Circulatory (CV and 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-de-loop loop of Henle”: Loop Di Diuretics uretics (furosemide, et ethacrynic hacrynic ac acid) id) • 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)