonselective β blocker with partial agonist activity (agonizing sound of tiny bugle pin in audience).

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Circulatory (CV & Renal) 1. Heart Failure 2. Diuretics 3. Anti-hypertensives 4. Antiarrhythmics 1.1 – “Pretty in Yellow”: Digoxin, milrinone, nesiritide • Inotropy = changes to ventricular contractility. Positive inotropy → ↑ contractility • Chronotropy = changes in HR. ⊕inotropy = ↑ HR, ⊖inotropy = ↓HR. • Digoxin (DJ foxglove): o Digitalis plants (foxglove) used to derive digoxin (DJ foxglove sounds like digoxin). Natural inotropic. o Indications: ▪ SSx treatment of CHF but provide no M&M benefit (lone kid with sad balloon). Narrow therapeutic index: only used when CHF is refractory of first line treatment ▪ Direct stimulation of vagus nerve (Las Vegas theme) used for treatment of some atrial arrhythmias s o Cardiac glycosides inhibit NA-K-ATPase, which is responsible for benefits & Side effects/toxicities (3Ⓟ powered Banana vending machine inhibiting supervisor from leaving the room; supervisor carrying salty peanuts). ▪ Inhibition of the NA-K-ATPase →↑intracellular Na, which stimulates Na-Ca exchanger efflux of Na & influx of calcium (student with peanuts allowing in ice-cream carrying students while the) →↑sarcoplasmic reticulum calcium stores → ↑contractility & LV systolic function (jock flexing arms) ▪ Inhibition of NA-K-ATPase → ↓K uptake and consequent serum hyperkalemia (excess bananas floating around outside). This is a sign of digoxin toxicity & correlates to ↑mortality. ▪ Can be used for symptomatic treatment of e.g. MI, although provides no M&M benefit. narrow therapeutic window; usually only used when diuretics & ACE-inhibitors have failed to control SSx. ▪ Can be to treat some arrhythmias d/t parasympathomimetic effects via vagal stimulation & M2 Receptor stimulation (“Las Vegas” dance theme; arrhythmia records; kids doing funky dances) • Affects atrial arrhythmias d/t preferential control of AV node (e.g. CHF d/t systolic dysfunction with concurrent AFib) o Toxicity is common d/t narrow therapeutic window. May include: ▪ Hyperkalemia d/t ↓K uptake. Important marker of acute toxicity; dose dependent relationship with mortality. ▪ Arrhythmias. Notorious for premature ventricular contractions, although many arrhythmias possible (variety of broken records on the floor) • Serial EKG & cardiac monitoring indicated in patients with digoxin toxicity ▪ Bradycardia d/t hindered SA & AV node d/t PNS activity at SA node (nodal notes on heart-shaped dance floor) ▪ May precipitate AV block (gal blocking inappropriate advances with heart shield pendent) • Contraindicated in patients with significant sinus or AV block • Should be used cautiously with other drugs that affect this physiology (“this door to remain un-Blocked” shield sign over door) ▪ Patients may be fine for several hours with initial administration, then present with GI symptoms including N/V, Abd pain (kid standing in spotlight looking like he’s going to be sick) ▪ Chronic toxicity: lethargy, delirium, disorientation. Alterations in color vision, especially for yellow (xanthopsia) (yellow spotlight) ▪ Increased susceptibility to or exacerbation of toxicity seen with • Hypokalemia d/t ↑binding of digoxin to Na-K-ATPase (freshman stuffed in vending machine) o Loop diuretics are the most common cause, but others (e.g. diarrhea, vomiting) may also precipitate • Renal dysfunction is often encountered in setting of chronic digoxin toxicity; increases serum half-life →↑susceptibility to toxicity (kidney shaped jukebox knocked over; vandal holding long, tapering flag for ↑half-life) o Regularly assessing renal function indicated in anyone on digoxin. o Renal clearance affected by many other drugs, including amiodarone, diltiazem, quinidine, verapamil; alter tubular transport of digoxin →↑serum transportation.

16 ▪ Digoxin immune Fab reverses toxicity (“Fabulous Las Vegas”) o “Digitalis effect”: ECG ST-depressions with “scooped” appearance, T wave changes, QT interval shortening (scoop out of Tasty ice cream). Not related to toxicity or detrimental effects, but seen with use. Apparently benign. • Milrinone (“One in a million!” campaign poster) o Positive inotrope used to improve cardiac output in acute HF decompensation. o β1 receptor stimulation →↑cAMP →↑cardiac contractility (flexed arm) o inhibit PDE →↓cAMP breakdown (“Phoster Disinterest” campaign slogan). Causes arteriolar dilation which can help reduce afterload in AHF (big dilated ears). Need to monitor for hypotension. • Nesiritide (elephant campaign poster) o Positive inotrope used to improve cardiac output in acute HF decompensation. o Synthetic form of BNP, which stimulates ↑cGMP in smooth muscle cells (BNP & cGMP = “Bump the Grump” campaign slogan). Leads to arterial & venous dilation, decreasing afterload and preload respectively (big arterial ears, and baggy venous pants). o Sodium loss results in diuresis, which may be helpful in the setting of acute HF (water pouring out of trunk).

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1.2 – “The House Always Wins”: ACE-inhibitors, ARBs, aliskiren RAAS (Renin-angiotensin-aldosterone system) • Renin is a protease released by kidney cortex in response to direct SNS β1 stimulation in juxtaglomerular apparatus (kidney shaped slot machines signs “raining” cash; winner with JGA). SNS stimulation can result from ↓renal arterial pressure, ↓renal Na delivery, direct SNS activation in other systems. • Renin stimulates angiotensinogen (loose tie gambler) cleavage to angiotensin-I (tense tie). Angiotensin-I has little biologic activity and is converted to angiotensin-II by angiotensin converting enzyme (ACE) (ACE = ace; tie-wearer is losing to suspender wearer – I going to II). ACE is distributed throughout the body, most notably in the vascular endothelium, particularly in the lungs (dealer with lung spots on uniform). • Angiotensin-II helps maintain arterial BP and electrolyte balance: • Acts on vascular smooth muscle → pressor effect (tight suspenders). Also acts on CNS & SNS → same effect. • Efferent arteriole constriction at glomerulus → increased pressure & blood back up → ↑ GFR (suspender-wearing patron pinching efferent side glomerulus-shaped straw; coffee ground filtration rate is way increased). This effect is especially important when there is ↓blood flow either d/t obstruction (as with atherosclerosis) or ↓CO (low coffee mug). • Acts at PCT to increase sodium bicarb resorption (suspender-wearer eating salty peanuts while watching Pro Cart Track) • Increases aldosterone (a mineralocorticoid) production & release (mineral crystal themed bar). Aldosterone acts at the collecting duct to ↑sodium & fluid retention at expense of potassium (peanut snacks on the bar; banana peels on the floor = ↓K) Meds • ACE-inhibitors & angiotensin receptor blockers (ARBs) reduce long-term M&M in HF & MI (guardian angel of April Shower’s Casino). • ACE-inhibitors o All end in -pril (April Showers Casino). Include captopril, enalapril, lisinopril, and several others o Effects result from prevention of angiotensin-I conversion to angiotensin-II (slumped gambler with floppy suspenders). Block vasopressor effects and aldosterone upregulation of angiotensin-II. ▪ ↓SVR. • When initiating treatment, significant hypotension can precipitate syncope d/t abrupt removal of constrictive effects (dude passed out at ACE-I table). To prevent, start low & slowly titrate up. ▪ ↓GFR by dilation of efferent arteriole. This commonly causes a transient bump in creatinine (up to 30%) within a few days of starting ACE-inhibitors (creatinine credit card). ▪ Promote natriuresis. Decreased Na retention at →↓Na & ↑K; may even precipitate hyperkalemia (raised banana daiquiri) ▪ Remember that if angiotensin-II is blocked, all the upstream products will increase o Indications ▪ First line agents for CHF (deflated heart shaped balloon) • Reduce afterload (↓SVR) & preload (salt & water loss). • Decrease SNS stimulation d/t ↓angiotensin-II effects. • Decreases mortality (angel over marriage); probably d/t attenuation of cardiac remodeling (remodeling behind couple). standard therapy post-MI d/t prevention of remodeling (heart banjo with broken strings). ▪ First line for primary HTN (“high pressure” candy pipes) ▪ Slow progression of diabetic nephropathy (kidney shaped lollipops) • Diabetic nephropathy classically defined by proteinuria, which may indicate glomerulosclerosis • Indication for starting ACE-inhibitors: persistent albuminuria + BP>130/80. Even in absence of HTN, recommend anyone with diabetes & any level of albuminuria start on ACE-inhibitors. Note that moderate albuminuria (30-300 mg/d) is not detectable on dipstick, only on urinalysis. o Side effects/toxicities ▪ Hyperkalemia (ACE-I winner with raised banana daiquiri) ▪ Mild dry coughing d/t ↑bradykinin (dealer with braids for bradykinin coughing; she’s inhibiting the ace because it’s in her pocket) (may also involve substance P or prostaglandins). Because ACE actually breaks down these other things too. • If this is bothersome to patient, change them to an ARB. ▪ Contraindicated with heredity angioedema (C1 esterase deficiency). Angioedema commonly manifests in face, lips, tongue (woman with C-shaped ring in lip). ▪ Contraindicated in pregnancy d/t risk of fetal hypotension, anuria, renal failure; can result in oligohydramnios and Potter’s sequence (pregnant woman with tarantula jacket) ▪ Coadministration with NSAIDs can cause AKI d/t NSAID mediated constriction of proximal afferent arteriole (fire extinguisher mounted in cracked kidney case).

18 ▪ Can cause AKI in bilateral renal artery stenosis, where kidney function is reliant on angiotensin-II efferent constriction to maintain blood flow (constricted straps on kidney purse). Presents with persistent ↑Crt, more than a few days after initiation of therapy d/t renal insufficiency (woman with credit card). Indication for discontinuation of therapy. • Angiotensin receptor blockers (ARBs) o -sartan suffix. Include losartan, candesartan, valsartan. (“Sorry, taken” sign by PCT screens) o Competitive antagonists of angiotensin-I receptor (taken sign competing for a seat). o Effective in HTN, diabetic nephropathy (although fewer renal protective effects in diabetes than ACE-inhibitors), HF o Side effects/toxicities ▪ Hyperkalemia d/t aldosterone inhibition (Banana daiquiri on chair) • Aliskiren (High Risk Limit cash slots) o Direct renin inhibitor prevents conversion of angiotensinogen to angiotensin-I (gambler losing tie) o Treatment of HTN o Side effects/toxicities ▪ ↓BP ▪ ↓renal function ▪ ↑K (3 bananas)

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2.1 – “Pro Cart Track”: Acetazolamide, mannitol Proximal convoluted tubule (PCT) physiology • Location of most renal resorption. (Pro cart Track; nephron map) • PCT is highly water permeable at PCT, maintaining a consistent concentration across epithelial cells and interstitium. • Na-K-ATPase pumps on the basolateral membrane (i.e. the intracellular compartment of the tubular epithelial cells) maintain a low intracellular sodium concentration to enable absorption (salty peanuts at the banana vending machine). • Na/H exchanger located on the apical membrane, transporting Na out of the lumen & H+ into the lumen (H+ helmeted kids walking in with peanuts; lumen = yellow track). Maintaining luminal H+ is critical for bicarb resorption. • H+ & HCO3 combine to form H2CO3 (bicarb cars). Luminal carbonic anhydrase catalyzes H2CO3 to H2O & CO2 (car battery = carbonic anhydrase). H2O & CO2 enter intracellular space via diffusion (water & fumes from cars entering epithelial tract. o Turned back into H+ & HCO3 via intracellular carbonic anhydrase (dude taking out car battery) o Intracellular HCO3 is transported into interstitium via basolateral transporter. Bicarb is taken out of the cell via a basolateral transporter and H is put back into the lumen by Na/H exchanger (car being taken to interstitium; helmet being reused). Diuretics • Acetazolamide (battery acid) o Reduces sodium resorption by inhibiting carbonic anhydrase, preventing bicarb resorption (leaking battery acid preventing bicarb car entering circulation). Bicarb stays in the proximal tubular lumen → urine alkalization. o Renal effects: ▪ Bicarb depletion causes increased NaCl resorption in the remainder of the nephron, such that diuretic efficacy falls within a few days. ▪ Also block sodium reabsorption →natriuresis (peanut wasting track lackey). ▪ Causes a normal anion gap metabolic acidosis with hypochloremia, as bicarb is not available to balance pH o Indications: Some of the first diuretics discovered. Not used as much for diuresis nowadays, but used in various other systems. ▪ Decreased production of aqueous humor, useful in the management of glaucoma (leaking eye-ball shaped cup). Most common clinical indication for carbonic anhydrase inhibitors ▪ Decrease rate of production of CSF. Useful in the management of idiopathic intracranial HTN (pseudotumor cerebri), although no indication of improved long-term prognosis (big head balloons) ▪ Useful in treatment & prevention of mountain sickness, which occurs with rapid ascension above 3000m (lackey on high wobbly guard tower). May be accompanied by life-threatening cerebral edema. Decreases CSF production and pH ▪ Urinary alkalization as with bicarb buildup, increases uric acid & cysteine buildup o Side effects/toxicities ▪ Like all potassium wasting diuretics, can cause hypokalemia d/t sodium resorption and potassium secretion in the collecting ducts (bananas on ground). Can avoid by combining with K-sparing diuretic. ▪ Can cause Type 2 renal tubular acidosis (two tubes on red cart). Can cause metabolic alkalotic hyperchloremia. • Can be seen in any defect in PCT bicarb reabsorption. May be useful in refractory metabolic acidosis ▪ Carbonic anhydrase inhibitors can enhance calcium phosphate stones d/t decreased solubility (rocks in front of dino car) ▪ Carbonic anhydrase inhibitors are sulfa drugs, so may cause hypersensitivity reactions including interstitial nephritis in patients who have a sulfa allergy (dino kid throwing rotten eggs) • Mannitol (tall man) o Osmotic diuretic acting at the PCT & descending limb of LOH (stream of water crossing into lumen) o Acts in other tissues by the same MOA: ▪ Draws free water out of brain tissue into circulation. Administered in urgent ICP. ▪ Draws free water out of other compartments, including eye. Useful in acute glaucoma (eyeball cup dousing fire) o Side effects/toxicities ▪ Extracellular volume induced by mannitol can case pulmonary edema (lung spots on wrecked driver) ▪ Rapidly distributed in extracellular compartment and cause hyponatremia d/t expanded extracellular volume. Can exacerbate HF (deflated balloon) ▪ Mannitol use without water replacement can cause water depletion dehydration, accompanied by hypernatremia (lots of spilled peanuts by wreck)

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2.2 – “Loop-de-loop of Henle”: Loop Diuretics (furosemide, ethacrynic acid) • Loop diuretics are extremely potent diuretics that affect the ascending Loop of Henle (LOH) (nephron map. riders ascending the loop). Produce rapid diuresis & fluid loss. Loop of Henle physiology • The thick ascending limb (TAL) is impermeable to water; only solutes are resorbed here (water in carts is security. Causes dilution of tubular fluid. Crucial to maintain renal hypertonicity that allows for water resorption further along in the collecting ducts. In all, 25% of filtered sodium is resorbed in the TAL. • Na-K-ATPase pumps on the basolateral membrane (i.e. the intracellular compartment of the tubular epithelial cells [platform of the ride]) maintain a low intracellular sodium concentration to enable absorption from the lumen (salty peanuts at the banana vending machine; lumen = yellow track). • Na/K/2Cl cotransporter (NKCC) at the luminal membrane of resorbs the eponymous ions (no food allowed on the luminal ride). Note that this ion combination is electrically neutral. • While the NKCC transporter is itself electrically neutral, action contributes to excess K accumulation in the cell. K diffuses back into channel via ROMK channel, producing a positive luminal electric potential which allows for cation resorption, including Ca & Mg. Loop diuretics • Include furosemide (furious kid) & ethacrynic acid (code of ethics sign) • Loop diuretics function by inhibiting the NKCC. Net effect is to impede sodium absorption in the ascending limb. ↓NaCl resorption → natriuresis. Not limited by the acidosis seen with acetazolamide. • Loop diuretics induce expression COX-2 → prostaglandin synthesis (pro-slugger bat). Prostaglandins dilate the afferent arteriole and enhance salt excretion, resulting in increased solute delivery to nephron, increasing loop diuretic efficacy. o NSAIDs can interfere with the action of loop diuretics by decreasing prostaglandin synthesis (fire extinguisher blocking baseball bat kid) • Indications: o First line for symptomatic treatment of acute decompensated HF with fluid overload (guy with lung-shaped vest & failing heart balloon) ▪ HF → hypoperfusion of kidneys → upregulation of RAAS, which causes fluid retention. ▪ Loops help with maximum diuresis in shortest time (#1 balloon) ▪ Particularly helpful with pulmonary edema (guy with wet lung-shaped life vest) ▪ Removing venous overload can help with ↓preload, preventing overfilling and increasing cardiac efficiency ▪ Do not have any effect on M&M. are symptomatic control only o Treatment of HF, particularly when there are comorbidities. ▪ Especially useful in cases of severe HTN (high pressure pipes), renal insufficiency, cirrhosis, or cardiac failure. o Treat ascites in liver failure (gal with yellow innertube). Can be useful when peripheral ascites and edema worsen in liver failure. • Side effects/toxicities o Potassium wasting. Can cause hypokalemia (banana peel falling). Must monitor potassium. Note this can exacerbate HF. o Loop diuretics cause decreased cation resorption d/t disruption of the luminal electric potential . In particular, calcium and magnesium will remain in the lumen, resulting in hypomagnesemia and hypocalcemia. (Kid on ride clinging to magnesium magnets & calcium ice cream; other kid with falling magnets & ice cream). Hypomagnesemia can be reversed by oral magnesium); hypocalcemia is rare d/t maintenance by other physiologic mechanisms including Vitamin D induced intestinal absorption & PTH-induced renal resorption. o May occasionally cause dose-related hearing loss (gong). Usually reversible with treatment cessation. o May rarely see interstitial nephritis with loop diuretics (kidney-shaped bucket filled with little blue tickets) o May cause hyperuricemia, relatively commonly (girl knitting with yellow yarn). Excessive use of diuretics → enhanced uric acid resorption in the PCT with hypovolemia. o Loop diuretics prevent salt reabsorption and therefore prevent water reabsorption, which may cause contraction alkalosis & dehydration (contracted bleach bottle). ▪ Former d/t many mechanisms including hypovolemia induction of RAAS. This ↑angiotensin-II which works directly on Na resorption in PCT. o Furosemide is a sulfa drug, so may see sulfa allergy (throwing eggs). ▪ Can be avoided by using ethacrynic acid (Ethics sign “be sulfa-less”).

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2.3 – “Distal Convoluted Tube Slide”: Thiazide diuretics Distal convoluted tubule (DCT) physiology • Sodium chloride are the most important ions in the DCT, but only about 10% of filtered Na resorbed here. • Na-K-ATPase pumps on the basolateral membrane (i.e. the intracellular compartment of the tubular epithelial cells [pool deck]) maintain a low intracellular sodium concentration to enable absorption from the lumen (salty peanuts at the banana vending machine; lumen = yellow slide). • Selectively impermeable to H2O. • NaCl resorption dilutes tubular fluid via electrically neutral NaCl transporter at the apical membrane transporting NaCl back into cell. • In LOH, back leak of potassium causes positive potential in lumen, driving out cations. Not so here. At DCT, calcium is actively resorbed by apical calcium channel regulated by PTH. Thiazide diuretics • Include hydrochlorothiazide (HCTZ), indapamide, metolazone, & chlorthalidone (kid on diving board in chloro suit with pasty thighs) • Bind to the Cl- site of the NaCl cotransporter, inhibiting NaCl resorption and dumping salt into the urine & causing natriuresis (security bumping salt barrel into pool) • Also enhance calcium reabsorption (ice cream falling off of slide). In PCT thiazide induced volume depletion → enhanced sodium & passive Ca resorption. In the DCT, block Na uptake into cell → ↑Na/Ca exchange at the basolateral membrane • Indications: o First line treatment of mild or moderate HTN with normal cardiac function (hypertensive pipes). Decrease cardiac output & vascular volume. Chlorthalidone is preferred to HCTZ d/t longer half-life. o Can be useful adjunctive treatment in HF, although not first line monotherapy (HF balloon). Often combined with loop diuretics, which are more effective in HTN secondary to HF or liver failure. o Paradoxically treat nephrogenic diabetes insipidus (DI) (urinating statue). Can reduce polyuria & polydipsia in this case. Thought to be by inducing a mild hypovolemia →↑ water & Na resorption in the PCT. ▪ Nephrogenic DI often caused by lithium o First line treatment for calcium nephrolithiasis (2/3 of kidney stones). Hypercalciuria can be leveraged to prevent calcium stone formation, e.g. secondary to sarcoidosis, hyperparathyroidism, hypervitaminosis D (removal of stones in slide). 2 mechanisms: ▪ Inhibition of Na/Cl cotransporter →↓intracellular Na concentration →activation of basolateral Na/Ca antiporter, which pumps Na into the cell in exchange for Ca, Resulting ↓intracellular Ca →↑ luminal Ca absorption. ▪ Hypovolemia →↑Na & H2O resorption in the PCT → passive increase in paracellular Ca2 resorption. o Attenuates osteoporosis therapy & may ↓fracture risk (broken chalk on “no accidents” chalkboard) • Side effects/toxicities o Hyperglycemia, hyperlipidemia, hyperuricemia, and hypercalcemia. Remember hyperGLUC (Glycemia, Lipidemia, Uric acid, Calcium) ▪ Hyperglycemia d/t impaired pancreatic release of insulin & ↓tissue glucose utilization. May return to baseline with prolonged use. (HCTZ on the high dive) ▪ Hyperlipidemia, although may return to baseline with prolonged use. (HCTZ on the high dive). Can imagine a fat kid up on diving board. ▪ Hyperuricemia (girl with yellow knitting) ▪ May cause hypercalcemia d/t enhanced calcium resorption (elevated high dive ice cream). Not especially common as a primary effect, but may unmask ↑calcium d/t other causes. o Sulfa drugs, although reactions are extremely rare (eggs). o Decrease renal clearance of lithium; lithium levels must be carefully monitored if coadministered. (lithium ion balloons) o Potassium wasting d/t blockage of Na-Cl cotransporter →↑K secretion in exchange for Na resorption. May see hypokalemia (banana peel) o Hyponatremia d/t decreased Na resorption with continued water absorption, unlike loop diuretics (spilled peanuts) o Contraction alkalosis secondary to hypovolemia induced activation of RAAS (contracted bleach bottle)

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2.4 – “Salty Mineral Food Court”: Potassium Sparing Diuretics (amiloride, triamterene, eplerenone, spironolactone) Collecting duct (CD) physiology • The CD is the final resorptive location of the kidneys (collecting duct gutter for lumen; park map; right side of sketch). It’s responsible for 2-5% of sodium resorption by the kidney. As the final site of resorption, is important for tight regulation of body water & sodium levels, as well as final osmolality of the urine. Most important site of potassium excretion by the kidney. • Principal cells are the major site of Na, K, & water transport (Principal Court signs indicating empty intracellular space). Transporters include: o Na-K-ATPase on basolateral membrane (banana vending machine). o ENaCs (epithelial Na channels) resorb Na across luminal membrane of the collecting duct (Salt-E sNAC carts along the edge of the luminal gutter). o K channels allow excretion of K into the tubular lumen of the collecting duct to maintain electric neutrality (banana man getting hit by Salt-E snack cart). o ENaC only draws Na, leaving a negative potential in the lumen → K+ excretion in order to maintain neutrality. This differs from elsewhere in the kidney, where NaCl transport is electrically neutral. • Alpha intercalated cells: excrete H+ into the lumen via H-ATPase pump on the apical membrane (Inter-continental food truck powered by 3Ⓟ batteries spewing acid into the gutter). Are involved in acid-base homeostasis. • Aldosterone’s main site of action is the CD; it is key to maintaining homeostasis (mineral court service man, holding intracellular mineral crystal [i.e. aldosterone] key). Promotes CD sodium resorption & volume retention. o Is a steroid hormone produced in adrenal cortex as the final product of RAAS. Receptor is intracellular and functions as a transcription factor to upregulate certain genes, including ▪ K+ channels on the apical membrane of the principal cells →↑K+ excretion (key on banana stand) ▪ ENaCs on the apical membrane of the principal cells →↑Na+ resorption (key in Salt-E snack cart) ▪ Na-K-ATPase on the basolateral membrane of the principal cells (key in banana vending machine) ▪ H-ATPase on apical membrane intercalated cells, increasing H+ secretion (key on food truck) o Results in ↑transepithelial electrical potential & dramatic rise in both sodium resorption & K secretion. • Note that loop & thiazide diuretics indirectly facilitate these same mechanisms by a few mechanisms o block sodium resorption → ↑CD Na concentration. This prompts ↑CD K+ secretion, causing hypokalemia. o Sodium resorption in the CD causes a negative luminal potential, favoring H+ secretion. Increase Na+ resorption can result in a metabolic alkalosis o all drop volume → upregulation of the RAAS. The end result is mineralocorticoid mediated increase in potassium loss & proton secretion Potassium-sparing diuretics • Potassium sparing diuretics work directly on the CD (left side of sketch). Enhance activity of mineralocorticoid aldosterone. • Amiloride (almond box) o Inhibits sodium influx through ENaCs, thereby reducing Na resorption, promoting natriuresis (angry moms bumping Salt-E Snack cart into the lumen) o Useful in treatment of Liddle’s syndrome which results in overactivation of ENaCs. By blocking, can correct HTN & ↓K associated with the disorder (mom blocking little gnome) o Useful in treatment of Lithium-induced nephrogenic DI (peeing cherub statue). Blocks lithium entry into CD cells →↑lithium excretion. • Triamterene (tangerines) o Inhibits sodium influx through ENaCs, thereby reducing Na resorption, promoting natriuresis (angry moms bumping Salt-E Snack cart into the lumen) o Useful in treatment of Liddle’s syndrome which results in overactivation of ENaCs. By blocking, can correct HTN & ↓K associated with the disorder (mom blocking little gnome) • Eplerenone (woman with apple) & Spironolactone (health inspector with spiral notebook) o Directly antagonize mineralocorticoid receptors (antagonizing miner food court service employee so he cannot use crystal key) o Disrupted gene transcription means ↓activation of sodium & potassium currents at apical membrane → less sodium retention & less K wasting. o Recommended in some cases of severe HFrEF d/t blockage of aldosterone effects on the heart, with morbidity & mortality benefits (kid in angel outfit with deflated heart balloon). Produces regression in fibrosis; inhibition of remodeling, especially post-MI (remodeling rock behind kid); and improvement in ventricular ejection. Can be used in conjunction with loop diuretics to blunt K+ wasting.

23 o most useful in states of mineralocorticoid excess, i.e. primary or secondary hyperaldosteronism (primary: Conn’s syndrome, ectopic ACTH; secondary: HF, hepatic cirrhosis, nephrotic syndrome, ↓intravascular volume) (Nephron Fun Zone Mineral Mountain, with abundant salty minerals) ▪ Clinical tip: HTN + ↓K levels suggest hyperaldosteronism! May also see metabolic acidosis, depressed plasma renin activity, or adrenal mass on CT o Treat symptoms of androgen excess in PCOS (e.g. hirsutism), as well as insulin resistance. Possible d/t lack of specificity for renal aldosterone receptors. • Side effects/toxicities o Hyperkalemia; may be mild or life-threatening (lady with raised bananas). ▪ Increased risk in kidney disease or concomitant use of drugs that inhibit renin or angiotensin-II activity (e.g. β blockers, ACE-inhibitors). o Normal anion gap metabolic acidosis (↓aldosterone → ↓function of H-ATPase) (Intercontinental food truck driving away, trailing acid) ▪ Similar to a type-4 renal-tubular acidosis, the only RTA with associated hyperkalemia (4 test tubes held in K-shape) o Spironolactone is not very specific to renal aldosterone Rs. Can have effects on other mineralocorticoid receptors & processing enzymes. Directly antagonizes androgen receptors. ▪ Block testosterone synthesis by blocking 17 α-hydroxylase → ↑cholesterol (17-α FRY-droxylase food cart) ▪ Treats symptoms of androgen excess in PCOS & the insulin resistance that often accompanies it; treats hirsutism in this case. ▪ Gynecomastia (dude holding plates to chest) ▪ Impotence & ↓libido (floppy churro)

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3.1 – “We All Scream for Calci-YUM!” Calcium Channel Blockers • Calcium channel blockers (CCBs) target voltage gated L-type calcium channels, the dominant calcium-ion channels in smooth muscle and cardiac muscle (pull on a handle, get some calcium influx) Dihydropyridines (dairy soft serve) • Include nifedipine, nicardipine, amlodipine, clevidipine (dipping station) • Have a greater ratio of vascular smooth muscle effects than cardiac depressant effects (dairy ice-cream on smooth muscle-like tile). Do not appreciably affect AV nodal conduction. • Clinical indications: o Used in chronic treatment of HTN (high pressure pipes). ▪ Cause vasodilation →↓SVR. ▪ Usually given as sustained release with goal of more balanced BP control. o Stable angina (anvil-shaped ice-cream bowl) ▪ β-blockers or nitrates first line; CCBs may be considered with contraindications or reactions, or if HTN not well controlled. ▪ Preferred to non-dihydropyridines because of coronary artery dilation (big red crown). Results in ↓coronary resistance, ↑coronary blood flow, & may enhance development of coronary collaterals. ▪ Cause peripheral vasodilation, ↓afterload, ergo ↓myocardial O2 demand (scale with reduced load) o Treats Prinzmetal angina (coronary vasospasm) (grandmother wearing an anvil medal) o First line treatment for vasospastic disorders which may be associated with Prinzmetal (e.g. Reynaud’s) that has not responded adequately to non-pharmacologic therapy (guy wearing fingerless gloves has cyanotic fingers) o Clevidipine & nicardipine can be administered IV for HTN emergency o Nifedipine used to treat HTN in pregnancy (pregnant woman with knife). Long acting formulations for management; shortacting formulations for emergent treatment of acute HTN. o Nimodipine prevents vasospasm following subarachnoid hemorrhage ▪ MOA unclear. Ideally administered within 4 days. ▪ Subarachnoid hemorrhage most commonly d/t rupture of cerebral hemorrhage (e.g. berry aneurysm, associated with PCOS — “Bubbles in your kidneys, bubbles in the brain”) (brain-shaped ice cream at dipping station with lots of berries on top) • Side effects/toxicities o Contraindicated in HF d/t risk of exacerbation (sad kid with sad balloon) o Hypotension. May → lightheadedness & headaches (collapsed patron in front of dipping station) o Peripheral edema d/t preferential vasodilation of pre-capillary vessels → ↑capillary hydrostatic pressure (collapsed patron with baggy sweatpants) o Reflex tachycardia, especially with more potent fast acting formulations (MD with reflex hammer) o Nifedipine has a relatively high incidence of all adverse effects d/t potency ▪ Also causes exacerbation of myocardial ischemia d/t reflex tachycardia. Contraindicated with unstable angina or MI (heart shaped fruit being cut with huge knife). Large doses increase mortality immediately post-MI. Non-dihydropyridines (non-dairy) • Include Verapamil (Very vanilla) & Diltiazem (delicious Dark Chocolate) • Greater ratio of cardiac effects to vascular smooth muscle effects (non-dairy options on cardiac myocyte like tile). o Verapamil has highest specificity for cardiac tissue. Greatest depressant effect on heart, →↓CO & HR, least vasodilatory effect (very vanilla with small nozzle) o Intermediate effect on both cardiac muscle and has some vasodilatory effects as well (medium-sized nozzle) o Decrease cardiac contractility d/t ↓calcium →↓output (kid cannot pull handle). o Both SA & AV nodal activity may be decreased d/t ↓Calcium (musical notes on non-dairy sign). Can cause bradycardia (dangling watch) • Clinical indications: o HTN control via reduced HR (high-pressure pipes). Usually given as sustained release with goal of more balanced BP control. o Treat stable angina (guy clutching his chest eating from anvil ice cream bowel ▪ β-blockers or nitrates are first line. Dihydropyridines generally preferred. ▪ Non-dihydropyridines ↓O2 demand by acting as a negative inotrope & chronotrope, and ↓systemic BP. o Treat Prinzmetal angina (guy’s shirt has a picture of an anvil on it). o Antiarrhythmic properties especially in SVT o ↓ventricular response to AFib o Verapamil used for migraine prophylaxis (pounding head bell) • Side effects/toxicities

25 o Contraindicated in HF d/t risk of exacerbation (sad kid with sad balloon) o Relatively contraindicated in heart block (V > D) (heart block shield) o Relatively contradicted with β-blockers d/t risk of heart block (heart block shield) o May cause hyperprolactinemia (not pictured, but remember the non-dairies can cause lactation) o Verapamil: causes constipation in 25% patients (janitor walking out of clogged toilet). Also gingival hypertrophy (janitor popping gum)

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3.2 – “High Tension on the High Seas”: Primary HTN & Hypertensive crisis • Antihypertensives (high pressure pipes) Primary (essential) HTN (primary deck) • No uniform agreement on best first line treatments for essential HTN. Regimen should be tailored to other co-morbidities. • Overall, all drugs have similar efficacy for ↓BP, but high variability between patients. Goal is to find best regimen that causes fewest adverse effects. o Elderly patients often respond better to CCB, specifically long acting dihydropyridines (older patient in dipping pool). o ACE-I/ARBs first line treatment for HTN in patients with HF, MI, or diabetes (balloon, broken strings on banjo, candy) • Monotherapy unlikely to work if BP > 20/10 mmHg above goal at initiation. Start with two (2 recommended if >20 # sign) • First line drugs: thiazides, ACE-inhibitors/ARBs, long-acting CCBs (white-thighed diver, card dealers, soft serve machines). Note that of the thiazides chlorthalidone has better evidence of ↓CV events. HTN emergency (sinking ship) • HTN emergency is defined as SBP > 180 or DBP > 120, or signs of end organ damage (respectively: the protractor & rule in the boiler room; hole in the hull heralds the end). • Don’t want to lower BP too quickly or too much. Goal is 10-20% decrease over first hour, 5-15% more over next 23 h. • Vasodilation is a common effect of many treatments (big red smokestack). Produce ↓SVR which can lead to hypotension and reflex tachycardia (doctor with reflex hammer), ↑renin & reflexive SNS activation (doctor with renin umbrella). ↓afterload (weight on loaded scale getting reduced) • β-1 antagonists (e.g. esmolol, metoprolol) (muted β buglers) o given IV by directly ↓HR & contractility. o Laβlol (α & β effects) may also be effective by directly ↓HR & contractility + vasodilation. • Dihydropyridine CCBs (clevidipine, nicardipine) (clover on a nice card) o IV administration o Vasodilation (arteriolar) (dilated sleeves) • Hydralazine (hydro boat) o Direct arteriolar vasodilator with little effect on venous dilation (direct hose to hydrant) o Primarily limited to pregnant women (pregnant woman) o Can cause hypotension (woman fainting). Can be sudden, within 30 min. o Reflex tachycardia (doctor with reflex hammer approaching woman) Often coadministered with β blocker to blunt this response (bugler stopping doctor). ▪ May worsen angina (anginal anvil). ▪ Contraindicated with angina or known coronary artery disease. o Can be useful for managing HTN with SHF. Combined with nitrates provides mortality benefit & systematic relief in LV-SHF (d/t afterload + preload reduction respectively) (dynamite + HF balloon; angel flag for mortality benefit) o Can rarely cause drug-induced lupus (wolf in the bow) • Nitroprusside (nitro-pressure speedboat) o Causes systemic vasodilation d/t NO. Promotes smooth muscle relaxation by ↑cGMP (grump in the water). o Unlike most nitrates, which only dilate veins that return to the heart to reduce preload, nitroprusside causes arteriolar & venous dilation (lady has dilated sleeves o Metabolized to cyanide (blue smoke). May cause cyanide poising especially in long-term use or with renal failure • Fenoldopam (old lady Pam) o D1 receptor agonist with no effect on α or β receptors (single dope rope) o Stimulates cAMP (tent). Results in vasodilation (dilated sleeves), especially renal, mesenteric, coronary (crown). ▪ Only agent that improves renal perfusion while ↓overall BP (renal flotation device) o Causes natriuresis (spilling peanuts)

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4.1 – “Soloist at the Heartbreak Hotel”: Class I (A, B, C) Antiarrhythmics – Na-channel blockers Physiology of arrhythmias • Arrhythmias are the result of abnormal pacemaker activity or AP propagation (heartbreak hotel). Can be caused or exacerbated acid/base disturbances, electrolyte abnormalities, ischemia, hypoxia. Antiarrhythmics decrease automaticity of ectopic pacemakers, inhibit conduction, a/o ↓excitability of cardiac tissue. • Ion channels can assume 3 different states: o Open. o Inactivation gate swings shut. o Channel is refractory to reactivation in the absence of excessive stimulation. • Normal cardiac myocyte action potential (AP) (shape as effected by Class I antiarrhythmics shown by the solo singer’s cord): o Phase 4: resting potential (diastole). determined primarily by membrane permeability to K+ ions while in the resting state at -90mV. o Phase 0: rapid depolarization (Upstroke). AP onset occurs when voltage-gated Na+ channels open and causes Na current into the cell. o Phase 1: initial rapid repolarization. Rapid closure of Na+ channels o Phase 2: plateau. Opening of L-type Ca-channels and the closure of some K+ channels; results in membrane highly permeable to Ca ions, minimally permeable to K ions. Ca-current dominated. Na-channels are inactivated. o Phase 3: late rapid repolarization. Closures of Ca++ channels and opening of K-channels. Efflux of K from cell restores resting potential. K-current dominated (longest state). Class 1 antiarrhythmics (solo-singer). • Block inactivated Na-channels (peanut butter jar) o bind to open but inactivated Na-channels) → decreased slope of phase 0 upstroke, slowing action potential conduction through the tissue (demonstrated by microphone & wire) ▪ Many also act on K+ current, and therefore length of refractory period o Note that these act only on the myocytes & transmission systems, not on the nodal currents (which rely on Ca-channels initially) • Demonstrate use-dependence d/t binding to inactivated channels (i.e. more effective in rapidly depolarizing tissue, as e.g. in tachyarrhythmias) (ticking heart watch!). Stronger binding = more strongly use-dependent • Type I antiarrhythmics all slow down conduction velocity of action potential → widening QRS on ECG (wide QRS). Because of use-dependence, QRS widening intensifies with elevated HR • Binding strength: Class IC > IA > IB Class IA • Include Quinidine (dining prom queen), Procainamide (prom king), Disopyramide (“disappears!” headline) • Intermediate use dependence → moderate slowing of AP upstroke (gal loosely holding peanut butter jar) • Block K+ channels → longer depolarization phase & prolonged effective refractory period (banana curtain pushed away) • Clinical indications o used in supraventricular & ventricular arrhythmias (Top & bottom of heart lighted) o WPW syndrome (an SVT) ( • Side effects/toxicities o All: QT prolongation d/t prolongation of cardiac AP because of blockage of K-channels (→ longer depolarization period) (twisted streamers) o Quinidine: ▪ cinchonism (a syndrome of tinnitus, headache, dizziness) (tin cans for tinnitus). ▪ Rare: immune reaction → thrombocytopenia (broken plates) o Procainamide: ▪ long-term may cause ↑ANA titer & may cause drug-induced lupus (SSx: arthritis, arthralgias; less common: pleuritis, pericarditis, parenchymal interstitial lung disease) (lupus wolf) o Disopyramide: ▪ can exacerbate or cause HF d/t negative inotropic effects at high concentration (heart balloon past newspaper headline) Class IB • Include lidocaine (“You LIED” sign), mexiletine (Mexican flag). Phenytoin has some 1B antiarrhythmic properties (friendly towing). • Low binding affinity for Na-channel (peanut butter jar not held at all) o low use dependence.

28 o Binding occurs and falls off so rapidly that cumulative effect over multiple cardiac cycles is minimal, with minimal effect on phase 0. o Shorten Phases 2 & 3 → shortened action potential (drawing banana curtain closed) o Highly selective for channels that stay in resting state longer (i.e. those in the ventricles & His-Purkinje system & dead tissue) (“DEAD to me” sign) • Used to treat ventricular arrhythmias, esp. in ischemic tissue d/t ↓membrane resting potential delays Na-channel transition from inactivated back to resting state (broken atrial light; “DEAD” sign). This is one of the most common causes of death postMI. • Side effects/toxicities o Neuro adverse effects/toxicities including paresthesias, tremor, convulsions, CNS depression (brain hat on tow guy) Class IC • Flecainide (corn flakes), propafenone (purple phone) • Strong binding affinity for Na-channel o Ergo strong use dependence and drastic slowing of phase 0. Slowest to dissociate. Have more dramatic effect on QRS duration. o Do not effect AP duration or refractory period (banana curtain looks like a normal myocyte action potential) • Can be used to treat both ventricular & supraventricular arrhythmias (top & bottom of heart lit up) • Restores normal rhythm in a-fib; can be used for cardioversion (remote to change channel). Can be used to maintain normal rate & sinus rhythm in A-fib (a-fib television). • Side effects/toxicities o Can cause a delay in conduction speed out of proportion to prolongation of refractory period. Can cause arrhythmias, particularly in structural HD (e.g. post MI) o Contraindicated in structural or ischemic HD (healthy heart cereal)

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4.2 – “β Brass Quartet”: Class II Antiarrhythmics - β Physiology of SA/AV node • SNS activation of β receptors increases cAMP activity, with multiple effects (Band camp poster) o ↑SA node automaticity by increasing pacemaker current causing ↑HR o increases conduction velocity though the AV node. • SA/AV nodal action potential o Funny current, dominated by Na+, is the pacemaker current (flat keys). o Phase 0: Upstroke. Ca dominated. o Phase 3: repolarization. K+ dominated. o Phase 4: depolarization. Ca-dominated. β blockers (Beta jazz club with Louis Heartstrong & Beta Fitzgerald; muted bugle) • Include o A-BEAM cardioselective antagonists: Atenolol, betaxolol, Esmolol, Acebutolol, Metoprolol o nonselective propranolol & timolol o carvedilol & others that have partial α antagonist effects. • MOA: o prevent arrhythmia-promoting action of β action (rather than directly modifying ion channel function). Inactivation leads to closure of membrane Ca-channels (crushed ice-cream cartons). β blockers prolong depolarization in phase 4 (β is extending flat stretch of keys). o AV nodal conduction time & effective refractory period is especially prolonged by βblockers (disconnected heart light represents “disconnect” at AV node) • Indications: o Especially helpful in treating supraventricular arrhythmias (upper half of heart lit up) ▪ Include a-fib with RVR, a-fib, atrial flutter (TV screen) ▪ Particularly useful for controlling ventricular rate (metronome) ▪ note that the first goal of a-fib treatment is rate control, then rhythm, so as to prevent ventricular tachycardia o Can be given IV to treat intraoperative acute arrhythmias (Ivy) • Side effects/toxicity o Can potentially cause heart block d/t ↓AV conduction, and serious arrhythmias especially with other medications that affect AV conduction (hat shielding heart) o Heart block manifests as a prolonged PR interval on ECG (PR guy)

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4.3 – “Tres Amigos”: Class III Antiarrhythmics – K+ channel blockers • Class III antiarrhythmics include Amiodarone (tres amigos), ibutilide, dofetilide (“Till I Die” sign for -tilide suffix), sotalol (soda bottles). (AIDS mnemonic for all four.) • Recall that outward K+ current is present in plateau & repolarization phases of cardiac myocytes, and is the main driver of the latter. By blocking K+ currents, depolarization takes longer (i.e. prolonged refractory period; prolonged phases 2 & 3), and AP is prolonged (banana curtain pushed away). • Clinical indications: o Used primarily for rhythm control, along with Class I. Not used for rate control, unlike Classes II & IV. o AP prolonging effects can be used to suppress both ventricular & supraventricular arrhythmias (Heart lamps illuminated on top & bottom). o Can be used for cardioversion in AFib (man changing channels on fibrillating TV) • Amiodarone o shares characteristics of Class 1-4 arrhythmias (uno, dos, tres, quatro). Blocks inactivated Na+ channels. Weak β adrenergic & calcium blocking effects o Side effects/toxicities ▪ Neurologic: tremor, ataxia, peripheral neuropathy, sleep disturbances (brained skull embroidery on hats) ▪ Gray corneal microdeposits seen in almost all patients within a matter of weeks (silver sunglasses). Generally asymptomatic; may rarely cause halos in peripheral vision, optic neuritis, or blindness. ▪ 40% inorganic iodine by weight (hence the name amiodarone), which can cause hyper- or hypothyroidism (various sized bowties = variable effects). Mediates two types of hyperthyroidism: • Type 1: found in patients with existing or unrecognized thyroid goiters. Excess iodine allows ↑↑ production of thyroid hormones. • Type 2: thyroiditis may result as a direct toxic effect of the drug, causing temporary increase in T3 & T4 d/t dumping of stores, and subsequent ↓production. • Important to get baseline thyroid function tests before initiating medication & to monitor thyroid function while on amiodarone. ▪ Pulmonary toxicity may lead to fatal restrictive fibrosis (fibrotic lung embroidery, with button restricting movement) ▪ Heart block (hat shielding heart) ▪ Many other heart effects, including HF, especially with rapid IV administration (failed balloons) ▪ Can cause QT prolongation (as do all the drugs with the banana curtain in the back). However, has very low rate of torsades occurrence, maybe because of effects on many different ion channels • Contrast with all the others in this class, which also have prolonged QT interval, with dose related incidence of torsades (twisted streamers throughout sketch) ▪ Hypersensitivity hepatitis; abnormal LFTs (hepatic liver shaped spot on cow) ▪ Skin deposits → photodermatitis, with a gray blue discoloration in sun exposed areas (photographer; gray-blue suits) ▪ Inhibitor of CYP450 (trailer with license plate) • Sotalol (soda bottles) o Also a β-blocker, hence the -lol suffix (blocked β bugle)

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4.4 – “Calci-YUM quartet”: Class IV antiarrhythmics • Non-dihydropyridine calcium channel blockers include diltiazem & verapamil (non-dairy Calci-YUM ice cream; Delicious Dark Chocolate & Very Vanilla) • Block activated & inactivated L-type calcium channels (L-shaped ice cream spigots) • Use-dependent (d/t blockage of activated & inactivated channels, rather than resting). More active in rapidly firing tissues & those that are activated more by calcium current – i.e. SA & AV nodes (nodal notes on heart-shaped music stand). • Effects of blocking are similar to effects of β-blockers. Recall AP upstroke is Ca2+ phase 0; K+ is phase 3 repolarization (note the upstroke of the keys). Most dramatic effect is at the AV node → slowed conduction (slowed conduction through the heart lamp). Particularly useful for treating supraventricular arrhythmias (top of heart light is lit). • Prolonged PR interval d/t slowed conduction from atrial P wave to ventricular QRS (PR guy). • When used in large doses or previous AV nodal disease, can cause heart block (hat shielding heart) • BY increase AV node refractory period, can slow ventricular response. Useful in rate control in A fib (rate controlling metronome; a-fib television).

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4.5 – “DJ Foxglove Discotheque”: Class V antiarrhythmics (basically everything else) • Basically a catchall term for all other drugs useful in arrhythmias that don’t fall clearly into Classes I – IV. Alternative antiarrhythmics include digoxin, adenosine, potassium, magnesium • Digoxin (DJ foxglove) o positive inotropic effects. o Exerts parasympathomimetic effects via direct stimulation of vagus nerve (Vegas sign). Because cholinergic effects are much more powerful in the atria → inhibition AV node somewhat selectively. o AV nodal activity useful as rate control in A-fib & flutter (A-fib screens) • Magnesium (magnetized moonwalk) o Used to treat torsade des points (torn up rhythm strips) o Mechanism is unknown; known that Mg can affect various ion channels, including Na-channels, K+ channels, & Na-K-ATPase • Potassium o May be administered in management of arrhythmias, as both hyperkalemia & hypokalemia can both induce arrhythmias (Banana dancers). o Hyperkalemia: Will present with cardiac conduction abnormalities, ascending weakness, and paralysis as well. ECG will display peaked T-waves with shortened QT interval (streamer shape over dancer pointing upward). o Hypokalemia: will present with severe muscle weakness, renal abnormalities, glucose intolerance. May see U waves on ECG (streamer shape with gal pointing down). • Adenosine (“Swing dancing” with purine shaped gate) o Activates inhibitory A1 receptors on the myocardium & SA & AV node (A1 sign). effects: ▪ ↑K conduction & increased outward K+ current → hyperpolarization (banana flying through the air) ▪ suppressed inward Ca current → suppressed Ca2+ dependent action potential (ice cream on the floor). Calcium dependent action potential occurs in nodes, predominantly AV. Depression → ↓AV conduction & prolonged AV refractory period (nodal notes on dance floor). Results in decreased AV conduction (disconnected heart sign) o half-life is only 10 seconds o Indications ▪ Acute treatment of supraventricular arrhythmias (e.g. #1 first line treatment for PSVT conversion) (upper half of a heart with #1 ribbon) ▪ Also a vasodilator → ↑ coronary blood flow (red crown). Mediated by binding A2 receptors. o Major CV effects → major adverse effects. Note that extreme toxicity is rare d/t short half-life. ▪ Flushing (flushed dude) ▪ SOB (resting with exertion) ▪ Chest pain (clutching chest) ▪ Sense of impending doom (looks worried) ▪ Headache (gal with hand to head) ▪ Hypotension (gal fainting) ▪ May have high-grade AV block of extremely short duration (hat shielding heart) o Less effective in presence of methylxanthines (including caffeine & theophylline) which block adenosine receptors (kid antagonizing adenosine entrance while drinking an energy drink)

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Blood & Inflammation 1 Anticoagulants and thrombolytics 2 Dyslipidemia 3 Anti-inflammatory drugs 1.1 – “Heparin Season”: Heparin & direct Factor X inhibitors • Normally, thrombin—aka Factor II (beaver with II-shaped teeth)—cleaves fibrinogen to form active fibrin, which crosslinks to form a clot (throm-beaver is crosslinking sticks to build a dam). Prothrombin is activated to thrombin by Factor Xa complexing with … TSII (Factor X is represented by the fox). • Unfractionated heparin is a glycoprotein produced endogenously that polymerized to various lengths. When administered clinically in its unfractionated form, there are a variety of lengths of polymer chains. Indirectly inhibits Factor X and ergo thrombin, by activating the antithrombin III complex, which in turn irreversibly inactivates Factor X. (The Heppy Heparin Hunter standing in the stream is carrying a cage with 3 bars in the middle for antithrombin III. The cage inhibits a thrombin beaver and a Factor X fox.) o Prevents clot formation but does not lyse extant clots (the hunter can’t destroy the dam the beaver had already built o PTT levels need to be monitored continuously with UFH (woodpecker making PTTTTTT sound is being monitored by a second heppy hunter, with a second woodpecker in the tree to remind us of intrinsic pathway testing). Administration is IV (ivy around the tree) o Clinical indications include acute management of clot conditions: ▪ DVT, commonly in iliofemoral & popliteal veins (iliofemoral river) ▪ PE, with ischemia distal to the clot (woodpecker sitting in the lung-shaped tree, with leaves off the ranch distal to the bird) ▪ Acute MI (heart-shaped banjo with broken stings) o Safe for use in pregnancy because does not cross the placenta, although LMWH is preferred d/t ease of use (pregnant woman is standing next to LMWH girl) o Toxicity: ▪ Heparin-induced thrombocytopenia (HIT): antibodies produced against heparin:PF4 complex → widespread platelet activation via Fc component of IgG antibodies. This results in a paradoxical hypercoagulable state & thrombosis (hunter is skeet shooting, and broken clay plates lie around. Despite the hunter, the beaver continues to build a sheltering dam around him). If this process results in a thrombotic event, may be referred to as heparin induced thrombocytopenia & thrombosis (HITT) or HIT type 2. • Tx: immediate removal of all heparin products and administration of alternative rapid-acting anticoagulation, e.g. direct thrombin inhibitors like bivalirudin (“no intruding” sign), argatroban or dabigatran (gators in the water); ▪ Bleeding (no duh) ▪ Hypoaldosteronism → hyperkalemia (depleted mineral mine boarded up in the shape of a K) ▪ Osteoporosis (bone shaped tree branch weakened by termites) • Low molecular weight heparin (LMWH) (enoxaparin & others) is a smaller molecule – only the smaller polymers are delivered. As such, while it has the same MOA as UFH, only inhibits Factor X, not thrombin (girl hunting is smaller than the adult heppy hunter. She carries a similar antithrombin III cage, but only inhibits a fox; no beaver here!) o Has a longer half-life than UHF (white flag that looks like an exponential decay plot). o Doesn’t require PTT monitoring, as dose is based on pt. weight rather than PTT. o Eliminated renally. As such, renal insufficiency can prolong half-life (girl standing flag on a fractured, or insufficient, kidney shaped rock). o Less likely to cause HIT (young girl skeet shooting is missing) • Fondaparinux acts similarly to heparin, except binds to antithrombin III with greater specificity (Fido has a pair of antithrombin III cages, because he’s so good at binding them). Has the lowest risk of HIT (Fido cannot even pick up the gun) • Protamine sulfate can be used to reverse heparin action, decreasing bleeding risk. It is a positively charged molecule that binds to the negatively charged heparin, preventing its action (“Protected Area” fence that is positively charged keeps the hunters out). Most effective against UFH, not so much against LMWH or fondaparinux (girl hunter and dog are able to avoid the fence).

34 • Direct factor Xa inhibitors include rivaroxaban, apixaban, darexaban, (-Xaban suffix) act in a self-explanatory fashion (guy directly grabbing fox without needing a trap). Do not require monitoring. Oral administration. Ease of use makes more appealing in managing A-fib & flutter (TV screen) o In cases of life-threatening bleeding, may administer andexanet alfa, a biologic that shares homology with Factor Xa but has no proteolytic effects. Functions as a decoy, binding to Xa receptors & enabling intravascular coagulation by increasing availability of endogenous factor Xa. Associated with significant thrombosis risk.

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1.2 – “Warfarin, what is it good for?” • Vitamin K (medics with VK symbol on helmets) promotes γ carboxylation of dependent clotting factors – factors II, VII, IX, & X (II: thrombin – beavers foxes; VII: seven deadly sins – devil; IX: cat of nine lives; X: foxes. The VK medic is working on VII, tying his wounds with a γ-shaped bandage.) Vitamin K also activates anticoagulation proteins C & S (Corporal C & Sergeant S in the background are holding back the troops from joining the coagulation war.) Vitamin K epoxide – the inactive form – is reduced to active form by hepatic Vitamin K epoxide reductase (VKOR). (Medic is grabbing a new kit from the VKOR boat.) • Warfarin inhibits VKOR (warfarin warhead has destroyed a VKOR boat), blocking restoration of Vitamin K and reducing systemic Vitamin K levels available to synthesize new clotting factors. This results in a long-lasting, delayed onset hypocoagulable state (undetonated warhead onshore has a ‘delayed onset’). Factor VII has the shortest half-life, so is the first to go down (VK medic is working on VII, who is the first man down). o Warfarin has a long half-life (trooper with a long, narrow white flag) and a narrow therapeutic range, so monitoring via PT/INR is important, testing the extrinsic pathway. Normal INR is 1; goal with warfarin therapy is 2-3. (Para Trooper is coming in as extrinsic reinforcements, with a devil to remind of testing factor VII. INtercom Radio is set between 2 & 3.) Metabolized by CYP450, so has significant drug-drug interactions; upregulation of CYP450 leads to decreased warfarin efficacy, and vice versa (Chrome plated tank with CYP450 license plate is squashing down a warfarin warhead). o Used as treatment/prophylaxis for high-risk coagulable states, including A-fib & DVT (boat with the A-fib monitor floating on the iliofemoral river). Note that in the case of acute thrombus, co-administer heparin for immediate effect. Administered orally (trooper popping pills in the foreground). o Side effects: ▪ Teratogenic, and can cross the placenta (teratogen tarantula on the foreground warhead). Outcome is fetal warfarin syndrome, with abnormalities including low birth weight, slow growth, mental retardation, microcephaly, and malformed bones, cartilage, and joints. LMWH is preferred for anticoagulation in pregnancy. ▪ New warfarin treatment can cause a hypercoagulable state. This results because endogenous antithrombin protein C has a short half-life, so is one of the first factors with levels to fall (warfarin warhead has taken out Corporal C, and troops in the background are charging past Corporal C). This results in patchy skin necrosis (black soot on corporal). Co-administer with heparin to prevent hypercoagulable state (heparin hunters on the bridge are controlling the overzealous coagulation fighters) o Reversal: ▪ Vitamin K has a delayed onset (new vitamin K medics coming in on a boat still in the distance). ▪ Fresh frozen plasma given for immediate effect to replenish factors short term (FFP planes are providing reinforcement in the moment)

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1.3 – “Bad News Platelets”: Antiplatelet Agents Physiology • Primary Hemostasis can be thought of as occurring in three steps. o Adhesion: Damage to vascular endothelium exposes collagen, to which von Willebrand Factor (VWF) binds (The “von Wille Brand Field” is looking a bit beat up, rather like damaged vascular endothelium with exposed collagen). VWF provides a substrate for platelet adhesion, binding platelets via the GpIb receptor (Ib on the bat the players are handing off). VWF binding induces a conformational change in the platelet, activating (the batter is ready to play because he now has a bat). o Platelet activation (home plate activates the game) induces degranulation, releasing various compounds including ADP, 5HT, TXA2, & Ca2+ needed for the coagulation cascade. ▪ Adenosine diphosphate (ADP): Powerful inducer of aggregation. Binds to platelet P2Y12 receptor, inducing platelet expression of surface GpIIb/GpIIIa receptors (“aggregate da players!” sign, with “Play Youth Ball 2-12” for P2Y12). GpIIb/IIIa receptors bind either VWF or fibrinogen. • Platelet surface receptor Glycoprotein IIb/IIIa binds fibrin & stimulates aggregation (Fibrinogen fries; seats 2b & 3b spectators attacking fry man). GpIIb/IIIa is activated by adhering to VWF, upregulated TXA2 synthesis, or binding ADP & inducing a conformational change. Circulating fibrinogen binds GPIIb/IIIa receptors, crosslinking adjacent platelets & forming a plug. ▪ 5-HT: Serotonin stimulates local platelet aggregation and vasoconstriction (helmet with smiley-face; yellow platelet players are all aggregating on the base to try to tag the runner). ▪ Thromboxane A2 stimulates local platelet aggregation and vasoconstriction(thromboxane A2: 2 batter boxes labeled A2 on either side of the home plate). • TXA2 is a synthesized from arachidonic acid (AA league baseball) by either constitutively active COX-1 or inflammation induced COX-2. (Coach Cox is the head coach, and so is always active, while the second coach napping in the pit is only active when needed. Coach Cox is twisting his hat in his teeth, tightening it like with vasoconstriction.) o Platelets aggregate; as they are activated, they recruit more platelets and coagulation factors. Fibrin activation (coagulation cascades are considered secondary hemostasis) and crosslinking stabilizes the platelet plug. Circulating fibrinogen binds GPIIb/IIIa receptors, crosslinking adjacent platelets & forming a plug. Drugs • Aspirin o Irreversibly acetylates COX-1 & COX-2 in existing platelets, preventing TXA2 synthesis until new platelets are formed (ASA referee is blowing acetylation whistle at Coach Cox for cheating, expelling him from the field until the end of the game). o Indications: ▪ Reduces CV events & angina in patients with arterial disease (“greasy pipes”) ▪ Used as a preventative measure for ischemic stroke (painter with a black stripe on his hat, recurring symbol for ischemic stroke, will no doubt be told off next by the ref) ▪ Used in MI (banjo with broken strings). Should be chewed or crushed for more immediate effect (ump chewing ASA while chewing out coach). ▪ Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis (the corked bat used by the home team to cheat looks remarkably like a mesh stent). Dual antiplatelet Tx usually given for 12 mos. – 2 years post stent placement (“play youth ball 2-12 yo”) o Side effects: ▪ Pseudo allergy (referee has a red, inflamed face). Usually seen in patients with comorbidities, e.g. the combination of asthma and chronic rhinosinusitis with nasal polyposis or chronic urticaria. reactions can be divided into four types: • Type 1 – NSAID-induced asthma and rhinosinusitis • Type 2 – NSAID-induced urticaria/angioedema in patients with chronic urticaria • Type 3 – NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals • Type 4 – Blended (mixed respiratory and/or cutaneous) reactions in otherwise asymptomatic individuals • ADP receptor inhibitors (ADPRIs) o Include clopidogrel, prasugrel, ticlopidine (thienopyridines) & ticagrelor (a cyclopentyltriazolopyrimidine; only reversible agent). Note that the most common of these have “-grel-” somewhere in their name (hence the hot dog grill man). o Inhibit platelet aggregation by irreversibly the ADP P2Y12 receptor, preventing induction of further platelet activation (hot dog man is grabbing the ball, preventing the platelet players clustered around first base from working). o Indications: ▪ Reduce CV events & angina in patients with arterial disease (“greasy pipes”, and the angina anvil under the second grill) ▪ Used in MI (banjo with broken strings)

37 ▪ Used as a preventative measure for ischemic stroke (painter with a black stripe on his hat is standing directly under the hot dog man) ▪ Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis (the corked bat looks like a mesh stent). Dual antiplatelet Tx usually given for 12 mos. – 2 years post stent placement (“play youth ball 2-12 yo”) o Adverse effects: ▪ Ticlopidine can cause neutropenia, thrombocytopenia, & granulocytopenia, even fatal (Ty Cobb shirt guy is holding a neutrophil hourglass) ▪ All can cause TTP, ticlopidine most. For both these reasons, ticlopidine is not used much nowadays. • Must obtain platelet count & WBC with differential every few weeks while on therapy. • Glycoprotein IIb/IIIa inhibitors o Include abciximab, a monoclonal antibody (ABC sports with IgG microphones); eptifibatide & tirofiban – “-fib-“ because also prevent platelet interaction with fibrinogen (tied for -ti- in names). o Have many of the same indications as APDRIs. o Block binding of the GPIIb/IIIa receptors (blocking conglomeration of the spectators by feeding fries) o Adverse effects: ▪ Thrombocytopenia (broken plates). Platelet count should be monitored ▪ Increased bleeding time (see this in all of the drugs d/t obstruction of platelet function). Used to ID patients with severe hemostatic defects (ketchup clock) • Phosphodiesterase inhibitors (“Don’t Phoster Disinterest”) o Include dipyridamole (pyramidal tent), cilostazol (3rd baseman has lost the ball) o Inhibition of PDE →↑cAMP within the platelet (green tent), which leads to activation of protein kinase A, ultimately inhibiting platelet function. o Causes arterial vasodilation (dilated sleeves). Direct coronary vasodilation associated with coronary steal (stealing a heart shaped base). ▪ In patients with stenotic coronary arteries d/t atherosclerosis, arteries beyond are already maximally dilated to maintain perfusion. When give a direct vasodilator, exacerbate ischemia by dilating other vessels and diverting blood away from stenotic area (crown-shaped red design on hat) o Can be helpful when treating claudication (dirt clods hitting legs); first line treatment for peripheral artery disease. o Dipyridamole used for coronary stress testing.

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1.4 – “Warning: Bleeding Hazard”. Thrombolytics • In a normal setting, thrombin (Factor II) activates fibrinogen to fibrin, enabling fibrin mesh formation (stick wall looks like the thrombin beaver dam in the heparin sketch). In the case of thromboembolus, the goal is to break down the crosslinked fibrin and thrombin clots (activated general toy is breaking down the fibrin wall by shooting at it). Use of any of these will result in ↑PT, ↑PTT, and ↑D-dimer levels (other kid is blowing long PTTTTTT raspberries, playing with PT paratroopers; twigs from busted fibrin wall look like two-Ds). o tPA is released endogenously from damaged endothelium to break down fibrin (Toy Play set = tPA). tPA (alteplase) can be administered exogenously, or alternatives reteplase (rPA), tenecteplase (TNK-tPA) (playset sounds similar to -teplase.) o Streptokinase is derived from streptococci (purple beads in the playset look like Gram⊕ cocci chains). Can cause allergic reaction, including anaphylaxis in up to 0.5% of patients (kid is choking and flushed). • Indications for thrombolytic treatment: o MI, only if PCI is unavailable within 90 minutes (heart-shaped banjo with broken strings; banjo player is sitting in the sandbox but engaging with baseball player with a stent-styled bat). o Ischemic stroke, if administered within 4.5 hours (painter with black stripe on hat painting a T1-weighted MRI of a distant ischemic stroke. Note that typically there would be no findings on T1 MRI within the timeframe of 4.5 hours post-ictus!) o VTE (PE bird nest in the pulmonary tree) • Toxicities & contraindications: o Increased risk of bleeding (girl is wearing a red hat) o Contraindicated in patients with a recent h/o head trauma (shooting laser beams at MRI painting), intracranial or intraspinal surgery (bloodied scalpel), stroke (within 3 mos. except when within 4.5 hours); any h/o intracranial hemorrhage (girl has splattered red paint on her MRI painting); severe uncontrolled HTN (high pressure tube of paint squirting everywhere); evidence or high suspicion of hemorrhagic stroke (blood on T2 MRI) or intracranial conditions that may increase risk of bleeding. All d/t risk of new intercranial bleed/hemorrhagic stroke. o Non-specific reversal of thrombolytic therapy with aminocaproic acid or tranexamic acid (a mean teacher capping paint [for aminocaproic] with exams [tranexamic acid] in one hand has taken the plasmin activating general toy). FFP or cryoprecipitate may be used to reverse coagulation factor deficiencies (fresh fighter plane & cryopack on upset kid).

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2.1 – “Statin Steampunks”: Statins Production & metabolism of lipoproteins • Lipoproteins (various vehicles) traffic cholesterol & triglycerides between the liver, intestinal tract, and peripheral tissues. • Chylomicrons o The intestines absorb exogenous lipids – free fatty acids (FFAs) & cholesterol (gold bars imprinted with sterol molecular structure)– at the luminal brush border in the small intestine (airship with processing facility with brush border cell flags and intestinal piping). After being absorbed in GI tract, lipoproteins are bound in chylomicrons (Hot air balloons). ▪ FFAs absorbed from lumen are combined with glycerol to form triglycerides, which are the main component of chylomicrons (helmeted people with 3-pronged tridents = triglycerides) ▪ Cholesterol is confined to the outside of the chylomicrons ▪ While in the in the luminal epithelial cells, cholesterol is esterified. Cholesterol esters fill the inside of the chylomicrons (packaging gold bars into chests = cholesterol esters). ▪ Apolipoprotein B48 (ApoB48) is included into the cell membrane to facilitate exocytosis into circulation. o Chylomicrons enter into lymphatic system via villi lacteals → transport along lymphatics to thoracic duct → make their way into circulation. Interact with HDL to pick up ApoE which facilitates liver uptake. o Chylomicrons deliver triglycerides from the intestine to peripheral tissues en route to the liver. ▪ LPL is attached to luminal service of capillary endothelium in extrahepatic tissues (lipo-port lighthouse). Facilitates removal of triglycerides into tissues (helmeted people reaching land by way of lighthouse) ▪ FFAs can be used for energy by heart and SKM (muscular seaweed) ▪ Alternatively, FFAs can be converted back to triglycerides & stored in adipose tissue (fatty sea foam). o Once depleted of triglycerides, chylomicron remnants are returned to the liver (central processing facility). ApoE interacts with LDL receptors (LDL-R) (Load-L Receptor flags) to transport chylomicron remnants into the liver via endocytosis (Pulling in empty E balloon and offloading chests). Cholesterol remnants will be excreted in bile acids or repackaged & put back into circulation. • At the liver o Cholesterol may be synthesized endogenously by HMG-CoA reductase (HMG Ore Processing produces gold ingots); the first intermediate in this process mevalonic acid, aka mevalonate (process is being evaluated). o Liver packages cholesterol (either endogenous or exogenous from chylomicron remnants) into VLDL (chests containing gold being packed onto VLDL zeppelins). o Synthesizes HDL. • VLDL o Synthesized in liver of cholesterol & triglycerides (triglycerides make up 60% total weight) (zeppelins). Include ApoB100 in the lipoprotein exterior (B-shaped anchors). o Deliver triglycerides to peripheral tissues ▪ VLDL is hydrolyzed by LPL, releasing FFA (helmet people entering island via lighthouse). o VLDL depleted of triglyceride forms IDL (essentially VLDL remnants). Some of the IDL particles head to the liver. Many stay in circulation where interact with HPL (not in the picture). Density increases, which is remodeled into cholesterol rich LDL particles. • LDL o Lipid rich transport proteins (little boats). Cholesteryl ester-rich core. Also include ApoB100(B-shaped anchors).. o LDL is the main source of cholesterol for all the peripheral nucleated cells in the body. Nucleated cells contain LDL-Rs which can endocytose entire LDL particles. ▪ LDLRs are upregulated by cells that need more cholesterol, downregulated when cells need less. o About 70% of LDL is removed from circulation by the liver (same mechanisms as described above). ▪ Also adrenals for hormone synthesis ▪ Those that aren’t picked up by the liver can penetrate the vascular endothelium → atherosclerosis • HDL o HDL particles contain mostly protein by weight (HG Wellsian subs). Nascent HDL is secreted by the liver & intestine. A complicated process leads to acquisition of surface apolipoproteins, including ApoE, ApoAI, ApoCII.

40 o HDL goes on to collect cholesterol from peripheral tissues – scavenged in form of free cholesterol from tissue cell membranes (scuba scavenger loading finds onto HDL platform). Esterified by LCAT (lecithin cholesterol acetyltransferase) (load catch platforms on subs). This is the mature HDL. ▪ Women less than 50 & men 1000) can cause acute pancreatitis. Less severely elevated levels are associated with atherosclerotic coronary artery disease. While cholesterol is the major driver of this, unclear if lowering triglycerides will lower risk of CVD. Clinical benefits of lowering serum triglycerides by any means have not been convincingly demonstrated. • Fibrates o Gemfibrozil (gemmed steampunk jellyfish with fibrils), fenofibrate o Several physiologic effects, which together decrease circulating triglycerides by 35-50%: ▪ Lower triglycerides by targeting VLDL. Fibrates activate PPAR-α (newspaper); PPAR-α upregulates LPL at extrahepatic sites and downregulates other inhibitors of lipolysis (using newspaper to light lighthouse). Results in facilitated clearing of VLDL & chylomicrons of triglycerides in peripheral tissues (jellyfish attacking VLDL airship → trident wielders escaping). ▪ Decreases VLDL secretion from liver. ▪ Results in ↓LDL d/t decreased baseline VLDL. However, effect is modest & inconsistent (compare with statins) (sinking LDL ship) ▪ ↑HDL (HDL submarine lifted out of water). Directly activate ApoAI & ApoAII production by hepatocytes, allowing increased production of HDL; effect is mild. o Adverse effects ▪ Muscle toxicity, especially in pts also on statins (statin pirate eating drumstick) ▪ Modest increase in risk of cholesterol gallstones d/t increased bile cholesterol (seagulls on piles of stones). Should be used cautiously in patients with existing biliary tract disease. • Niacin = Vitamin B3 (steampunk sea monster “Nessie”) o At pharmacological doses, ↓VLDL secretion (sea monster eating VLDL ship over by liver base). Mechanism poorly understood. Can also decrease triglyceride release from adipose tissues. o ↓LDL d/t ↓VLDL (breaking LDL ship) o ↑HDL as much as 30%; most effective medication for increasing HDL currently available (lifting HDL sub). Mechanism poorly understood. Decreases HDL cholesterol transfer & delays HDL clearance o Adverse effects ▪ Poorly tolerated overall ▪ Cutaneous flushing and warmth mediated by prostaglandins on administration (sea monster is red & furnace driven; soldiers using a pro-slugger bat). Uncomfortable, but harmless. • NSAIDs can be used to prevent flushing from niacin. Aspirin ½ hour before niacin can help mediate this effect. ▪ ↑glucose, with hyperglycemia in already susceptible patients (rider with candy jar) ▪ ↑LFTs (white LFT flag). May cause severe hepatotoxicity, jaundice, fulminant hepatitis (burning liver base). Unpredictable. Regular monitoring of LFTs is mandatory. ▪ ↑urea. Occasionally precipitate gout (yellow needles – recurring symbol; yellow yarn for gout tophus) • Omega-3 fatty acids o Most often from fish oil (steampunk fish with omega-shaped tails). o Can decrease production of VLDL & ApoB; reduce serum triglycerides by as much as 30% (anchors & tridents in the water) o Has been shown to improve several CV risk factors, including mortality from CV disease, with little to no associated risk.

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3.1 – “NSAIDs in the outfield” Physiology • Arachidonic acid is the precursor molecule for prostanoids & leukotrienes (AA next to dugout; dugout players are the precursors). It is a membrane bound polyunsaturated fatty acid that must be released from the membrane prior to metabolism to prostaglandins. • Injury (chemical or physical) → ↑intracellular Ca → activation of Ca dependent translocation of phospholipase A2 (PLA2) (play ball) which hydrolyzes arachidonic acid membrane bonds. • Free arachidonic acid is metabolized to various inflammatory compounds (prostaglandins, thromboxane, and prostacyclin) by cyclooxygenases COX-1 or COX-2 (Head Coach Cox 1, Assistant Coach Cox 2). • COX-1 is constitutively active in many cell types and is responsible for housekeeping prostanoids (coach 1 constitutively active on the field),: o Prostaglandins (pro-slugger): maintain gastric mucus (pro-slugger protecting gastric-garbed umpire) ▪ Hence why COX-1 inhibition causes gastric ulcers o synthesized to TXA2 (batter’s box), which stimulates platelet aggregation. Is also a potent vasoconstrictor (twisting red hat) • COX-2 is expressed in vascular endothelial & smooth muscle cells, mainly in the setting of inflammation, and is responsible for many vascular effects (vascular endothelium pattern on wall of dugout) o markedly upregulated in inflammatory processes (assistant coach is running from fire). This is the main target of NSAIDS. o Prostacyclin (PGI-2) causes vasodilation & inhibits platelet aggregation (pro-cycler pitching machine; dilated cone; kids with plates being dispersed). Maintains non-thrombogenic vascular endothelial surfaces. ▪ NSAIDS that excessively blocks COX-2 can thus cause a hypercoagulable state. o prostaglandins → ↑vascular permeability (leaky sprinkler activated by pro-slugger), increase pain sensibility (pro slugger with painful inflamed foot), & induce fever (pro-slugger with flaming head) • COX-1 + COX-2 help maintain normal renal function. Produced in glomerular endothelium → afferent arteriolar dilation (prosluggers at the afferent tunnel). Activity is especially important in the situation of hypotension & ↓renal perfusion; in this case, prostaglandin maintains perfusion and limits ischemia. NSAIDs • Non-steroidal anti-inflammatory agents (NSAIDs) (fire extinguisher) decrease production of the prostaglandins that cause fever, edema, & pain associated with inflammation. Directly inhibiting cyclooxygenases COX-1 (constitutively expressed) & COX-2 (expressed in inflammation) (coach 1 constitutively active on the field; assistant coach 2 on fire). Various NSAIDs have differing affinities for the cyclooxygenases; most are non-selective (fire extinguisher dowsing both Cox coaches). • Include aspirin; ibuprofen; diclofenac & ketorolac (black sox) - ketorolac specifically is used mainly as an analgesic; indomethacin (indigo Sox) - used to accelerate closure of patent ductus arteriosus; meloxicam & piroxicam (Sox Cam) - meloxicam has some preference for COX-2; naproxen (approximately 110 mph) • Shared Adverse effects: ▪ D/t COX-1 inhibition o Inhibition of COX-1 → ↓ production of gastric mucus, even at low NSAID concentrations. Can result in gastritis, erosions, ulcerations (burning catcher). ▪ Can change anti-inflammatories or add a gastric acid inhibitor o Are the number one cause of GI bleeds (ketchup on GI pads). o inhibition of thromboxane production → ↓ platelet aggregation. Long-term use can increase risk of hemorrhagic stroke & other bleeding. ▪ Inhibition of COX-1 can prolong bleeding time (ketchup on clock) ▪ Contraindicated in patients with preexisting platelet defects o Pseudo-allergic reactions can be elicited by COX-1-inhibiting NSAID; likelihood is related to the strength with which that drug inhibits COX-1. Reactions usually seen in patients with one of the following comorbidities: the combination of asthma and chronic rhinosinusitis with nasal polyposis or chronic urticaria. Reactions can be divided into four types: ▪ Type 1 – NSAID-induced asthma and rhinosinusitis ▪ Type 2 – NSAID-induced urticaria/angioedema in patients with chronic urticaria ▪ Type 3 – NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals ▪ Type 4 – Blended (mixed respiratory and/or cutaneous) reactions in otherwise asymptomatic individuals ▪ D/t COX-2 inhibition o COX inhibition in the kidney → ↓sodium excretion → ↑BP (exploding fire extinguisher). Occurs in both normotensive & hypertensive patients. Usually mild.

44 o Can cause acute interstitial nephritis (baseballs in blue kidney shaped container = acute leukocyte infiltrate). May have eosinophilia, casts in urine, systemic dysfunction. o AKI d/t afferent arteriolar constriction (constricted proximal end of fire extinguisher hose) →↓GFR. use should be minimized in patients at high risk for AKI (fire extinguisher behind cracked kidney glass by emergency exit) ▪ May cause renal papillary necrosis (sloughing off cleat spikes) o Reduced GFR →↓excretion of renally excreted drugs ▪ e.g. lithium (lithium balloons – “liftium”) can lead to ↑serum lithium & lithium toxicity o Aplastic anemia (rare) (bone balloon); indomethacin specifically. o Neutropenia (all NSAIDs) o ↓ renal prostaglandin synthesis → ↓renin →↓aldosterone → decreased K excretion. ▪ Hypoaldosteronism (depleted mineral mine) ▪ Hyperkalemia (K shaped board) o Contraindicated in 3rd trimester d/t risk of premature closure of the ductus arteriosus (indomethacin & ibuprofen are highest risk) (pregnant lady bounding toward emergency exit) Aspirin (ASA on coat) • Irreversibly acetylates COX-1 & COX-2 in existing platelets, preventing TXA2 synthesis until new platelets are formed (ASA referee is blowing acetylation whistle at Coach Cox for cheating, expelling him from the field until the end of the game, permanently). All other NSAIDs are reversible. Thromboxane production doesn’t begin again until platelets are reborn (~1 week) • Indications (nowadays used less as an anti-inflammatory & more as an antiplatelet): o Reduces CV events & angina in patients with arterial disease o Used as a preventative measure for ischemic stroke o Used post-MI o Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis o Used as an anti-inflammatory in Kawasaki’s disease, the most common vasculitis syndrome of childhood (Kid on ATV). ▪ Characterized by systemic inflammation manifesting as fever, erythema of lips & oral mucosa, cervical lymphadenopathy, rash, & conjunctivitis. ▪ Tx with high-dose aspirin during acute phase of illness. Generally transitioned to low dose ASA when fever subsides. • Side effects: o Can cause Reye’s syndrome when given to children with viral infection (rays on shirt). ▪ Presents as rapidly progressive encephalopathy (confusion, vomiting, seizures, coma) (brain cap) with hepatic dysfunction (hepatic steatosis, hepatomegaly) (liver spotted goat) o Anion gap metabolic acidosis (Mud pile). ▪ Stimulates respiratory center directly → initial respiratory alkalosis before metabolic acidosis sets in (blowing bubbles on pitcher mound) ▪ MUD PILES – causes of anion-gap metabolic acidosis: methanol, uremia, DKA, propylene glycol, iron OD or isoniazid, lactic acidosis, ethylene glycol, salicylates o Tinnitus (tin cans). Common with acute poisoning or chronic intoxication o Poisoning ▪ Activated charcoal can be used in setting of acute toxicity; indicated in all patients appearing within 2 hours of acute toxicity (dark paint under eyes) ▪ Alkalization of urine with sodium bicarb since salicylate is weak acid (hose is loading bases). Increasing urine to pH 8 from normal of ~5 can increase excretion 5x COX-2 selective inhibitors (coxibs) • Celecoxib (celebrating catcher) o No inhibition of COX-1, so no effects on platelet aggregation, thus minimizing bleeding risk. ▪ ↓ risk of GI bleed (happy colonic catcher) o Cause reduced synthesis of prostacyclin, decreasing smoothness of endothelial surface ▪ may increase risk of ischemic CV disease (blood cubes). Relatively contraindicated in ACS. o Sulfa drug (sulfa eggs) • Acetaminophen (paracetamol) o Equivalent for use as an antipyretic & analgesic, but lacks anti-inflammatory effects (icy medicine spray) o Used in treatment of mild to moderate pain when anti-inflammatory effect is less desirable (e.g. Osteoarthritis) o Poisoning is common. ▪ Metabolized by liver, with small percentage metabolized to the toxic metabolite NAPQI by CYP450. Generally NAPQI is conjugated to glutathione; at toxic levels, NAPQI is produced in excess and depletes available glutathione (hepatic goat [goat-a-thione] scared by icy spray)

45 ▪ Toxic metabolites can cause widespread hepatocyte injury ▪ TX: • N-acetylcysteine given IV or oral (N-flower seeds). Probably restores glutathione stores (glutathione goat eating seeds) • Oral activated charcoal can be given within 4 hours of OD (dark paint under eyes).

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3.2 – “Confessions of a knit-wit”: Gout drugs (allopurinol, febuxostat, probenecid, pegloticase) Physiology • Purine metabolism: Nucleic acids broken down to nucleotides (purine-shaped collection plate). Purine is broken down into hypoxanthine by Xanthine oxidase (XO letter from hypo kid) → Xanthine (larger kid). Xanthine is broken down into uric acid by Xanthine oxidase, sent to kidney for excretion. • Uric acid is a poorly soluble product of purine metabolism that is generally excreted in the urine (yellow aisle = tubular lumen). Overproduction or underexcretion will result in hyperuricemia; underexcretion is more common. o Causes of increased urate production: idiopathic primary gout; myeloproliferative & lymphoproliferative disorders; tumor lysis syndrome; Lynch syndrome (HGPRT deficiency) o Causes of decreased clearance: CKD; thiazide & loop diuretics. • Gout is a metabolic disease characterized by deposits of uric acid. o Most often an initial attack of gout will occur in a single joint, classically a knee or the big toe (priest with flaming toe). Crystal precipitate induces local activation of prostaglandins & lysosomal enzymes, attracting neutrophils & increasing inflammation. o Over time, uric acid crystals can precipitate in the joints and skin, resulting in formation of tophi. o Uricemia can precipitate uric acid renal calculi, or even interstitial nephritis o Uric acid crystals are needle shaped & negatively birefringent under polarized light (knitting needles) • CPPD disease aka pseudo-gout o Calcium pyrophosphate crystal deposition disease o Presents like uric acid induced gout, but results from deposition of calcium pyrophosphate (it’s lying in looking like gout – hence “thou shall not lie”). Differentiated by microscopy: calcium pyrophosphate crystals are rhomboid-shaped & positively birefringent (blue rhomboid censor). o Deposition triggers an inflammatory response much like that seen in gout o Acute treatment is very similar to gout • Uric acid crystals can form in tumor lysis syndrome (cancer crab stained glass shattered into crystals); o most commonly occurs in treatment of aggressive lymphomas & acute lymphoblastic leukemia (white T-cell crusaders). o Allopurinol used preventatively. • Lesch-Nyhan syndrome o Deficiency of HGPRT results in excess uric acid production. o Skin and lips are common sites of deposition for uric acid crystals → pain (may be the stimulus for the self-injurious behavior) (kid poked in flesh with knitting needle) Treatment of acute gout (tripping over yarn) • All also suitable for CPPD • NSAIDs are first response; mediate inflammation (kid with fire extinguisher) • Glucocorticoids can be used in Tx of severe, systematic gout, depending on the level of pain (moon face). • Colchicine (chorus) o First line for acute gout. o Administered orally to relieve gout within 12-24 h o Binds intracellular tubulin, preventing polymerization into tubulin (palm fronds; kid binding fronds in hands). Disrupts cytoskeletal function, including phagocytosis, degranulation, and neutrophil migration (blocked first responders) o Brush border cells in GI tract are sensitive → diarrhea (muddy shoes) o N/V, Abd pain Management of chronic gout • Goal is to prevent recurrent of episodes and to minimize risk of urate nephrolithiasis • Allopurinol (pure nun) o First line for chronic management o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes) o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Febuxostat (XO -stopped) o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes)

47 o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Probenecid (Cid the probation officer) o Uricosuric agent used to manage underexcretion. Second line agents for underexcretion o Inhibits organic anion transporter, site of active transport sites of reabsorption & secretion in the PCT (preventing punk kid grabbing yarn) o Adverse effects: ▪ Increase in uric acid in urine increases risk of uric acid stones (lots of yellow yarn balls) ▪ Can inhibit the excretion of many drugs (e.g. penicillin, anionic agents, antibiotics) (penicillin pencil) ▪ Can precipitate an acute attack. Must be started 2-3 weeks after resolution of an acute attack ▪ Sulfa drug (kid throwing stinky eggs) • Aspirin (ASA umpire) o At high doses prevents reabsorption of uric acid (ump blocking yarn collector); at low doses, can block urinary excretion (kid catching yarn) o d/t need for high dosing, should never be used as treatment for hyperuricemia. • Pegloticase o Urate oxidase enzyme that converts uric acid to more water soluble allantoin (holy water – just in case) o Used in refractory gout. o Used to prevent gout symptoms in patients at high risk for tumor lysis syndrome. o Adverse effects: ▪ Can cause hemolysis in G6PD deficiency (G6PD watermelon with bite) o Can cause anaphylaxis (kid suffocating). Seen in 6-15% of patients. Must be administered IV in an inpatient setting by a qualified provider d/t high risk of severe Adverse effects (ivy around door)

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Smooth Muscle 1. Vasoactive drugs 2. Allergy & Pulmonary drugs 1.1 – “The Ballad of Johnny Nitro”: Nitrates Physiology • Angina results from an imbalance in oxygen demand & delivery → ischemia (rock looks like anvil). For acute treatment of symptoms, need to immediately have vasodilator to ↑oxygen delivery (blasting open obstruction). o Prinzmetal angina is d/t coronary vasospasm (John Henry wearing angina medal) • Phosphorylation of myosin light chain in vascular smooth muscle cells allows myosin interaction with actin → muscular contraction & consequent vasoconstriction (chain around legs & arms of chain gang = myosin light chain; P locks [= phosphate groups] allowing chain to constrict prisoners’ legs; baggy blue pants & red shirts constricted at cuffs = arterial & venous constriction). • Nitric oxide (NO) is produced endogenously by endothelial NO synthase (eNOS) in response to platelet-derived factors, shear stress, acetylcholine, and cytokines. NO increases cGMP in vascular smooth muscle cells (grumpy man controlling steam drill) → ↓Ca. Decreased calcium decreases activity of myosin light chain kinase, resulting in myosin dephosphorylation, preventing myosin interaction with actin (P locks being removed, preventing chains from working & decreasing constriction of prisoners’ legs; freed prisoner). • cGMP cases venous dilation & ↑venous capacitance; veins are most sensitive → ↓preload (Preload tank with ↓↓ arrows). Results in ↓cardiac filling & wall stress, ↓pulmonary vascular pressure, ↓CO, which combined add up to decreased myocardial oxygen demand (blacksmith has removed O2 mask). Have some vasodilation of larger arteries → mild ↓SVR Nitrates • Exogenous nitrates include nitroglycerin, isosorbide mononitrate (single stick of dynamite), & isosorbide dinitrate (double stick of dynamite) • Organic nitrates are metabolized in vascular smooth muscle cells → release of gaseous NO (white NO exhaust emanating from steam drill). Act analogously to endogenously synthesized NO →→ Decreased myocardial O2 demands • Oral bioavailability is low. Sublingual is preferred to avoid first pass metabolism for acute symptom relief. Duration of action is very short, and is not suitable for prophylaxis or maintenance therapy • Indications: o Given orally for maintenance therapy in chronic stable angina (anvil rock; dynamite being thrown into mouth-shaped cave). Isosorbide mononitrate & dinitrate are oral formulations. Doses much higher for sufficient levels to survive first pass metabolism o Sublingual formulations for acute symptoms of either Prinzmetal or “angina of effort” (folded shoe tongue on anvil) o Acute coronary syndrome (ACS) (broken string guitar). Symptomatic treatment only; no mortality benefit in ACS. ▪ ACS includes: unstable angina (episodes of angina at rest, increase in severity, frequency, or duration of chest pain in patients with previously stable angina), NSTEMI, STEMI. o Acute treatment of pulmonary edema (guy with lung-shaped sweat stains on shirt), as seen in a hypertensive crisis o Lowering BP in HTN crisis (involving the presence of end organ damage) (emergency shut off switch) • Adverse effects o Orthostatic hypotension, up to syncope d/t venous blood pooling in lower extremities (fainting gal) ▪ ↓BP can lead to reflex tachycardia (doc with reflex hammer). To maintain low levels of heart stress, may combine with a β-blocker in some patients to prevent this occurrence (β bugler blocking doctor). o Throbbing headaches, flushing d/t vasodilation (guy holding his head, looking a bit sunburned) o Prolonged infusion of high dose nitrate may cause methemoglobinemia (rusty wheels on dynamite cart) o May develop tolerance to nitrate effects over time (tachyphylaxis) (“We will not tolerate” protester). May be d/t decreased metabolism over time in vascular endothelium (tachycardia, ↓contractility, salt & water retention) ▪ Avoid with nitrate free intervals of one day (“We will not tolerate 24h days!”) ▪ Seen more with continuous exposure as in workplace – may see loss of tolerance over weekends, causing headache & dizziness to recur on Mondays; hence the name Monday Disease (Monday clock). o Contraindications

49 ▪ Do not coadminister with sildenafil (coal filling station) or other PDE5 inhibitors (synergism ↑risk of severe hypotension). Nitrates should be avoided in patients who have taken such rx in last 24 hours d/t risk of hypotension ▪ ↓preload should be avoided in hypertrophic obstructive cardiomyopathy (as ↑preload will cause ↑outflow tract obstruction) & R-sided MI d/t decreased RV preload (want the latter to be enhanced) (large heart-shaped smokestack on train with right side painted white)

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1.2 – “Pounding at the Sumo Festival”: Triptans & migraines • Classic migraine consists of aura of variable duration ± n/v visual scotomas, speech abnormalities, followed by severe, throbbing unilateral headache that lasts for a few hours up to a few days (throbbing bell). Common migraine is similar but sans aura. Pathology is unknown. Pain is d/t activation of trigeminal nerve afferents that innervate intracranial arteries, particularly in the meninges (three gems on protective meningeal hat). Trigeminal afferents release vasoactive peptides (e.g. CGRP, substance P, neurokinin A) onto meningeal vessels → vasodilation & protein extravasation → neurogenic inflammation (dilated sleeves). Mechanical stretch by perivascular edema may be the immediate cause of neurogenic pain. • NSAIDs can be used for migraine as well. Combined with triptan seems to be more effective than either alone. Triptans • Sumatriptan and others (sumo wrestlers) • Acute treatment for migraines. o Triptans + inhaled oxygen are acute treatment for cluster headache (lantern cluster) • Combat neurogenic pain, but MOA is not entirely understood. Act as selective agonists for 5HT-1B & 5HT-1D receptors in trigeminal nerves, meningeal vessels & brainstem (smiley face headband; b & d shaped fingers). o Activates receptors directly on meningeal & cerebral → vasoconstriction, and may reduce pressure/stretch sensitive pain receptors (red constricting headband) o Acts on 5HT-1B & 5HT-1D on the trigeminal nerve, preventing release of vasoactive peptides promoting vasoconstriction (taking out ref in 5 gem hat) o Causes 5HT receptors in brain stem, inhibiting pain pathways • Adverse effects o Mostly mild. Include tingling, dizziness, muscle weakness. o Chest discomfort or pain, likely d/t vasospasm. Contraindicated in CAD (tiny coronary crown), known trigger of Prinzmetal angina (tiny anvils) Long term migraine prophylaxis (long term fans) • Calcium channel blockers (Calci-yum ice cream), although questionable efficacy • Triptans • β blockers (ref with bugle) • Valproic acid can be used (festival pro sign) • Topiramate (toupee) • Tricyclic antidepressants, e.g. amitriptyline (tricycle)

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1.3 – “Pro-Slugger Sporting Goods”: Prostaglandins, prostacyclin, bosentan, PDE-5 inhibitors • Prostaglandin R is an important mediator of vasoconstriction & inflammation. Recall arachidonic acid pathways, produced by Cox-1 & COX-2 (coaches in the back). Numerous prostaglandins are synthesized endogenously, and may be administered exogenously in certain clinical scenarios with effects on smooth muscle of GI,, vascular, genitourinary tracts. • PGE1 & PGE2 (Extreme Sports) o Alprostadil = synthetic PGE1 (dill pickle themed board). ▪ Acts as a vasodilator ▪ Indications • ED therapy (erect pro-slugger bat). Second line treatment, either monotherapy or in combination therapy. Works because PGE1 is a vasodilator with potent smooth muscle relation effects. • Maintains patency of fetal ductus arteriosus (knocking air duct open with bat). PGE2 acts locally in the womb on fetal vasodilatory receptors. After birth, PGE2 levels fall, causing closure of the PDA. In conditions where maintaining patency is important (as in certain congenital heart diseases), may administer PGE1 via continuous infusion. o This closure is why NSAID/prostaglandin use is not recommended in third trimester o when PDA doesn’t close after birth, which may induce respiratory failure in preemies, can give indomethacin – an NSAID – to promote closure. o Misoprostol = synthetic PGE1 analog (kid in front missing the ball) ▪ Indications • Cytoprotective in the GI tract at low doses, ↑secretion of gastric mucosa. Protects against NSAID-induced peptic ulcers (kid knocking over fire extinguisher) • Potent oxytocic actions. Used to increase uterine smooth muscle tone to facility labor or terminate pregnancy (uterus shaped bags expelling contents). Hence is a pregnancy category X drug. ▪ Adverse effects • Abdominal discomfort, diarrhea (flooded bathroom) o Dinoprostone = PGE2 analog (kid in a dino helmet) ▪ Stimulates contraction of uterus throughout pregnancy. May be used to induce abortion. (open uterus bag) ▪ Directly affects cervix, promoting softening. May be applied locally for cervical ripening in preparation for labor induction • PGF2a (footwear section) o Carboprost = PGF2a analog (cardboard box) ▪ Used in obstetrics to increase uterine tone. May be used to induce abortion or to control refractory post-partum hemorrhage (uterus bags) o Latanoprost & travoprost (La Tan Sandals, Traveler boots) ▪ Stable, long-acting prostaglandin agents used in the management of glaucoma (leaky eyeball containers). Increase aqueous humor outflow → ↓IOP (cleaner flowing off of glasses) ▪ Causes increased iris pigmentation. Most commonly seen in green-brown eyes (brown sunglasses) Pulmonary hypertension management • Narrow and fibrosed pulmonary arteries result from long-term untreated HTN. Idiopathic pulmonary HTN specific classically manifests as dyspnea & exercise intolerance in women aged 20-40. All treatments have direct vasodilatory effects on pulmonary vasculature (high tension lung-shaped rackets). For most patients with pulmonary HTN, treat underlying conditions. • Prostacyclin (PGI2) analogs o Prostacyclin is a potent vasodilator and platelet inhibitor produced by COX-2 at the vascular endothelium (pro-cycler pitching machine) o Epoprostenol & iloprost (iLOW – ePRO setting). Epoprostenol is first line as has been shown to improve symptoms, prolong survival, & delay need for lung transplant. However, must be given as continuous IV infusion. o Major adverse effects include flushing, headache, hypotension (fainted girl) • Endothelin R antagonists o Bosentan (boss man stan) o Endothelin is a potent vasoconstrictor & promotes endothelial proliferation (end o’ the line). Bosentan inhibits endothelin → vasodilation (untucked shirt) o Adverse effects ▪ Associated with fatal hepatotoxicity (liver shaped spot). Calls for monthly LFTs. ▪ Can cause hypotension. (fainted girl) • PDE-5 inhibitors o Sildenafil, tadalafil (ball FILL)

52 o Potent vasodilation o Inhibit PDE breakdown of cGMP, increasing intracellular levels (Don’t Phoster Disinterest = inhibiting phosphodiesterase; grumpy employee). ↑cGMP → dephosphorylation of myosin light chains → vasodilation. o Also used to treat ED (erect bat in photo)

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2.1 – “A Midsummer Night’s Diphenhydramine”: Antihistamines • Histamine is a biologically active amine that plays an important role in gastric acid secretion, functions as a NT, and mediates allergic inflammation. Most tissue histamine is stored in mast cells & basophils. Once mast cells are exposed to IgG, they will burst open at exposure to specific antigens (like an irritated beehive). • H1 receptor is involved in allergic response. o coupled to GqPCR (one Q-shaped dandelion). o Mediates type 1 allergic reaction → hives & allergic rhinitis (fairy dust making Hermia sneeze and break out in hives) ▪ ↑nasal & bronchial mucus production (dripping nose) ▪ Endothelia H1 receptors stimulate extravasation of fluid. Mediate pain, puritis, vasodilation, seen in allergies. Urticaria results from increased vascular permeability (bloody sap) o Causes constriction of bronchial smooth muscle (constricting lung branch). ▪ Asthma is in part a hypersensitivity to this effect. • Non-mast cell associated histamine functions as a neurotransmitter, acting via CNS H1 receptors to regulate sleep & arousal, neuroendocrine & CV regulation (brain shaped tree). • H2 receptors are coupled to GsPCR →↑cAMP (2 S-shaped handles on honeypot). Located on gastric principal cells and activate gastric acid secretion (stomach shaped honey pot leaking yellow honey) Antihistamines (Hermia swatting away bees) • Antihistamines work at the H1 receptor, located in vascular endothelial cells, bronchial airways, and CNS. • First generation: Diphenhydramine & dimenhydrinate (diphenhydramine salt) (dragonfly fairy), chlorpheniramine (colored beetle, Queen Tatiana), hydroxyzine, cylizine, promethazine (cuisine) o Indications ▪ Used as initial treatment for type 1 allergic reactions. Blockade of H1 prevents type 1 responses. ▪ Treat vestibular nausea/motion sickness. Are lipophilic so easily enter CNS, acting on H1 receptors in the vestibular system and brainstem (sailor outfitted fairies riding current in front of brain tree) ▪ As an extension of antimuscarinic effects, can acutely suppress anti-pyramidal effects cause by antipsychotics (e.g. dystonia, drug induced parkinsonism) (parking cone) i.e. Help reestablish dopaminergic/cholinergic balance. (Antipsychotics interfere with dopaminergic transmission via nigrostriatal tract.) o Adverse effects ▪ Cause drowsiness (Lysander sleeping). Sufficiently potent as to treat insomnia. ▪ antagonize many other Rs in the periphery & CNS, including muscarinic Rs → significant antimuscarinic effects (Mad Hatter’s Tea Party) • Urinary retention, dry mouth, pupillary dilation, constipation, exacerbation of glaucoma, & delirium ▪ Anti-serotonergic effects: antagonize serotonin R in the CNS, stimulating appetite & causing weight gain (chubby fairy asleep on branch) ▪ Antagonize α1 receptors → dizziness & hypotension (α candle & passed out fairy) ▪ Can cause cognitive impairment in the elderly d/t central antihistamine & antimuscarinic effects (delirious Egeus) • Second generation: fexofenadine, cetirizine, loratadine (fox, satyr, and rat respectively) o Less lipophilic, so do not cross the BBB and are generally less sedating (trio standing far away from brain tree). Also less antimuscarinic, anti-serotonergic, and anti-adrenergic activity. o Can be used to treat allergic rhinitis or urticaria with significantly fewer adverse effects.

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2.2 – “Fant-asthmic Parade”: Asthma treatment (β-2 selective agonists, leukotriene inhibitors, methylxanthines, cromolyn, sulfate omalizumab) • Asthma involves two processes: o Widespread reversible narrowing of bronchial airways and increased responsiveness to inhaled allergens o Eosinophilic and lymphocytic inflammation of bronchial mucosa o Both bronchodilation therapy & anti-inflammatory therapy are important in asthma management. The level of control depends on the level of disease. • Classic allergic asthma is mediated by IgE produced in response to exposure to foreign antigens (dust, dander, pollen). IgE binds to high affinity mast cell receptors in airway mucosa, stimulating degranulation and release of histamine, tryptases, PGs, leukotrienes, all of which stimulate bronchoconstriction and vascular leakage (guy shooting mast cell beehive with IgE shaped gun) • Leukotrienes are involved in aspirin induced asthma. In 5-10% of patients with asthma, even small doses of aspirin or other NSAIDs can causes profound vasoconstriction and systemic inflammation. Thought to be d/t inhibition of COX pathway, shifting Arachidonic acid metabolism from prostaglandin synthesis toward leukotriene synthesis (ASA ump on balcony with Cox blocking activity) Management • Chronic or more severe is associated with more severe SSx (especially at night) with long-term constriction of airways → thickening of bronchial wall & remodeling, hyperplasia of secretory glands & goblet cells, SM, bronchial vasculature. Management is critical to prevent chronic irreversible loss of pulmonary function. Therapy is stepwise until appropriate management of symptoms is obtained. Dose or number of rx is increased as necessary until control is achieved. • Selective β2 agonists o albuterol, metaproterenol, pirbuterol o counter bronchoconstriction (dilated β2 bugles; -rol Roll Call sheet). o β2 selective are preferred d/t lack of CV activation. Terbutaline also (“Do not disturb” sign in window) o Available as metered dose inhalers – short acting β-agonists (SABAs). Rescue inhalers (tuba player with inhaler). o In mild asthma, symptoms only occur intermittently and may be managed with only SABAs. • low-dose inhaled corticosteroids o beclomethasone, budesonide, fluticasone o With persistent symptoms, may be used as daily maintenance therapy. o After immediate inflammation of asthma attack, there is a delayed response with influx of inflammatory cells into bronchial mucosa; cytokines produced by these infiltrating cells → mucus production & recruitment of further inflammatory cells. Corticosteroids block cytokine production (moon eclipsing inflammatory sun). o Daily maintenance inhalers (controllers). ↓bronchial hypersensitivity and ↓frequency of exacerbations. o Inhalation avoids systemic adverse effects of glucocorticoid use. o Adverse effects: Inhaled corticosteroids can result in oropharyngeal candidiasis (Canadian snow cone). Prevent by gargling water after each use. • Leukotriene inhibitors o LTA activity results from action of 5-lipoxygenase (LOX) on arachidonic acid (AA lacrosse league with coach LOX); synthesized by many airway inflammatory cells including mast cells, macrophages, eosinophils. ▪ Leukotrienes are important regulation of inflammation and include LT-B4, C4, D4, & E4 (lacrosse players in flaming jerseys) ▪ LTB4 is a chemoattractant for inflammatory cells including neutrophils (B4 fallen off truck and attracting neutrophil first responders) ▪ C4 & D4 are potent bronchoconstriction; increase vascular permeability, & mucus conduction (clamping down on airwayesque lacrosse sticks with lung-shaped nets) o Inhibitors can be used clinically in mild or moderate asthma, although less marked decrease in reactivity than corticosteroid. Two mechanisms: ▪ Include montelukast, zafirlukast (monte the broadcaster). ▪ Direct inhibition of binding of LTD4 (most potent LT) to CysLt1 receptor (lacrosse net being guarded) → dilate airways (bronchodilator scarf). ▪ Taken orally, so fewer issues with compliance than inhaled therapies (broadcaster popping pills). o Other approach to interrupting this pathway involves inhibition of lipoxygenase, preventing leukotriene synthesis. Include zileuton (Godzilla balloon falling on Coach Lox). ▪ Small risk of hepatotoxicity; monitor of LFTs (liver spot). Not recommended for routine use in asthma. • Long-acting β agonists (LABAs) (β bugle formation) o Salmeterol & formoterol (salute formation)

55 o High lipid solubility → long duration of action (long tapering flag). Can last for 12+ hours. o Can be given as a daily control regimen. Always given in combination with inhaled corticosteroids. o This step-up therapy may involve increased dose of inhaled corticosteroids as well (elevated moon balloon in formation) • Methylxanthines (xanthine energy drink) o Theophylline (“you’ll be flying”) o Alternative therapy for mild to severe persistent asthma. Reduces severity of SSx in chronic asthma and can act acutely decrease airflow obstruction. Administered orally. o PDE inhibitors; increase intracellular cAMP → smooth muscle relaxation. Inhibit of cytokine release (“don’t phoster disinterest! Go Camping!” sign in background) o Adverse effects ▪ Not used as much anymore d/t safer, more effective treatment. ▪ Very narrow therapeutic index. Toxicity can be fatal & levels must be monitored ▪ CNS effects include nervousness & tremor (shaky kid) ▪ CV effects include tachycardia (heart watch) ▪ CYP450 metabolism (car with chrome bumper) • Omalizumab (limousine) o Adjunctive therapy for moderate or severe persistent asthma o Monoclonal activity directed against Fc potion of IgE, prevents mast cell sensitization (limo driver with IgG-shaped gun binding to Fc portion of IgE gun) o Limited to patients with evidence of allergic sensitization (e.g. demonstrated by skin test) • Cromolyn sodium (Lynn’s Bee Control chrome smoke dispenser) o Inhibits mast cell degranulation (preventing beehive degranulation) o Once widely used as a prophylactic, particularly in pediatric allergic asthma. Now, used much less widely d/t increased efficacy of the inhaled rx. Emergent treatment of acute asthma exacerbation • Inhaled short acting β2 agonists (β2 tuba) • Systemic corticosteroids if no evidence of rapid improvement, or ASAP if patient has h/o severe asthma (ivy for IV) • Nebulized ipratropium bromide anticholinergic to treat acute severe exacerbation (caterpillar balloon) • Subcutaneous or intramuscular E can be used to treat severe exacerbation, especially with absence of rapid improvement (EPIC! Sign)

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GI & Endocrine 1. Gastrointestinal 2. Diabetes 3. Thyroid, parathyroid, & adrenals 4. Hypothalamic & Pituitary 1.1 – “Stadium Vomitorium”: Anti-emetics – Ondansetron, metoclopramide, H1 receptor antagonists, scopolamine, aprepitant • The Nucleus Tractus Solitarius (NTS, or vomiting center), located in the medulla, receives inputs from the GI tract (white lines connecting stomach to track), vestibular system (semi-circular canal running outside the track), & area postrema. NTS neurons project to other medullary nuclei to coordinate vomiting response (vomiting on track directly in front of NTS sign). o The stomach communicates directly with the NTS via vagal stimulation (white lines run underneath “Vegas” sign). GI irritation for any reason (e.g. infection, chemo, distention) causes mucosal serotonin release (stomach competitor throwing serotonin smiley face weights). Serotonin activates 5-HT-3 receptors on vagus afferents, relaying signal to NTS (1-2-3 sign). o Vestibulocochlear system is responsible for vertigo & motion sickness (vestibular nausea); CN VIII communicates directly with NTS (seasick sailors racing vest-wearers; semicircular canal directly behind NTS track). o Area postrema is the chemoreceptor trigger zone, located outside the BBB in the 4 th ventricle, immediately adjacent to the NTS. Responds to emetogenic substances including chemo agents (gymnast doing “extreme postures” on exposed pommel horse immediately adjacent to NTS track). Contains D2 dopamine receptors (gymnast on two D-rings). Triggered by Neurokinin 1 receptors bringing substance P (plaNK1 pommel horse bound by competitors; competitors must first have their pee checked). ▪ Antagonized by Aprepitant (participants). Crosses BBB. Often combined with serotonergic Rx. No impact on dopamine, serotonin, muscarinic receptors, limiting adverse effects compared with other antiemetics. This is a very new drug, so side effect profile is not well-established. Antiemetics • Ondansetron (out-of-bounds dancer) o locks vagal afferent 5HT-3 receptors in the GI tract (distracting from the accurate throw of serotonin hammer). o Highly effective in post-op or chemo-induced nausea/vomiting. Used off-label for other n/v; effective for any cause involving vagal stimulation. o Side effects: ▪ Constipation (hammer wrapping around runner’s stomach, tightening gut) ▪ Headache, dizziness (hammer hitting head) ▪ Rarely: QT interval prolongation, increasing risk of torsades des pointes (dancer with twisting ribbon) ▪ Rarely: Serotonin syndrome; usually only occurs if combined with other serotonergic agents (pile of smiley-face hammers seems like an overload) • Antihistamines o Histamines are involved in vestibular system, specifically H1-receptors coupled to GqPCR (allergenic dandelions shaped like Qs along canal). Histamine receptor blockers (bee swatters) effective to treat motion sickness (sailor uniforms) include diphenhydramine, meclizine. Also Africanized bees add adventure to the race! o Side effects a result of crossing BBB ▪ Sedation ▪ Antimuscarinic properties (recall the tea party sketch) d/t M1 receptor antagonism (motorcycle parked in spot M1) • Scopolamine – a muscarinic agonist – can be used to minimize these effects (telescope) ▪ Other effects of antihistamines are described in respective sketches • Metoclopramide (cheating tickling gymnast – me tickle -pyramid) o D2 receptor antagonist in the area postrema; used for treatment of chemo induced vomiting (cheater is antagonizing gymnast on two D-rings). Also has upper GI prokinetic effects, useful for treatment gastroparesis & delayed gastric emptying post-

57 surgically or d/t diabetes (second gymnast has fallen off D-rings onto stomach-shaped cushion). Can cause diarrhea for same reason (mud beyond the gastric cushion). o Contraindicated in small bowel obstruction d/t stimulation of motility (“do not obstruct” sign by ring-set) o Side effects: ▪ d/t central D2 blockade ▪ Drowsiness (sleeping judge) ▪ Depression (crying coach) ▪ Extrapyramidal effects, including dystonia, akathisia, Parkinsonian features (judge wearing a pyramid shaped “EXTRA” hat). With chronic use, may cause tardive dyskinesia (judge sticking out tongue). Long term used should be avoided, especially in the elderly. ▪ Neuroleptic malignant syndrome (judge eating “Now More Spicy!” chicken); symptoms include fever (man is flushed), rigidity, mental status changes, autonomic instability, rhabdomyolysis (bite out of drumstick). Usually seen with higher potency D2 blockers, but may occasionally be seen here too ▪ Elevated prolactin → galactorrhea, gynecomastia, menstrual disruption (judge laughing so hard, milk is coming out his nose) ▪ Prolonged QT (twisted torsades streamers)

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1.2 – “Gastroesophageal Refund”: Acid control therapy with H2 receptor blockers & PPIs Physiology • Parietal cells in the gastric mucosa are responsible for gastric acid production, secreting acid into the gastric lumen (“Pour-it-all” lemonade, with lemonade spilling into the lumen-like sidewalk). Acid is secreted via Na-K-ATPase pump, maintaining electrolyte balance to secrete H+ ions into the lumen (Lemonade pump on the side of the stand is secreting acidic lemonade; mom is adding a potassium-laden banana to mix it up a bit; operated by 3 Ⓟ batteries). • Gastrin (gas cans) stimulates parietal cells, primarily by way of stimulating Enterochromaffin-like (ECL) cells (tree with the “Enter Carefully” sign) → release of H2 (gas driven leaf blower has disturbed histamine bees on the ECL tree) → activation of H2 receptors (GsPCR) (kid holding honey pot with S-shaped handles is attracting bees) → stimulation of parietal cells (honey-pot boy is knocking over lemonade pitchers, spilling onto sidewalk). Gastrin has a much smaller direct stimulatory effect on the parietal cells. Gastrin is released from G-cells in response to vagal stimulation via cholinergic M3 receptors using gastrin-releasing peptide (GRP) (truck is releasing gas tanks, in response to GRP lever being pulled. Parked next to motorcycle with “Vegas” sticker in M3 spot). • Zollinger-Ellison syndrome is seen with gastrinoma, where excess gastrin production over-activates ECL cells (jumbo gas tank on the cancer crab lawnmower is over activating bees). Results in heartburn, diarrhea, GI bleed Rx • H2 blockers o cimetidine, ranitidine, famotidine, nizatidine (tie-dye shirts for -tidine suffix; 2 bee swatters for H2 blockers). o Reversibly bind to H2-receptors, inhibiting acid secretion from parietal cells. H2 receptor blockers have a strong effect on nocturnal acid secretion, but minimal effect on prandial secretion. Fast action & short duration make this class suitable for symptomatic relief. o Indications ▪ Can be used to treat GERD and ulcers (gastric & duodenal), although PPIs are preferred for both (girl gurgling lemonade while standing on a cracked sidewalk). o Adverse effects ▪ Cimetidine is notorious for adverse effects (tie-dyed kid in the cement) ▪ CYP450 inhibitor (beating up the car with the CYP-450 plates) ▪ Antiandrogen effects: Hyperprolactinemia (kid laughing milk out nose), gynecomastia (kid holding lids to his chest), impotence & decreased libido (floppy honey wand) ▪ Can cross BBB → confusion, dizziness, headaches, especially in the elderly ▪ Crosses placenta ▪ Cimetidine & ranitidine both →↓Crt secretion (although have no actual negative effects on GFR) • Proton pump inhibitors (PPIs) o omeprazole, lansoprazole, esomeprazole, pantoprazole, dexlansoprazole (“prize” sounds a bit like -prazole). o Form a covalent disulfide bond with Na-K-ATPase. By blocking the final common pathway to acid production, these are the most effective treatment for acid production, regardless of the etiology (girl scouts are blocking the lemonade pump). o Indications ▪ First line agents in GERD, with both erosive & non-erosive esophagitis (gargling girl) ▪ duodenal &, to a less extent, gastric ulcers (cracked sidewalk) ▪ Zollinger-Ellison syndrome ▪ stress ulcer treatment ▪ Part of routine H. pylori triple therapy (helicopter hat on girl scout). ▪ Clinically, often used for unexplained dyspepsia o Side effects: ▪ Up to 3x increased risk of C. diff infection (chocolate fountain). ▪ Increased risk of respiratory infections/PNA, both nosocomial & community acquired (dark lung shaped chocolate spots on scouts tee). Possibly d/t ↑levels of upper GI bacteria. Note that the evidence for this in the literature is relatively weak. ▪ Decreased absorption of calcium, magnesium, and iron, as all three rely on an acidic environment (electrolyte medals on wagon), all easily treated by supplementation. If untreated, may result in : • Exacerbation/cause of osteoporosis (termite-eaten wagon) • ↑risk of osteoporotic fractures (broken bone-shaped axel) • Hypomagnesemia (falling magnets) • Vitamin B12 deficiency • Octreotide (exogenous SST)

59 o Endogenous somatostatin (SST) inhibits gastrin release (G-cells) & histamine (ECL cells). can be administered to manage some cases of excess acid production, notably in SST-sensitive gastrinoma (octagonal stop sign blocking irritation of bees).

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1.3 – “Relaxatives”: Laxative agents (lactulose, magnesium, polyethylene glycol, docusate, Senna, psyllium, loperamide, diphenoxylate) & antidiarrheals Laxatives • Alternatively, eat enough fiber, exercise, and stay hydrated; that’ll be enough for most folks, and has far fewer adverse effects! • Note that laxatives ≠ prokinetics (those would be the muscarinic agonists, metoclopramide, erythromycin). Laxatives work on the stuff that comes out, and may indirectly stimulate peristalsis by increasing stool volume → luminal distension. Osmotic laxatives • Nonabsorbable substances draw water into the intestinal lumen(bubbling spa water). Serves to loosen stool, as well as distending the lumen → stimulating peristalsis. Can cause rapid movement of water and rapid action (rapid relaxation by hanging out in the water filled tub). Can result in dehydration d/t water loss (water spilling down drain). OTC availability leads to potential for abuse, as in eating disorders. • magnesium hydroxide & magnesium citrate (magnets) act rapidly, resulting in large volumes of water and consequent high volume of stool. Can result in hypermagnesemia, especially in patients with kidney disease • Polyethylene glycol (PEG) is used for endoscopy prep (peg used as a drain plug). Usually combined with electrolytes to keep balanced • Sodium polystyrene sulfonate (Kayexalate) used occasionally as a laxative. Used as well to manage hyperkalemia. • Lactulose o Non-absorbable sugar (“relaxulose” tub additive). Used occasionally as laxative, but causes severe gas and cramps (bubbling tub). o More often used in cases of hepatic encephalopathy (liver and brain-shaped corals in fish tank). Gut flora degrade lactulose into lactic acid & acetic acid, driving down the pH of the intestinal lumen (fish gobbling up lactulose; acid meter on side of tank). This in turn favors NH4+ (non-absorbable) over NH3 (absorbed form), favoring excretion of the excess ammonia (tank cleaner guy has ammonia cleaner is his belt, and is drawing NH4 out of tank). o May be combined with rifaximin to eradicate ammonia-producing gut bacteria in the case of hyperammonemia (fisherman is removing fish altogether) Bulk forming laxatives • Psyllium, methylcellulose (bulky seaweed). Works as a hydrophilic colloid, absorbing water in the lumen → distention & peristalsis. Cause bloating & gas in some patients. • Surfactants (stool softeners, emollients) • Docusate & glycerin, given PO or as enema. Work by allowing water & lipids to penetrate stool (canoe on the dock is filling with water). Not known for being especially effective. • Stimulant laxatives, a.k.a. cathartics • Senna and others. Work by direct stimulation of enteric nervous system → electrolyte & fluid secretion. MOA is not entirely understood. (Guy tanning in sun, with masseuse rubbing oil into skin, stimulating stomach). Chronic use of Senna may cause benign brown pigmentation of the colon called melanosis coli (brown stomach) Antidiarrheals (muddy slippers) • ONLY use in cases where there is neither infection nor hemorrhage (red stool outside of the massage parlor). In either of those situations, need to treat the underlying cause. • Most of these are opioid agonists which act on μ-receptors, present in high density in the GI tract (“Utopia μ-ssage”). Like all opioids, these are notorious for causing constipation (clogged bathroom) o Loperamide increases colonic transit time by increasing colonic phasic segmenting activity, pushing colonic juju back and forth more (lop-eared rabbits hopping back and forth across person’s back). Does not cross BBB, so has no analgesic or addiction potential. o Diphenoxylate increases colonic transit time by the same mechanism (two dolphins). At high doses, typically higher than prescribed, can cross BBB. To prevent abuse, typically combined with atropine such that doses high enough to cross BBB will cause miserable atropine adverse effects. • VIPomas & carcinoid tumors cause secretory diarrhea along with other systemic symptoms (“VIP customers” crab sign). If unable to fully resect, can use octreotide to limit (octagonal stop sign). Can also use octreotide for other causes of secretory diarrhea (e.g. Chemo)

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2.1 – “Langerhansel & Gretel”: Insulin, sulfonylureas, meglitinides, GLP-1 agonists, DPP-4 inhibitors • Insulin is a major storage and anabolic hormone of the body, and “invites” fat & carbs into cells (“welcome inside” mat for creepy high carb house). Produced pancreatic β-cells in the islets of Langerhans. Release is stimulated by glucose (most potent), or direct sympathetic activation of β-cells (holding candy; β bugler). o 1) When glucose enters into circulation from GI tract, resultant hyperglycemia increases intracellular ATP levels. ↑ATP stimulates closure of ATP-gated K+ channels (closed garden gate). o 2) Closed K channels → ↓K efflux and increased intracellular K concentration → membrane depolarization (elevated bananas in garden). Membrane depolarization leads to opening of voltage gated calcium channels → Calcium influx, which stimulates insulin release from secretory granules (Gretel riding a calcium ice cream flower to carry the candy out of the cell). o 3) Insulin binds receptor tyrosine kinase insulin receptors (tyrosine tire swing). Downstream has a number of effects: ▪ Increases GLUT4 glucose transporter expression in the cell membrane (#4 door) ▪ Increase hepatic glycogenesis (candies in liver-shaped container) ▪ Increased glycogen storage & protein synthesis in skeletal muscles (ham with glycogen glaze) ▪ ↑storage of triglyceride in adipocytes (jar of donuts) ▪ ↓serum K+ by enhancing Na-K-ATPase in skeletal muscle (witch holding eaten banana candy). • Prior to release from β cells, C-peptide is cleaved from proinsulin in the secretory granule; endogenous insulin release is accompanied by equimolar release of C-peptide (Candy wrappers on the ground). • Note that insulin is cleared by both kidneys and liver. Injectable insulin preparation & analogs • Used in Type 1 Diabetes mellitus (T1DM). May be used in the case of severe insulin resistance or severe pancreatic insufficiency in late stages of T2DM. • Long acting for basal control, short acting for control of post-prandial glucose spike. Intermediate acting formulations were the earliest produced, less used now. (note the shape of the house mimics the graph of insulin onset & duration) • Rapid acting, short duration o Include insulin glulisine, insulin aspart, & insulin lispro formulations (Girls & lads sign on tower). “Do not LAG” o Amino acid modifications → slower onset o Rapid onset & short duration of action (onset of 15 minutes, peak 45-75 minutes) (high peaked tower). Used for postprandial spike; mimics endogenous postprandial insulin (Birds pecking away). • Intermediate acting o Regular & neutral protamine Hagedorn (NPH) (Rest Now sign) o Delayed onset & intermediate duration of acting d/t formation of dimers & hexamers, which take time to break down, similar to endogenous insulin (low-peaked gable). NPH is somewhat slower onset. o Regular insulin can be administered IV (ivy). ▪ Particularly useful in DKA (diabetic key). Administer in conjunction with glucose & K. ▪ Monitor potassium, as insulin in the setting of DKA can precipitate hypokalemia. ▪ Should never use subcutaneous insulin in DKA. o IV regular insulin also useful in hyperkalemia. o NPH is less predictable with delayed onset within 2 hours. Not used as much clinically nowadays. • Long acting o Insulin detemir & glargine (“Don’t Go”) o Long duration with steady basal level of insulin (flat roof). Glargine is longest acting, 24h activity with no distinct peak • Adverse effects o Hypoglycemia risk with tachycardia palpitations, sweating, nausea, hunger (ANS hyperactivity, both SNS &PNS). May progress to convulsions & coma if untreated. Falling candies = falling glucose levels ▪ Treat with IM glucagon (glucagon when glucose is gone), or glucose by PO or IM Other agents All of the following function of endogenous β cells or external insulin sensitivity. Note that is only works with T2DM. Will see increase C-peptide levels with increases endogenous production. • Sulfonylureas (swan/Mother goose)

62 o Upregulate endogenous insulin release. Binds ATP dependent K+ channel in β cells → release of endogenous insulin by the mechanisms described above (geese in intracellular garden). o First generation: ▪ Include tolbutamide, chlorpropamide, others (mother Goose in maid outfit = -amide) ▪ Longer acting, rarely used nowadays ▪ Some, including chlorpropamide, may cause disulfiram-like reaction when combined with alcohol (“Do not drink” sign) o 2nd generation: ▪ Include glyburide, glipizide, glimepiride (gosling riding on mother’s back for -ride) ▪ Smaller dosing, longer duration of action (goslings are smaller) • Glipizide has shortest duration of action (Z’s in water). So has a lower risk of hypoglycemia o Adverse effects ▪ Is a sulfa drug (sulfa eggs). ▪ Risk of hypoglycemia (falling candies). Increased risk with renal failure. ▪ Weight gain (lady under tree) • Meglitinides o Include repaglinide, nateglinide (Gliding goose for -glinide) o Similar MOA to sulfonylureas. Bind ATP dependent K+ channel in β cells (geese in intracellular garden) o Non-sulfa drugs so can be used in allergy to sulfa drugs. o Adverse effects ▪ Risk of hypoglycemia (falling candies). Increased risk with renal failure. ▪ Weight gain (lady under tree) • GLP analogs o endogenous glucagon-like peptide (GLP) (old lady eliciting gulp from tuba player). GLP is secreted from intestinal L-cells in response to food intake. Acts in opposition to glucagon; binds GLP-1 receptor ▪ Induces satiety ▪ ↓gastric emptying (full stomach shaped water container) ▪ ↓glucagon release (empty glucagon packets) ▪ ↑insulin release from β cells ▪ Combine to decrease serum glucose levels o GLP effects are glucose dependent, so agonists do not cause hypoglycemia (candies not falling from tree) o GLP-1 Agonists ▪ Include exenatide, liraglutide (TIDE detergent) ▪ GLP-1 agonists function as exogenous agonists of the GLP-1 receptor ▪ May increase risk of pancreatitis (pancreas sponge). o DPP-4 inhibitors (gliptins) (dripping laundry) ▪ Include sitagliptin, saxagliptin, linagliptin (clipped in laundry for -gliptin) ▪ Dipeptidyl peptidase-4 (DPP-4) breaks down GLP. Inhibition increases endogenous GLP availability (witch gulping) ▪ Can cause increased risk of nasopharyngitis & URIs (witch with clothespin on her nose)

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2.2 – “Rosiglitazones are Red, Pioglitazones Thiazolidinediones, Pramlintide, SGLT2 inhibitors

are

Blue…”:

Metformin,

• Drugs that lower glucose levels by a variety of means can be used in Type 2 diabetes (2nd grade); require functional β cells. Unlike the sulfonylureas, meglitinides, & GLP analogs, these drugs act outside the pancreas →↓serum glucose • Metformin (kneeling kid reciting metaphors) o First line oral agent for T2DM. o Decreases serum glucose by poorly understood mechanisms. The only biguanide used clinically. ▪ Inhibits mitochondrial glycerophosphate dehydrogenase, the first step in hepatic gluconeogenesis, decreasing glucose production (girl eating candy, but distracted by serenade so is not taking candy out of liver-shaped bag) ▪ Activates AMP-activated protein kinase (AMPK) (AMP Kandy), decreasing liver gluconeogenesis (friend stopping candy release from bag). ▪ Increasing peripheral insulin sensitivity, resulting in increased peripheral glucose uptake & utilization, by enhancing glucose mediated insulin utilization (“Inside” notice on mailbox) ▪ Decreased intestinal glucose absorption. o Excreted by kidney as active drug (kidney shaped lunch tray) o ↓ risk of hypoglycemia o Adverse effects ▪ Lactic acidosis d/t lactate inability to enter gluconeogenesis(spilled sour milk). Rare. More likely to occur in conditions of renal failure or tissue hypoxia (kidney shaped lunch tray is broken). ▪ GI adverse effects anorexia, nausea/V, diarrhea (girl looks sick) ▪ Can cause modest weight reduction or stabilization (thin physique). • Thiazolidinediones (aka glitazones) o Include rosiglitazone, pioglitazone (“Roses are red” card filled with glitter) o Oral agents. Because these drugs affect gene transcription, take days to weeks for improvements. o Increase glucose utilization & decrease glucose production in adipose tissue, liver, & muscle. o Thiazolidinediones are ligands of peroxisome proliferator-activated receptor γ (PPAR-γ) (PPAR-γ on kid’s shirt). PPAR-γ receptors are intracellular nuclear receptors found in muscle, fat, & liver; part of the steroid & thyroid family of intranuclear receptors. ▪ Regulated genes include those affecting lipid & glucose metabolism, insulin signal transduction, adipocyte differentiation. ▪ One of the more important genes: adiponectin, which is low in patients with T2DM, obesity (turtleneck). Increases insulin sensitivity & fatty acid oxidation; increases differentiation & number of adipocytes (elevated donut jar). ▪ Increased availability of adipocytes increases triglyceride storage combined with increased fatty acid oxidation → ↓circulating TG levels ▪ Upregulate GLUT4 in peripheral tissue →↑glucose uptake (door to mailbox) o Adverse effects ▪ Weight gain d/t increased triglyceride storage — a little “extra glit in your zone” (fat kid) • May be exacerbated when coadministered with sulfonylurea ▪ ↑sodium resorption can cause fluid retention & peripheral edema (kid wearing baggy sweatpants • Contraindicated in HF d/t risk of exacerbation (balloon!) in ▪ Increased risk of atypical extremity fractures in women d/t decreased bone mineral density (fractured chair leg). Exact mechanism unknown, possibly d/t ↓osteoblast activity • Amylin analogues (twins Amy & Lynn) o Pramlintide o Analog of endogenous islet amyloid peptide (i.e. amylin) usually present in insulin secretory granules. ▪ Decreases glucagon secretion (glucagon packets) ▪ slows gastric emptying (closed stomach shaped water cooler) ▪ Appetite suppressant o Used for glycemic control. Can be used to manage postprandial hyperglycemia in either T1DM or T2DM (peaked cupcakes). Injected immediately before eating o Adverse effects ▪ Can cause hypoglycemia (knocking over candy jar) ▪ GI SSx (n/v, anorexia) (kid is nauseated) • Alpha-glucosidase inhibitors o Include acarbose & miglitol (box of A-carb wigglers in corner)

64 o Intestinal α-glucosidase normally converts disaccharides in the intestines into absorbable monosaccharides. Blocking this enzyme decreases absorption of dietary sugars at the intestinal brush border, delaying carbohydrate absorption (“Monosaccharide FREE” box label; brush border flags; delayed access to wiggles) o Can be used to blunt postprandial serum glucose spike by as much as 30-50% (peaky cupcakes). Can be administered regularly through the day. o Side effects generally limit use. GI adverse effects (diarrhea, flatulence, abdominal pain, etc.) result from fermentation of undigested carbs by gut bacteria (leaky bathroom) • SGLT2 inhibitors o Include canagliflozin, dapagliflozin (flossing). Are the newest class. o Sodium-glucose cotransporter 2 (SGLT2) is a low affinity, high capacity transporter responsible for resorbing 90% of glucose in the PCT (Salty Glucose peanuts; pro-cart track poster). Inhibition causes significant glucose loss in the urine. o 2nd or 3rd line for diabetes management. Usually added to existing oral regimen o Side effects are mostly d/t glucosuria: ▪ UTI (bladder cup) ▪ Yeast infections (snowball in the crotch) ▪ Increased osmotic diuresis can cause symptomatic hypotension in some patients, especially elderly & those on diuresis (kid diuresing pants & falling over) ▪ Contraindicated in renal insufficiency d/t ↓ efficacy, ↑ risk of Adverse effects (cracked kidney tray)

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3.1 – “Iodine is Forever”: Propylthiouracil, methimazole, levothyroxine Physiology • Thyroid hormones are T3 (triiodothyronine) & T4 (thyroxine). They are involved in most metabolic functions (like a secret criminal organization). Both contain iodine (anionic form: iodide). • Synthesis: o Iodide is transported into thyroid follicular cells (follicu-LAIR) via a sodium-iodide symporter (peanut box with iodide smuggled). This concentrates iodide; is an energy dependent process. o Iodide is oxidized to iodine by thyroid peroxidase (TPO) (transport with rusty truck). o TPO further catalyzes iodine biding to tyrosine to form iodotyrosine molecules; this process is organification (Organic Food truck with tyrosine tires) o iodotyrosine molecules are stored in the thyroid lumen bound to thyroglobulin (Thyro-Global). While bound, the mono- & di-iodotyrosine molecules couple; mono + di forms T3, di + di forms T4 (vegetables in logo are coupled). • Release & effects: o thyroglobulin is drawn into parafollicular cells, where T3 & T4 are cleaved off (bombs). T3 is the more potent form (activated bomb), T4 produced in greater quantities in the thyroid gland (more bombs with 4:00 timers in the lair) o In the peripheral tissues, T4 is de-iodinated to T3 by 5’-deiodinase (T4 detonator). o T3 enters the nucleus, acting as a transcription factor. Some effects: ▪ Increased sensitivity to SNS catecholamine-mediated stimulation by increasing β 1 receptors (catfish; dead man sensitive to catfish). Increased SNS sensitivity mediates many of the SSx of hyperthyroidism, including hypermetabolic & hyperadrenergic SSx (nervous henchmen with big bowtie) Hyperthyroidism • Presents with hypermetabolic & hyperadrenergic SSx (e.g. tachycardia, palpitations, insomnia, tremor, anxiety, heat intolerance, weight loss) (nervous henchmen with big bowtie) • Causes may include toxic adenoma, toxic multinodular goiter, thyroiditis • Most common cause is Graves’ disease. o Associated with Graves Ophthalmopathy (bulging infrared goggles). Activation of T-cells → lymphocytic infiltration of retroorbital space → cytokine production → fibroblast secretion of hydrophilic glycosaminoglycans → osmotic muscle swelling, muscle inflammation, and increased adipocyte count → exophthalmos. Note that chronic ophthalmopathy doesn’t necessarily correlate to treatment of thyroid levels; may decrease, may not. • Management: o In the US, patients with can be treated with ablative doses of radioactive iodine (I-131). This is done particularly with Graves’s disease. ▪ Can cause hypothyroidism in as many as 80% of patients (undone bowtie burned by radioactive vial) ▪ Can cause transient hyperthyroidism d/t dumping of excess thyroid hormone (anxious radioactive henchman). Particularly in those who are more susceptible (elderly, those with severe thyrotoxicosis), may treat with thioamide drug prior to radioablation to prevent. ▪ Can cause transient exacerbation of ophthalmopathy for unknown reasons; relatively contraindicated in patients with preexisting ophthalmopathy (bulging radioactive goggles) o thioamides ▪ Propylthiouracil (PTU) (secret agent with gunshot “PTU” sounds) • Inhibits TPO and 5’-deiodinase (shooting at bomb detonator). Acts centrally & peripherally. • Use generally limited to those with reactions to methimazole, in the first trimester of pregnancy, or treatment of acute thyrotoxicosis • Adverse effects: o Use limiting reaction: severe hepatotoxicity (mounted liver beaker). o Maculopapular pruritic rash o agranulocytosis (neutrophil norfloxacin > ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin.

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4.3 – “Murder on the Metro Express” • Metronidazole (metro) • Bacteroides fragilis. Coverage of polymicrobial anaerobic infection, as e.g. in intraabdominal infection (man stabbed in stomach). Also has activity against some protozoa. • MOA: Forms toxic free-radical metabolites that disrupt bacterial DNA; bactericidal (oxidized DNA-shaped rails) • Clinical indications (clindamycin above the diaphragm, metronidazole below) o Activity against Entamoeba histolytica. Intestinal protozoa → dysentery, liver abscess (Do not enter sign from entamoeba sketch). o Giardia (protozoan shield) o Trichomonas: treats vaginitis & cervicitis with strawberry cervix (magician with hat & strawberry) ▪ STD. Given to both patient and partner (couple in the back) ▪ Wet mount test to inspect for trichomonas (“does the alibi hold water?”) o Gardnerella caused vaginosis (Ms. Gardner with Venus fly trap) o Substitute for amoxicillin for H. pylori treatment in penicillin allergy (helicopter outside) o Activity against anaerobic bacteria including (gas masks) ▪ Bacteroides, Prevotella, Fusobacterium, Clostridium ▪ C-diff pseudomembranous colitis (chocolate fountain) • Concurrent ingestion of alcohol during metronidazole treatment (oral or vaginal administration) causes a disulfiram-like reaction, with flushing, tachycardia, palpitations, N/V (hip flask with XXX) • CYP450 inhibitor (cars yield to trains)

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5.1 – “Bio 101 meets Music 101”: amphotericin, flucytosine, nystatin • Amphotericin (amphibians with fungi) o Ergosterol found in fungal cell membranes (compared to human & bacterial cholesterol) (“non-sterol” sign). Amphotericin forms pores in ergosterol cell wall allowing leakage of cell electrolytes & macromolecules and eventual cell death (frog aquarium has holes and amphibians are escaping). o Resistance evolves when structure of ergosterol involves changing molecular components of membrane (e.g. ↓ergosterol) o Amphotericin B has the broadest spectrum of action of the antifungals. Used for severe systemic or life-threatening fungal infections (body model with exposed organs). o Generally administered IV (ivy in terrarium). Given as a liposome, because of the high toxicity of the drug (liposome shaped frog). o For CNS infections, administered intrathecally (frog tongue looks like intrathecal line). Used to treat cryptococcal meningitis, often in conjugation with flucytosine (Anthony & Cleopatra, Act V: The Crypt). o Toxicities ▪ All result from amphotericin binding to mammalian cholesterol instead of ergosterol (frog binding to cholesterol themed necktie) ▪ Infusion related immediate reactions • Nearly universal • Fever, chills (“shake & bake”), spasms, vomiting, headache, hypotension, fainting (baking frog; fainting from frog on tie) • Thrombophlebitis at injection site (blue veiny frogs) ▪ Slow cumulative toxicities • Renal damage is most significant. Occurs in nearly all patients. (chemist) o Reversible prerenal azotemia o Irreversible tubular injury (Type 1 RTA) (graduated cylinder shaped like 1 filled with acid). Associated with hypokalemia (banana peel) o Renal magnesium wasting (falling magnets) o Usually have volume expansion with IV normal saline prior to amphotericin administration to help prevent renal damage (emergency saline wash). o Anemia d/t ↓EPO production (drained kidney scaring off white frog; broken tubules) ▪ Intrathecal administration • Seizures and major neuro damage (seizure lines) • Flucytosine o Flucytosine starts as a fluorinated cysteine. Converted by cytosine deaminase into 5-FU (Music C knocked over to U). o Halts fungal DNA & RNA synthesis (DNA and RNA like music on chalkboard being smeared by frog). • Nystatin o Forms pores in ergosterol cell wall allowing leakage of cell electrolytes & macromolecules and eventual cell death (frog aquarium has holes and amphibians are escaping; “Be Nyce” sign) o Active against most candida spp. (Canada flag with snow) o Topical Treats mucocutaneous candidiasis, including vaginal (snowball to the crotch) o Nystatin rinse for oropharyngeal candidiasis (drinking fountain). Esophageal candidiasis treated by systemics.

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5.2 – “We’re not in Candida Anymore”: azole antifungals • Azoles include the imidazoles: ketoconazole, miconazole, clotrimazole; & triazoles: itraconazole, fluconazole, and voriconazole. Spectrum of actions broad. • MOA: ergosterol forms fungal membrane (emerald ergosterol blocks; postmodern fungus). Synthesized from lanosterol (munchkin builders inhibited by crushing house; “Lane Closed”). Azoles halt fungal CYP450 that synthesizes ergosterol (crushed car) o All are prone to drug interactions d/t effects on mammalian CYP450. • Voriconazole (car crushing vortex) o Preferred for invasive aspergillosis (aspirating scarecrow with lung hyphae) o Excellent treatment for candida, including candida esophagitis (Canadian flag). o Adverse effects ▪ Blurry vision or flashes of light, changes to color vision, usually transient (blurry flashes of light in tornado; sepia tones) ▪ Particularly potent inhibitor of mammalian CYP450. Dose reduction of many CYP450 substrates (including cyclosporine, tacrolimus, statins) required on initiation of therapy • Fluconazole (flying monkeys) o Used to treat mucocutaneous candida (yeasty snow). Given in a 1-time dose to treat vaginal candidiasis (crotch monkey). o Systemic fluconazole treats candida stomatitis & esophagitis in which case it’s given IV (esophagus like gutter snow) o Treats cryptococcal meningitis for lifelong maintenance (crypt with permanent monkey statues) o High levels of CNS penetration (meningitis mohawk helmets). Works some against dimorphic fungi but not drug of choice, but mainly against monomorphic. • Itraconazole (good witch) o Systemic infections with dimorphic fungi (e.g. histoplasmosis, blastomycosis, coccidioidomycosis, Sporothrix) (dimorphic butterflies) – “itraconazole for fungi with two iterations” o Used for onychomycosis & dermatophytosis (ruby slippers with tarnished toes) • Topicals, often miconazole or clotrimazole (“My cone” & close trim) o Tinea (tin man with ring-like rust rash) o Vaginal candidiasis (snowball to the crotch) • Ketoconazole (tin man’s key) o Cream form to treat cutaneous dermatophytosis o Other agents have a much better safety profile when administered systemically, as ketoconazole has a greater affinity for the mammalian CYP450. o Inhibits overproduction of cortisol in Cushing’s syndrome (moon face). May be used o Adverse effects ▪ Inhibition of cholesterol hormones (adrenal & sex hormones) by inhibiting 12,20-desmolase & 17-α-hydroxylase (first step of steroid synthesis from cholesterol) (key “locking” the adrenal gland shaped lock; moon face, M & F symbols. Witch synthesizing) ▪ Antiandrogenic Adverse effects, including gynecomastia, d/t inhibition of 17,20-lyase involved in synthesis of androgens

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5.3 – “There’s no place like Canada”: Griseofulvin, terbinafine, echinocandins • Dermatophyte infections include tinea corporis, tinea pedis, & tinea cruris (rust spots on the tin man) • Griseofulvin (grease can) o Fungistatic. Binds fungal cell microtubules, halting mitosis in M-phase (vines binding tin man look like M-phase) o Administered orally to treat dermatophytosis (grease in mouth). Has been largely replaced by newer agents. o Accumulates in keratin containing tissues. Most effective in treating scalp & skin. Can be used for onychomycosis, although recurrence is common (farmhand has some gnarly nails). o First line therapy for tinea capitis in children, along with terbinafine (kid in tin-funnel hat standing between the tin man and the pigpen). o Adverse effects ▪ GI distress ▪ Headache ▪ Rash ▪ Hepatotoxicity ▪ Granulocytopenia ▪ Activation of CYP450 (chrome bumper & CYP450 license plate on a functioning car; thumbs up for upregulation) • Terbinafine (turban) o Fungicidal. Interferes with ergosterol synthesis by inhibiting squalene epoxidase → accumulation of squalene (squealing pigs) o Dermatophytosis (little tin man in crystal ball) o First line therapy for tinea capitis in children, along with griseofulvin (kid in tin-funnel hat standing between the tin man and the pigpen). o Administered orally for onychomycosis (wiz is biting his nails) o Adverse effects ▪ GI upset (mud in pigpen) ▪ Hepatotoxicity. Rare, but calls for monitoring (liver shaped mud spots) • Echinocandins (Echino-Canadians fur cap) o Caspofungin, micafungin, anidulafungin o Inhibit synthesis of β-1,3-glucan, a major polysaccharide component of fungal cell wall (note the cell wall, not the cell membrane which is composed of ergosterol) (walled hay truck) o Excellent activity against candida (Canada flag and yeasty snow). Given IV for systemic candida infections (ivy on flagpole) ▪ Also given for mucocutaneous candidiasis, candidemia, and prophylaxis of candidiasis in transplant patients. ▪ Candida esophagitis (exhaust pipes on truck) o Invasive aspergillosis, particularly with poor response to amphotericin (scarecrow with straw coming out of his lower lung fields) o Adverse effects: extremely well tolerated, with GI & flushing reported rarely.

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6.1 – “Le Morte d’HIV”: NRTIs (abacavir, diadnosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine) • 6 classes of ARTs are combined depending on the characteristics of the patients, adverse effects, and bug profile. Usually 2 NRTIs + at least one other agent from a different class form the backbone of multidrug therapy. • Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs) (Knights of the Round Table). Act by competitive inhibition of HIV reverse transcriptase (reverse trasncriptum spell book has been stolen). Because NRTIs are nucleotides/sides, incorporate into DNA transcription but lack the 3’ hydroxyl, blocking 3’-5’ phosphodiester bond formation and causing premature chain termination (nucleoside mace with broken 3’ -OH group; page #s; broken helix bookmark) • “-dine” suffix attached to some of the NRTIS (meal) • Nucleosides must be phosphorylated & activated by cellular enzymes (activating Ⓟ scroll). • Shared adverse effects o All are associated with mitochondrial toxicity (table shape) o Lactic acidosis (sour milk) • Lamivudine (Sir Lancelot) o Used to treat Hep B (hippo, hippies, secret society banner). Especially helpful in HIV/Hep B coinfection. Note that in the latter case, discontinuation of the drug may lead to a hepatitis flair. o Adverse effects ▪ Peripheral neuropathy (Lancelot’s stockings and gloves) • Tenofovir (Sir Tristan) o Nucleotide not nucleoside (Tenofovir starts with a T) o As a nucleotide, does not need to be activated by cell enzymes (sailing on the tide while the others must wait inside, doesn’t need to wait for the Ⓟ signal) o Also has hep B activity • Zidovudine (Isolde with the dove crest) o Used during pregnancy and breastfeeding to reduce vertical transmission (pregnant woman) o Infants born to HIV+ mother usually receive several doses of zidovudine in the first weeks of life. o Adverse effects ▪ May cause myelosuppression (empty bone-shaped dish), causing anemia/neutropenia & agranulocytosis (white dress; sand timer) ▪ Lipodystrophy, with ↑central adiposity, ↓peripheral fat (silly looking horse) • Stavudine (Sir Steve) o Adverse effects ▪ Peripheral neuropathy (Lancelot’s stockings and gloves) ▪ Lipodystrophy • Didanosine (Sir Dan) o Major toxicity: dose dependent pancreatitis (pancreas shaped sponge) o ↑risk of peripheral neuropathy when coadministered with stavudine (Lancelot’s stockings and gloves) • Abacavir (abracadabra; merlin) o Hypersensitivity strongly associated with HLA-B 57:01 allele (Spell name). Presentation of cell peptides to immune system → delayed Type 4 HS reaction (he’s distracted and has a delayed reaction to spotted rash) • Emtricitabine (Excalibur) o Hyperpigmentation of palms and soles (badass gloves)

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6.2 – “The Council of Elfavir”: NNRTIs (Nevirapine, efavirenz, delavirdine) • Non-nucleoside RT inhibitors. Do not need intracellular phosphorylated for activation. (Outside Camelot, so not knights of the round table; Ⓟ knight riding away toward Camelot) Bind directly to HIV RT resulting in allosteric inhibition, preventing viral synthesis of DNA polymerase activity (spell book blocked directly by arrow cleaving DNA bookmark) • Adverse effects o May have Life threatening hepatic failure within 6 weeks of starting therapy. Abrupt onset flu-like symptoms, abdominal pain, jaundice, fever (stag with yellow glow and liver shaped spot) o Teratogens (massive spider & pregnant lady) o Numerous drug-drug interactions d/t induction of CYP450 system (functional buggy with CYP450 plates). Both efavirenz & delavirdine activate & inhibit system, as well as broken down by it; nevirapine less activating. o Skin rash; Stevens-Johnson syndrome-TEN (orc with tengu mask) • Efavirenz (Elf Queen) o Principle adverse effects unique to efavirenz are all CNS. Include dizziness, drowsiness, headache, psychosis, insomnia, nightmares (queen clutching head; gazing at trippy antlers; dark night). • Delavirdine (Princess Delavir) o Not an NRTI despite the suffix!

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6.3 – “Lady Guinevere and the Sword in the Stone”: Protease inhibitors • Protease inhibitors often end in -navir suffix (Guinevere) including ritonavir, atazanavir, indinavir. Do not need Ⓟ by intracellular enzymes (knight running away with Ⓟ scroll). • HIV proteases serve to cleave the single long poly-protein product of the HIV gene products, which must be cleaved into proteins needed to construct virion particles (sword to cleave things). With proteases inactivated, the virion remains immature (immature page boy). • HIV pol gene encodes enzymes including RTs & proteases (Paul the blacksmith crafting protease blades). o Pol gene mutations → resistance. Never used as monotherapy, as may rapidly develop resistance to the entire class. • Adverse effects – many are metabolic o Hyperglycemia d/t insulin resistance, which may lead to diabetes eventually (elevated candy) o Dyslipidemias, with ↑TG & LDL (elevated butter) o Lipodystrophy (silly steed) o Inhibition of CYP450 (chrome bumper on inoperable wagon) causing numerous drug-drug interactions. Ritonavir especially (Right on! High fives) ▪ Can be used to advantage by boosting levels of other protease inhibitors ▪ Rifampin contraindicated when taking protease inhibitors d/t CYP450 activation → ↓protease inhibitor levels (rifampin crossbow utilized by wizardly henchman). May use rifabutin. • Indinavir (indigo princess) o May cause nephrolithiasis d/t urinary crystallization (stones in kidney fountain). May occur within days of beginning therapy. Adequate hydration is critical (drinking kid)

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6.4 – “How HIV was thwarted at the Gates of Camelot”: Entry inhibitors, fusion inhibitors, integrase inhibitors • HIV infects macrophage, dendritic cells, & CD4 T-cells (crusader cross on neighboring castle). Once incorporated into host DNA, commandeers host machinery to transcribe viral genes. Gag, pol, env code for polyprotein precursors that produce viral virions, which will then bud off and invade next cells o gag structural gene encodes for virion core proteins, including p7 & p24 (sundial, gagged prisoners guarded 24/7) o env structural gene encodes envelope proteins including gp41 & gp120 needed for infiltrating membrane of host cells (envoy boat). Proteins are initially sent to the host cell ER for processing (reef around env boat) o pol gene encodes for proteases, reverse transcriptase, and integrase (Paul the blacksmith) • HIV invasion 1) For HIV to infect a cell, HIV surface glycoprotein gp120 must bind host cell CD4 molecule + a chemokine R (CCR5 or CXCR4) (envoy gaining entry with 120 battering ram; helper squire and CCR5 banners). 2) Fusion. Gp41 facilitates HIV fusion (envoy throwing 41 grappling hooks over castle walls). 3) Once inside the cell, RT transcribes viral RNA into dsDNA (reverso transcriptum spell book) 4) Integrase allows viral DNA to integrate into host cell DNA (keys to unlock nucleus of castle with double helix stairs) • Entry inhibitors o Maraviroc (rearing mare) binds CCR5 receptor, blocking HIV binding and consequent invasion. Before beginning therapy, should determine if HIV strain invades via CCR5. • Fusion inhibitors o Enfuvirtide binds gp41 surface protein, preventing fusion (knight on wall deflecting grappling hook; enfuvirtide for fusion) • NRTIs & NNRTIs act against RT (King Arthur & Queen Elfavir defending the castle) o Mutations to pol gene confer resistance to these classes as well as protease inhibitors & integrase inhibitors (Paul the blacksmith making swords, spell books, and keys for proteases, RT, & integrases respectively). • Integrase inhibitors o Raltegravir disrupts ability of HIV DNA to integrate into host chromosomes; may also be considered to prevent transcription of viral mRNA (knight deflecting key) o Mutations to pol gene confer resistance (mutated key not deflected by slacking knight) o May rarely cause rhabdomyolysis (bite out of chicken leg)

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7.1 – “Insert Cytocoin to Continue”: Interferon α, IFN-β, IFN-γ • Interferons are host cytokines than produce antiviral, immunomodulating, & antiproliferative effects. Released by infected cells → intracellular signals activating immune response (virus infected manager is spreading cyto-coins). Upregulation of INF synthesis in infected cells accomplished by interleukins (Luke enabling activating kiddos). • Clinical uses of IFN-α (pachyderm man) o Interferon α treats hep B & C infections (hippo). Given as injections. Pegylated INF allows longer half-life and steadier concentrations, requiring less frequent dosing. o Approved for treatment of many neoplasms ▪ Hairy cell leukemia (hairy creatures) ▪ Malignant melanoma (melatonin ghost) ▪ Kaposi’s sarcoma by HHV-8 (Kate’s posies on cabinet and in maze) ▪ Renal cell carcinoma (crab in kidney shaped claw machine) o Condyloma acuminatum caused by HPV (pill bug jar) o Has many adverse effects (why we want new Hep C treatments!) ▪ Flu like syndrome with headaches, fevers, malaise, myalgias within 6h after dosing (fevered kid). In as much as 30% of patients after initiating therapy. Generally resolves. ▪ Neuropsychiatric complications with chronic treatment, including tinnitus, retinopathy, confusion, psych disturbances, profound fatigue (sick kid) • Depression resulting from INFα treatment can be profound and may include suicidal ideation. Contraindicated in severely depressed or suicidal patients. ▪ Pneumonitis, interstitial fibrosis ▪ Myelosuppression (maze is bone-shaped and red cell dots are being eaten). Important to consider when giving other myelosuppressive agents. ▪ Metabolic complications, including thyroid dysfunction, low-grade fever ▪ Dermatologic complications, e.g. alopecia ▪ Rarely, drug induced lupus (plush wolf in claw machine) • Interferon β (β Invaders) o Approved for use in relapsing type MS (“Combat lesions though Time & Space”) • Interferon γ (Gammaga game) o Treats CGD. May activate macrophage otherwise unable to form oxygen species needed for oxidative burst (bursting asteroids)

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7.2 – “Dr Liver-stone, I presume?”: Hep-C treatment (Ribavirin, sofosbuvir, simeprevir) • Hep C can cause acute and chronic hepatitis. Acute infection is often self-limited and commonly causes chronic infection. Decision of treatment regimen, dosing, and duration of therapy depends on stage & state of infection as well as infecting genotype (sketch of yellow hippo with genotype? highlighted). Fibrosis stage usually assessed as well, usually by history and exam; biopsy is not necessarily standard of care (stony “fibrosed” liver under microscope). • Treatment causes ↓M&M and improved quality of life in all patients with virologic evidence of chronic HCV infection (photographic evidence on board). Standard of care is to treat all HCV⊕ patients except those with limited life expectancy. Goal of treatment is the eradication of viral RNA which is predicted by a sustained virologic response (i.e. HCV RNA not detected by PCR for 6 months after stopping treatment) (6 mos. sustained search for Sea Hippo). Achieving SVR means 99% change of sustained seronegativity on long term follow-up. • Treatment: Once weekly pegylated-IFN-α (α-antenna) + daily oral ribavirin (ribs) is traditional therapy. Several newer therapies with fewer adverse effects are available. • Ribavirin o Given oral daily as part of combination therapy along with pegylated-IFN-α o Guanosine nucleoside analog (purine shaped stakes). Needs Ⓟ by intracellular enzymes into active nucleotide form (3 pepper shakers) o Inhibits RNA production (RNA ropes) o Also used in RSV (though has largely been replaced with palivizumab) (RSV tombstone) o Adverse effects ▪ Dose dependent hemolytic anemia (tomatoes) ▪ Teratogenic – category X (enormous tarantula). Not to be used in M or F of childbearing age not on birth control. • Polymerase inhibitors: sofosbuvir (sofa with nucleoside pattern) o Nucleoside analog that inhibits the NS5B RNA-dependent RNApol inpatients infected by genotypes 1,2,3,4 (nucleotide pattern on sofa). o Direct polymerase inhibitor that disrupts RNA production (disrupted ssRNA rope) o May be part of a regimen with ribavirin, IFN-α, or the newer ones that are all oral; latter regimens highly effective & welltolerated, without interferon toxicities. o Adverse effects (tired Dr Livingstone) ▪ Fatigue ▪ Nausea • Protease inhibitors (NS3/4A inhibitors) (machete) o Simeprevir (and other protease inhibitors) work with HCV genotype 1 (simmering food over the fire). o Cleave HCV-encoded polyproteins o Adverse effects ▪ Photosensitivity & rash (flashing camera) ▪ Substrate & inhibitor of CYP450 system (broken down truck in the background) • New investigational drugs (North Sea investigative map) o 2nd gen NS3/NS4A protease inhibitors o NS5A inhibitors o None require ribavirin & INF administration

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8.1 – “You are Now Free to move about the Ganglia”: Acyclovir, valacyclovir, famciclovir, cidofovir, foscarnet • Oral purine nucleoside analogs used for HSV (Hermes for herpes) & VZV (Zeus) infections • Acyclovir, valacyclovir, famciclovir all treat HSV. Short course of 7-10 d Tx with primary oral, genital, HSV infection → ↓viral shedding, time for lesion healing, and ↓local pain. Does not affect recurrence rates. o Can offer in recurrence daily to take any of the medications daily. Valacyclovir preferred as it is dosed qid & has superior bioavailability (“valet parking for frequent flyers” & “Daily rate” signs; attendant popping pills over “↑available↑” sign) o Can also be used as HSV prophylaxis in immunocompromised patients (lady with cane) ▪ In pregnancy with active recurrent genital herpes, give suppressant acyclovir at 36w to reduce risk of C-section & active shedding (pregnant lady) ▪ Transplant patients (organs on ice) • Acyclovir (recycling bins) o G-purine nucleoside analog that gets Ⓟ via herpesvirus encoded thymidine kinas → acyclovir monophosphate; occurs selectively in virus-infected cells (guanosine nucleoside shaped Gucci luggage labeled with Ⓟ luggage tag by Hermes attendant). This is the rate-determining activation step (“Rate limit”) (also the point where bugs can develop resistance). Subsequent Ⓟ steps taken over by cellular kinases (blue-collar workers slapping on 2nd & 3rd). Triphosphate can compete with deoxy-guanosine triphosphate. When incorporated, halts viral DNA synthesis via DNA-dependent DNA polymerase (bags jamming DNA-shaped conveyor belt) o Absence of thymidine kinase confers resistance (absence of attendant at closed baggage check) o Effective against herpes zoster (shingles is reactivated VZV) o Only drug here that is available for IV use in US (ivy). ▪ Treatment of serious HSV & VZV infection, including HSV encephalitis (helmet wings), neonate HSV infection (baby). • Valacyclovir o Acyclovir prodrug with better oral bioavailability (oral eating; ↑available) o Effective against herpes zoster (Zeus sign). Superior activity and less frequent dosing. ▪ Hasten resolution of cutaneous lesions & acute neuritis. ▪ Unknown effect on post-herpetic neuralgia. ▪ Valacyclovir & famciclovir are most effective when administered within 3d of symptom onset (“Great Value: 3-Day family vacation”) • Famciclovir o Effective against herpes zoster (“3-Day family vacation”) • Cidofovir (Cid the security guard) o Does not require viral kinase Ⓟ so effective against acyclovir or ganciclovir resistant HSV, VZV, CMV (Cid the security officer has Ⓟ tags so can bypass the closed luggage counter). This is especially important in immunocompromised patients, as thymidine resistant strains of VZV are found almost exclusively in immunocompromised populations o Directly inhibits viral DNApol (security officer directly turning off conveyor belts). • Foscarnet (car with a net) o Does not require Ⓟ by viral kinase (cart bypassing closed checkpoint). Active against acyclovir or ganciclovir resistant HSV, VZV, CMV. o Directly inhibits viral DNApol; pyrophosphate analog that selectively inhibits the pyrophosphate binding site on viral DNApols (security officer directly turning off conveyor belts). • Adverse effects o IV acyclovir can cause interstitial nephritis or crystalline nephropathy (sharp crystalline objects causing tubular obstruction in kidney shaped can). Uncommon with slower infusion rate & sufficient hydration (tossing water bottles) o All can cause CNS effects (delirium confusion, vertigo, hallucinations). Especially with high dose a/o IV administration (shaky kid setting off alarm in detector)

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8.2 – “Clean up on Aisle HHV-5”: CMV treatment (Ganciclovir, valganciclovir, cidofovir, foscarnet, probenecid) • CMV infection (Mega-lo Market) occurs predominantly in immunocompromised, notably HIV (CD4 < 50) (“50 items or less” – should be “fewer”) & organ transplant (organ counter). Classically presents with CMV retinitis with retinal hemorrhages and infiltrates (pizza box). • Shared adverse effects o Associated with bone marrow suppression (bone marrow tray). Usually managed with hematopoietic growth factor s. Should be monitored for hematologic suppression. Effects may be additive with other myelosuppressive agents, especially with Zidovudine (pregnant princess eating bone marrow). • Ganciclovir (cans only recycle bins) o Guanosine analog, like acyclovir. Has to be tri-phosphorylated, before incorporating into viral DNA & jamming DNApol (jammed DNA conveyor belt). ▪ First Ⓟ step converts to ganciclovir monophosphate with a virus encoded kinase (UL97) which enables CMV-infected cell specificity (Market employee labeling Ⓟ for virus encoded . ▪ Following steps done by cellular kinases (kids going crazy with label guns) ▪ Protein kinase mutations can cause resistance o Incorporation stops DNA synthesis • Valganciclovir (great value samples) o Prodrug of ganciclovir with increased oral bioavailability (lady with open mouth) o As effective as IV ganciclovir for CMV retinitis o Used for prophylaxis in bone marrow & organ transplant (organs on ice) o Same MOA as ganciclovir • Foscarnet (fast car with a net) o Does not require Ⓟ by viral kinase. Active against acyclovir or ganciclovir resistant HSV, VZV, CMV. o Directly inhibits viral DNApol (kid crashing into register); pyrophosphate analog that directly selectively inhibits the pyrophosphate binding site on viral DNApols (bypassing phosphorylating CMV worker) o Available IV o Adverse effects ▪ May induce renal insufficiency. Appears to be directly toxic to renal tubular cells (spilled kidney beans) ▪ Hypocalcemia (broken milk bottles) ▪ Hypomagnesemia (falling magnets) ▪ Hypokalemia (banana peels) ▪ Seizures may result from electrolyte disturbances (shaky lines) • Cidofovir (Cid the security guard) o Does not require viral kinase Ⓟ so effective against acyclovir or ganciclovir resistant HSV, VZV, CMV (Cid the security officer has Ⓟ tags). This is especially important in immunocompromised patients, as thymidine resistant strains of VZV are found almost exclusively in immunocompromised populations o Directly inhibits viral DNApol (directly stopping DNA belt shut off switch) o Adverse effects ▪ Nephrotoxic, → proteinuria, azotemia, metabolic acidosis (broken kidney-shaped bottles) ▪ Must be coadministered with probenecid (probation officer Cid); blocks tubular secretion of cidofovir, limiting renal toxicity (probation offer protecting). Also blocks excretion and increases plasma concentration of many different drugs, including penicillins, MTX, & NSAIDS (druggie cashier not touching kidney bottles).

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Antineoplastic Drugs 1. Antimetabolites 2. DNA & Cellular division 3. Kinase inhibitors, monoclonal antibodies 1.1 – “Imitation folate”: methotrexate, leucovorin, 5-Fluorouracil, hydroxyurea CA can be treated with targeted radiotherapy, excision (local therapy) or systemic administration of cytotoxic drugs to eradicate or control proliferative cells, but affect systemic as well. CA cells produces larger amounts of DNA/RNA per unit time than most healthy cells, so affecting these pathways is highly attractive. • These agents affect thymidine synthesis, particularly those affecting folate cycle. • Thymidine is a pyrimidine deoxynucleotide (hexagonal plates), synthesized by thymidylate synthetase – methylates dUMP → dTMP (dUMP dumplings → single dumpling with T-shaped chopsticks). Process powered by folate cycle: o Methylated THF (4 leaves + C-shaped sushi) converted to DHF (removing C-shaped sushi & knocking off 2 leaves). Catalyzed thymidylate synthetase. o DHF converted back to THF by DHFR (adding back 2 leaves). THF is then methylated (adding back C-shaped sushi). • Thymidine is only found in DNA. Ribonucleotides are synthesized first. So precursor to both thymidine & uracil is UDP (U Dining in? Please sign in!). Ribonucleotide reductase converts UDP → deoxy-UDP, which is precursor molecule (wait list waitress crossing out oxy). Antimetabolites • Methotrexate (MTX) (meat stix) o Folate analog competitively & irreversibly binds to DHFR, preventing THF renewal (meat stick chef has blocked leaf boats) → Buildup of folate & DHF (boat jam). Results in blocking de novo synthesis of DNA, RNA, and key cellular proteins. o Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) o Indications ▪ Treats a range of malignancies including leukemias, lymphomas, breast cancer, head & neck cancer, lung CA (cracked cancer crab) ▪ Treats non-neoplastic conditions with abnormal cellular proliferation • MTX + misoprostol as abortifacient (uterus-shaped backpack). Used for non-surgical treatment of early, unruptured ectopic pregnancy (baby keychain outside of uterus). Gestational trophoblastic neoplasia (choriocarcinoma, trophoblastic tumors, invasive molar pregnancy) – most can be treated with short course of MTX (mole for molar pregnancy) • Chronic inflammatory conditions, d/t immunosuppressive effects (torn antibody lantern) o Disease modifying anti-rheumatic drug (DMARDs). Effects take a few weeks (joint lantern with inflammatory candle). May manage with glucocorticoids, NSAIDs for short term SSx relief o Psoriasis (hyperproliferation of epidermis), as well as arthritis & nail disease (potentially d/t immunosuppressive effects) (silvery scaled kneepads) o Other inflammatory conditions, including IBD, SLE, Vasculitides, dermatomyositis o Adverse effects ▪ Folate deficiency (falling foliage) ▪ Megaloblastic (macrocytic) anemia d/t folate deficiency (blasting lanterns) ▪ Myelosuppression is the dose-limiting effect in high dosing needed for chemo. Causes immunosuppression (empty bone serving tray; immunocompromised cane) ▪ Pulmonary fibrosis (restrictive pattern) (restricted growth of lung-shaped bonsai tree) ▪ Hepatotoxicity, likely d/t direct cell damage (liver stain on apron). Monitor LFTs. ▪ Alopecia (bald chef) ▪ Stomatitis (burning mouth with hot meat) o Leucovorin rescue (folinic acid) can be used to reverse or prevent the worst of the adverse effects (maneki-neko, i.e.. lucky feline). Does not require DHFR for activation; displaced MTX from binding sites, restoring normal folate levels. • 5-fluorouracil (5-FU) (full guy waving 5 fingers)

131 o Pyrimidine analog (hexagonal plates). Inhibits thymidylate synthase (guy blocking transfer of C-shaped sushi). Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) o Metabolized to active form, 5-dUMP. Forms complex with thymidylate synthase & DHF. Results in buildup of dUMP (dumpling buildup) o Indications ▪ CRC, breast, head & neck, liver, pancreas CA (cracked cancer crab) ▪ Topically for basal cell carcinoma o Adverse effects ▪ Diarrhea d/t damage of intestinal epithelium (patron with messy pants) ▪ Cutaneous complications • Photosensitivity (camera flash) • Hyperpigmentation • Number of other rashes ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane) ▪ No leucovorin rescue here! (falling feline) • Hydroxyurea (hydro-rock area) o Inhibits Ribonucleotide reductase (inhibited wait list waitress). Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) o Indications ▪ AML, CML, head & neck CA ▪ Sickle cell anemia, d/t ↑production of HbF (sickle by Zen garden; raising baby with Hb coin up) o Adverse effects ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane) ▪ GI upset

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1.2 – “Hunchback of Notre DNA”: Azathioprine, 6-MP, mycophenolate mofetil • nucleosides consist of nitrogenous base, ribose, phosphate groups. Purine synthesis begins with phosphoribosyl pyrophosphate (PRPP) (synthesis continues! Pentagon pedestal being built with 3 P-shaped hammers). Metabolized to inosine monophosphate (IMP) (gargoyle imp), which is metabolized to AMP and GMP by separate pathways (gold gramps & grump statues respectively with purine haloes; “Pure As Gold”) Purine analogs • Azathioprine (AZA) & 6-mercaptopurine (6-MP) (Aza-merelda with purine earrings; captured gypsy) o AZA is converted to 6-MP, which must be activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) (high priest activated captive). Blocks synthesis of IMP (knocking over gargoyle imp) → halting DNA & RNA synthesis o Cell cycle specific for S-phase (dilapidated stairs) o Indications ▪ Hematologic malignancy (cracked cancer crab, antibody archers, and T-cell knights in rose window) ▪ Chronic inflammatory conditions, d/t immunosuppressive effects (torn antibody lantern). Include treatment of graft rejection, SLE, autoimmune hemolytic anemia, inflammatory myopathies, IBD (inflamed colonic haustra lanterns) ▪ Disease modifying anti-rheumatic drug (DMARDs) (joint lantern with inflammatory candle). Not as effective as MTX; usually used in refractory disease. o Adverse effects ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane on statue) ▪ Pancreatitis (pancreas sponge) ▪ Hepatotoxicity (both direct and d/t reactivation of latent infectious hepatitis) (liver spots) ▪ Inhibition of XO → increased 6-MP levels. Risk of adverse effects hugely increased with allopurinol or febustate coadministration (allopurinol nuns with purine beads) • Mycophenolate mofetil (Quasi-mofetil) o IMP dehydrogenase inhibitor, blocking GMP synthesis (knocking over grump statue) o Powerful anti-lymphoproliferative drug. Used in a variety of inflammatory and lymphoproliferative disorders (torn antibody lantern) o Adverse effects ▪ GI distress is common (queasy Quasimodo) ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane on statue)

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1.3 – “Neolithic antineoplastics”: cladribine, cytarabine, gemcitabine • All are phosphorylated to triphosphate form, which can incorporate into DNA → breaks or blockage of synthesis & repair by blocking DNApol-α & DNApol-β (cracked replication fork demonstrating gene flow out of Africa; cracked glass). Cell cycle specific for S-phase (Stone phase) • All share the same limiting toxicity: Myelosuppression & pancytopenia → immunosuppression (broken bone spilling marrow; immunocompromised cane) • Cladribine (clad in bearskins) o Cytotoxic purine analog (purine-shaped club) o Resistant to adenosine deaminase → ↑↑ intracellular levels. o Indications ▪ Hairy cell leukemia (hairy caveman) ▪ CLL, NHL • Cytarabine (saber-toothed tiger) o Cytotoxic pyrimidine analog (hexagonal patterned fur) o Only active against hematologic malignancies, e.g. AML, non-Hodgkin lymphoma (scratched out antibody archers, crab, & Tcell swordsman) • Gemcitabine (gems inside geode) o Cytotoxic pyrimidine analog (hexagonal patterned fur) o Active against both hematologic malignancies and solid tumors (tumorous rocks, with crab not scratched out)

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2.1 – “Alkylating Odyssey”: Cyclophosphamide, Ifosfamide, Busulfan, Nitrosoureas • Recall that an alkyl group is a molecular group with the formula -CnH2n+1. Alkylating agents add an alkyl group to nucleotide bases, most commonly to the guanine N7. This leads to the cross-linking of DNA strands, which causes DNA damage, interferes with DNA replication, and ultimately results in apoptosis. • Alkylating agents can act any point during the cell cycle. • Cyclophosphamide o The most commonly used alkylating agent (Cyclops Polyphemus). Like all of the alkylating agents, cross-links DNA (ankle chains). Once activated, forms a nitrogen mustard (similar to mustard gas). o Related agents are ifosfamide, melphalan, chlorambucil, mechlorethamine. o Activated by CYP450 in the liver (chariot with the CYP450 tag plate). o Indications ▪ variety of different cancers, both hematologic & solid tumors (sail torn through the image of a crab). ▪ Uniquely among the alkylating agents, used for autoimmune conditions (red lanterns look like immunoglobulins and are closer to the Cyclops than any of the other pharm avatars). o Toxicities ▪ Myelosuppression (bone club) ▪ An alternative metabolism pathway results in the toxic metabolite acrolein, responsible for several of the adverse effects of this drug ▪ Hemorrhagic cystitis caused by acrolein (red Greco-Roman fountain). Can preventatively administer mesna (“Maze”-na), the sulfhydryl group of which will bind acrolein and prevent the damage. ▪ ↑risk of bladder cancer (gold crab at the level of the bladder) ▪ SIADH & consequent hyponatremia (ADH bucket on cyclops head). Resultant encephalopathy in 10-30% of patients if not controlled. Worsened with hyperhydration during chemo, for unknown reasons. ▪ Infertility (M & F) & premature menopause (F) (dried up ovarian tree) ▪ Ifosfamide: Fanconi syndrome • Busulfan o Used for bone marrow ablation to prepare for BM transplant (beautiful sirens surrounded by cracked bones with bloody marrow exposed). Does not require bioactivation. o Toxicities ▪ Nigh universal severe myelosuppression (hence use as ablative) ▪ Lung toxicity, including acute ling injury, interstitial fibrosis, alveolar hemorrhage (sirens wearing golden chest plates with lung outlines) ▪ Hyperpigmentation – “busulfan tan” (dark-skinned sirens) • Nitrosoureas o include Carmustine, Lomustine, Streptozocin (mustang centaurs – sounds like -mustine; zebra striped centaur for streptozotocin). o Cross BBB, enabling treatment of CNS tumors including glioblastoma multiforme. o Toxicities ▪ CNS toxicities, including convulsions, dizziness, ataxia (centaur stumbling around clutching head) ▪ Myelosuppression ▪ Rarely, pulmonary fibrosis

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2.2 – “Breakfast at Cisplatin’s”: Cisplatin, carboplatin, amifostine • Platinum-containing cancer chemo drugs include cisplatin, carboplatin, and oxaliplatin. All act by cross-linking DNA, similar to alkylating agents (double-helix chains with crossed links). Used to treat a variety of cancers, including solid tumors and hematologic malignancies (crumpled bag with a crab on it). • Toxicities: • Ototoxicity (gong-shaped earrings) results from targeting of outer hair cells in the Organ of Corti, causing a high frequency sensorineural hearing loss with tinnitus. Dose dependent. Cisplatin is notorious for this, although can also occur with high-dose carboplatin • Peripheral neuropathy in a stocking glove pattern (black arm gloves). Subacute neuropathy characterized by paresthesias and loss of sensation. Cisplatin > oxaliplatin >> carboplatin. • Nephrotoxicity & AKI, particularly with cisplatin (kidney shaped purse on Golightly’s flank). Can also cause acute tubular necrosis with muddy brown casts (muddy drainpipe). Two ways to prevent ATN o Amifostine, an organic thiophosphate, scavenges free radicals from cisplatin in the kidney (“Free Amethyst” sign over the visual of amethysts in a kidney-shaped purse) o Alternatively, IV saline diuresis (essentially induced polyuria) will flush toxic metabolites out of kidneys (cleaning the window with what appears to be a salt spray). • Myelosuppression, especially with cisplatin, and resulting immunosuppression (bone shaped box that has been depleted of its wares next to older woman with immunocompromised cane)

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2.3 – “Doxorubicin’s Locker”: Bleomycin, anthracyclines, doxorubicin • Certain antibiotics have anti-tumor activity so are used on cancer treatment (cancer crab). • Bleomycin o Uses iron & oxygen to induce free-radical formation → breaks in the DNA strands (bleomycin beluga is holding a rust-colored crab and breathing out bubbles which are breaking the double helix of kelp). Acts primarily during G2 phase (Galleon). o Used to treat testicular cancer & Hodgkin’s lymphoma. o Adverse effects ▪ Inactivated in the body by bleomycin hydroxylase. Tissues with lower production of this enzyme, notably lungs and skin, have more toxic effects. ▪ Pulmonary fibrosis, pneumonitis, pulmonary infiltrates (lung-shaped coral) ▪ Skin hyperpigmentation, classically in a striated pattern termed “flagellate erythema” (hyperpigmented stripes on beluga) ▪ GI adverse effects (sea urchin being eaten in the background) ▪ Myelosuppression, although less so than some other anti-cancer agents (bone shaped chest is sitting empty and has been cleaned out of treasure) ▪ Alopecia (whales are pretty bald) • Anthracyclines o Most commonly used doxorubicin & daunorubicin; less commonly, idarubicin, epirubicin, & mitoxantrone (Santa Anthracycline was apparently a pirate ship; chests of rubies remind of the -rubicin suffix). o Several mechanisms interfere with cancer growth: ▪ 1) generate free radicals in the presence of NADPH, oxygen, and iron (bubbles rising from the treasure chest). ▪ 2) Intercalate into DNA, causing breaks in the DNA, inhibiting with replication and transcription (rubies have become incorporated into the double-helices of the kelp near the chest). ▪ 3) Interfere with the action of topoisomerase II, preventing repair of DNA. Used in the treatment of both solid tumors and hematologic malignancies. o Toxicities: ▪ Cardiotoxicity, most often a dilated cardiomyopathy → SHF with ↓LVEF (this is rarely seen at low doses) (dilated heartshaped sacks sit next to the ruby chest). • Prevented with dexrazoxane, an iron chelating agent (skeleton on deck is holding a non-dilated heart sack, waving a rusted iron razor; “deck razor” sounds a bit like dexrazoxane) ▪ Myelosuppression (empty bone-shaped chest sits on the deck of the ship) ▪ Alopecia (skeletons don’t have hair) ▪ Mucositis and stomatitis • Actinomycin D/dactinomycin o Intercalates in DNA, blocking RNA synthesis (artifacts from the ship have intercalated into the kelp helices). o Often used to treat pediatric malignancies, including Wilms tumor, Ewing’s sarcoma, rhabdomyosarcoma (the child-sized doll is sitting off to one side). o Toxicities are the usual: myelosuppression & alopecia (creepy bald doll).

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2.4 – “Untangled”: Topoisomerase inhibitors • Topoisomerase enzymes relieve the tension in DNA supercoils by nicking and re-ligating the DNA. Topoisomerase I nicks ssDNA and is involved in the process of DNA unwinding during replication, while topoisomerase II breaks and re-ligates dsDNA breaks. The topoisomerase inhibitors interfere with one of these steps and are used in cancer treatment (crab flag). • Inhibitors all specific to S-phase of the cell cycle, preventing movement to G2 (Rapunzel cannot descend the Stairs because they are broken and the witch is Gone 2 the forest). • Etoposide & teniposide o inhibit topoisomerase II →↑DNA degradation. (Rapunzel is climbing down the side of the tower on two-strand twists; but both strands have broken!) o Used in treatment of solid tumors, particular testicular and small cell lung cancer, as well as leukemias & lymphomas. o Toxicities: ▪ Myelosuppression and consequent immunosuppression (empty bone-shaped luggage. Witch with immunocompromised cane) ▪ Alopecia (Rapunzel is losing a lot of hair) • Topotecan and irinotecan o topoisomerase I inhibitors (man’s toucan sounds like -tecan. Man has a single-stranded ponytail rather than a double-stranded twist). o Used to treat ovarian and small cell lung cancers; irinotecan is used in colon cancer. o Toxicities ▪ Myelosuppression ▪ Severe and profuse diarrhea, some days after initiating treatment, d/t cell toxicity in GI tract (bird pooping). Can be so severe as to cause volume depletion.

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2.5 – “Me taxane, You Christine”: Microtubule inhibitors • The taxols and the vinca alkaloids are all plant derived (yew and Vinca rosea, or periwinkle, respectively) and used in the treatment of cancer (forest setting; crab dinner). • Vinca alkaloids o bind β-tubulin, inhibiting polymerization into microtubules (woman – Cristine – is caught up in vines that look like metaphase spindles; the vines are breaking). This prevents mitotic spindle formation and results in M-phase arrest (monkey is swinging on vine, forming M shape). o Vincristine ▪ treats ALL, multiple myeloma, Hodgkin & non-Hodgkin lymphoma, and some pediatric tumors (Cristine). ▪ Toxicities: • Neurotoxicity, presenting with areflexia, peripheral neuritis and sensory neuropathy in a stocking glove pattern (Cristine is wearing stockings and gloves). Results d/t inhibition of axonal transport in the nerves. • Constipation and paralytic ileus (monkey with a plunger sitting on the outhouse) • Alopecia (bald monkey) o Vinblastine ▪ treat lymphomas and solid tumors (hunter blasting away with his gun). ▪ Toxicities • Myelosuppression (bones at the hunter’s feet). Note that this is not a side effect of vincristine. • Alopecia • Taxanes o hyper-stabilize β-tubulin in polymerized microtubules, arresting cells at the metaphase/anaphase transition (Tarzan is stabilized by a monkey holding his vine). o Used in breast and ovarian carcinomas, other solid tumors, small cell & non-small cell lung carcinomas. Are also a component of drug-eluting stents to prevent neointimal hyperplasia. o Toxicities: ▪ Hypersensitivity reactions are extremely common, in as many as 30% of patients. Can treat prophylactically with steroids, antihistamines. ▪ Alopecia ▪ Neurotoxicity, often presenting with burning paresthesias on extremities (Tarzan is holding Cristine’s glove) ▪ myelosuppression

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3.1 – “Revolutionary Kinase inhibitors”: imatinib, erlotinib, sorafenib, sunitinib, vemurafenib • Many cancers arise from kinase mutations → constitutive activation of proliferation signals, making these mutated kinases desirable targets for cancer therapy. • Many of the small molecule kinase inhibitors end in -nib (broken pen nib). Used to treat a variety of hematologic & solid malignancies (cracked crab bell). Tyrosine kinase inhibitors (inhibited tire swing) • End in -tinib • Imatinib (imitating portrait of King George III) o Indications ▪ CML, characterized by increased levels of mature granulocytes, including eosinophils, neutrophils, basophils (colorful granules). Inhibits BCR-ABL fusion protein (“breakable” label) • BCR-ABL fusion protein results from t(9;22) – aka Philadelphia chromosome (hence the setting). The protein stimulates granulocytic precursors →CML. ▪ Blocks c-kit, found in GI stroma tumors (Congress Kit held by guy with beer belly & crab buttons) o Adverse effects ▪ Fluid retention → ankle & periorbital edema (king impersonator with baggy pantaloons) • Erlotinib (Earl of Tinib) o Blocks EGFR (Earl Geoffrey) ▪ Activation of EGFR → uncontrolled cell growth, metastasis, proliferation, angiogenesis. overexpressed in several solid tumors including non-small cell lung CA, pancreatic CA (crab on lung shaped lapel) o Adverse events ▪ Cutaneous involvement common, d/t EGFR expression in the skin. Classically papulopustular acneiform rash (Earl’s spotty rash) ▪ Diarrhea (muddy pants). Not usually severe. • Sunitinib (rising sun), Sorafenib (soaring eagle) o Inhibit multiple Y-kinases, including VEGF receptors – angiogenic growth factor . Result in blocking vasculogenesis needed for primary & metastatic tumors (hoeing up vegetables) o Indications: ▪ Sorafenib: RCC (flank crab suspender buckles), HCC ▪ Sunitinib: RCC (flank crab suspender buckles), GIST o Adverse effects ▪ Cutaneous effects including hyperkeratosis & rashes (farmer’s hyperkeratotic callouses & sunburn) ▪ ↑risk of hemorrhage, d/t disruption of VEGF-R on the vascular endothelium (farmer bleeding) • Vemurafenib (venomous snake) o -rafinib for B-Raf inhibit (B. FRA signature inhibited by broken nib). ▪ BRAF is a protein kinase involved in activation of melanocyte proliferation. V600E (valine → glutamic acid) seen in 4060% of patients with melanoma – hence vemu- for V→E mutated BRAF inhibitor. o Treats V600E BRAF positive malignant melanoma (disseminated ink). Improved survival & long-term events

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3.2 – “The MAB who would be king”: Rituximab, cetuximab, bevacizumab, alemtuzumab, trastuzumab • Antibodies used in treatment of B-cell lines, created by a single cell line, hence monoclonal Ab. -mab = monoclonal Ab; -ximab = chimeric Ab – human derived + mouse derived variable region; -zumab = humanized Ab. • Rituximab (coronation ritual) o Chimeric Ab targeting CD20 (chimera sigil; XX straps). Results in in depleting B-cells and increases cellular killing via targeting for killing. o Indications ▪ CD20 ⊕ hon-Hodgkin lymphomas ▪ CLL (abnormal proliferation of abnormal B-cells & T-cells) (chronically worn tapestry with B-cell archers & T-cell knights) ▪ Disease modifying anti-rheumatic drug (DMARDs) (joint lantern with inflammatory candle). Usually in combination with MTX for treatment-resistant RA. ▪ Immunosuppressive therapy, including for granulomatosis with polyangiitis, microscopic polyangiitis (torn Ab lantern) o Adverse effects ▪ Immunosuppression (bishop’s cane). Not as much as one might expect, as Ig levels generally stay fairly normal. May see immunosuppression d/t neutropenia ▪ Hep B reactivation ▪ Rarely associated with progressive multifocal leukoencephalopathy, from the JC virus (laurel leaves) ▪ Infusion reaction common in 50% of patient. Presents headache, fever, rash, puritis, dyspnea, hypotension (swollen pink cherub with ivy). Thought to be d/t Ag-Ab interaction → activation of immune cells • Managed with antihistamines, acetaminophen, NSAIDS ▪ Serum sickness – type III HS reaction, resulting from tissue deposition of circulating immune complexes, causing fever, rash, arthralgia, proteinuria, LAD within 7-10 days (Delayed onset poisoning) • Occurs d/t targeting of non-human Ab components • Cetuximab (elephant tusks) o Binds EGFR (giraffe). EGFR acts via a tyrosine kinase. o Adverse effects ▪ Infusion reaction common in 50% of patients e.g. headache, fever, rash, puritis, dyspnea, hypotension (swollen pink cherub with ivy). Thought to be d/t Ag-Ab interaction → activation of immune cells • Managed with antihistamines, acetaminophen, NSAIDS ▪ Serum sickness – type III HS reaction, resulting from tissue deposition of circulating immune complexes, causing fever, rash, arthralgia, proteinuria, LAD within 7-10 days (Delayed onset poisoning) • Less common than in rituximab • Bevacizumab (beverage lady) o VEGF inhibitor by binding directly to VEGF (chopped vegetables). Anti-angiogenic (chopped vascular vegetables) o Useful for treating certain metastatic cancers (Cracked crabs) o Used for wet macular degeneration, characterized by retinal hypoxia → subretinal VEGF production → angiogenesis (pillow with macular wet spot) o Adverse effects ▪ Bleeding, sometimes serious and even fatal (bloody aprons) ▪ ↑thromboembolic events (clot cubes) ▪ GI perforation (perforated sack of vegetables). Most commonly in metastatic CRC, epithelial ovarian CA. • Alemtuzumab (Alms) o IgG monoclonal Ab that binds CD52 found on normal & malignant cells of lymphoid lineage (natural killer cells, B & T cells). Initiates direct cytotoxicity by recruitment of complement. (Alms-seeker is begging from archer and knight; 52 design etched on knight’s scabbard) o Used in treatment of CLL (chronically worn tapestry with B-cell archers & T-cell knights) o Adverse events ▪ Marrow suppression, increased risk of AI disorders, infection risk • Trastuzumab (tapestry weaver) o Monoclonal antibody against HER2/neu ⊕, a Y-kinase (tire swing with her 2 babies). Inhibits MAPK & PI3K/AKT signaling pathways, & facilitates antibody mediated destruction tumor cells. ▪ HER2 ⊕ seen in 20% of breast CA (crab bra), as well as adenocarcinomas of the ovary, lungs, stomach, salivary glands. o Adverse effects

141 ▪ Cardiotoxicity (unraveling heart tapestry). Presents most often as ↓LVEF, less commonly as HF. Generally resolves with cessation of treatment.