Circulatory (CV & Renal)

Circulatory (CV & Renal) 1. Heart Failure 2. Diuretics 3. Anti-hypertens Anti-hypertensives ives 4. Antiarrhythmi Antiarrhythmics cs 1.1 – “Pretty in Yellow”: Digoxin, milrinone, nesirit nesiritide ide • 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. ▪ 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). 1.2 – “The H House ouse Always Wins”: ACE-i -inhibitors, nhibitors, ARB ARBs, s, aliskiren RAAS (Ren (Renin-angiotens in-angiotens in-angiotensin-aldostero in-aldostero in-aldosterone ne 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). ▪ 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) 2.1 – “Pro Cart Track”: Acet Acetazolamide, azolamide, ma mannitol nnitol Proximal con convoluted voluted tubule (PCT) pphysiology hysiology • 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) 2.2 – “Loop “Loop--de de--loop of Henle”: Loop Diuretic Diureticss (furosemide, ethacryn ethacrynic ic 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 He Henle nle 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 diuret diuretics ics • 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”). 2.3 – “Distal C Convoluted onvoluted Tube Slide”: Thiazi Thiazide de diuretics Distal convol convoluted uted tubule ((DCT) 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 ddiuretics iuretics • 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) 2.4 – “Salty Mineral Food Court”: Potassium Spari Sparing ng Diuret Diuretics ics (am (amiloride, iloride, triamterene, ep eplerenone, lerenone, spironolactone) Collecting duct ((CD) CD) phys physiology iology • 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 PotassiumPotassium-sparing sparing diuret diuretics ics • 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. 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) 3.1 – “We A All ll 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 (primary y 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”: Class I (A, B, C) Antiarrhythmics – Na Na-channel -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 bblockers 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)