Circulatory (CV and Renal) Part 2

3.1 – “We A Allll Scream for Calci Calci--YU YUM!” M!” 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) Dihydropyridin Dihydropyridines es (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-dihydrop Non-dihydropyridines yridines (non (non-dairy) -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 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) 3.2 – “High Te Tension nsion on the High Seas”: Primary HTN & Hypert Hypertensive ensive crisis • Antihypertensives (high pressure pipes) Primary (es (essential) sential) HTN (primar (primaryy 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 emerg emergency ency (sinking shi ship) p) • 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) 4.1 – “Soloi “Soloist st at the Heartbreak Hotel”: Cl Class ass I (A, B, C) Antiarrhyth Antiarrhythmics mics – Na-channel blockers Physiology of ar arrhythmias rhythmias • 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 ant antiarrhythmics iarrhythmics (solo (solo-singer). -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. 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) 4.2 – “β Bras Brasss Quartet”: Class II Antiarrhythmics - β Physiology of SA SA/AV /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 Beta jazz clu club b with Louis Heartstrong & Beta Fitzger Fitzgerald; ald; 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) 4.3 – “Tre “Tress Amigos”: Class III Antiarrhythmic Antiarrhythmicss – K+ channel b blockers lockers • 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) 4.4 – “Calc “Calcii-YUM quartet”: Clas Classs IV antiarrhythm antiarrhythmics ics • 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). 4.5 – “DJ Fox Foxglove glove Discotheque Discotheque”: ”: Class V ant antiarrhythmics iarrhythmics (ba (basically sically everyt everything hing 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)