CVPR 03-28-14 11am-Noon Diuretics-RAAS Antagonists - French Flashcards
Diuretics – when to use
Often used 1st to reverse Na/water retention & relieve signs of symptoms of volume overload (dyspnea & peripheral edema); May be used chronically or acutely
Preferred type of diuretic
Loop diuretics preferred b/c of efficacy, but can be augmented with thiazide diuretic; Most commonly used is furosemide, but some pts respond better to torsemide or bumetanide due to better & more reliable absorption
Angiotensin converting enzyme inhibitors (ACEIs) – when to use
Started during or after optimization of diuretic therapy; 1st at low doses then titrate up to goal dose
ACEIs – effects
Produce vasodilation & decreased aldosterone activation, plus anti-remodeling effects
Angiotensin II Receptor (AT-1) Blockers (ARBs) – when to use
Used in pts intolerant to ACEIs (usually due to cough) but NO apparent benefit from dual therapy w/ACEI + ARB
Aldosterone Antagonists (aka Mineralocorticoid receptor antagonists, MRA) – when to use
Added to therapy for NYHA class II with LVEF <35%
Aldosterone Antagonists (MRAs) – what must be monitored
Must carefully monitor for serum potassium (30ml/min)
Aldosterone Antagonists (MRAs) –action
Blocks aldosterone effect on kidney, producing additional sodium loss (since ACEI/ARBs block of aldosterone is incomplete) PLUS anti-remodeling effects
Spironolactone vs. Eplerenone (Aldosterone antagonists/MRAs)
If endocrine side effects occur with spironolactone, can use eplerenone (much more expensive)
Site of action of diuretic agents
Almost all effect lumenal (urine) surfaces of renal tubule cells
Mechanisms of diuretic agents
- Interact w/membrane transport proteins (thiazides, furosemide, triamterene)….. 2. Specifically interact w/ enzymes (acetazolamide) or hormone receptors (spironolactone)….. 3. Prevent water reabsorption bia osmotic effects (mannitol)
Movement of Na+ between compartments in the kidney
Na+ is the major extracellular cation & its movement between compartments is controlled by regulated active transport via Na+-K+-ATPase activity at the interstitial (blood) surface —> produces gradient needed for Na+ reabsorption from urine back into blood; But, NO diuretics act via inhibition of Na+-K+-ATPase
How diuretics work
No current diuretics can inhibit the Na+-K+ ATPase pump; Rather, diuretic agents decrease Na+ reabsorption at various sites in the nephron, resulting in increased amounts of Na+ (and other ions) entering urine along with H2O entering passively to maintain osmotic equilibrium.
Events in Proximal Convoluted Tubule
- Almost all of glucose, amino acids, NaHCO3, and other metabolites are reabsorbed here, along with 60-70% of Na+ (w/Cl- & H2O following passively)…. 2. H+ ion + enzyme carbonic anhydrase (CA) on luminal surface —> reabsorption of HCO3- (& exchange of H+ for Na+); …….. Site of organic acid (diuretics, antibiotics) and base (procainamide) secretion.
Acetazolamide & the PCT
Inhibition of CA (carbonic anhydrase) by acetazolamide results in retention of HCO3- in lumen (urine) with mild alkaline diuresis.
Significance of PCT for drugs
Important site for delivery of diuretics to their specific site of action in nephron and for potential drug-drug interactions.
Carbonic Anhydrase (CA) Inhibitor
Acetazolamide (Diamox)
Pharmacodynamics (Actions) of CA inhibitors (Acetazolamide)
Inhibition of carbonic anhydrase enzyme depresses NaHCO3 reabsorption in proximal tubule; Also inhibits formation of aqueous humor & CSF that is dependent on HCO3- transport;
Pharmacokinetics of CA inhibitors (Acetazolamide)
Well absorbed orally….Effects in 30 min … Duration of 12 hrs… Secreted into proximal tubule
Clinical Uses of CA inhibitors (Acetazolamide)
Major use is NOT as diuretic agent and NOT used in HF; Rather, used in Glaucoma (topical), Acute mountain sickness (systemic admin.; slows pulm./cerebral edema)
Adverse Reactions / Toxicities of CA inhibitors (Acetazolamide)
Minor: Loss of appetite, drowsiness, confusion, tingling in extremities, hypersensitivity rxns…..Hyperchloremic metabolic acidosis, renal stones (via increase in urinary pH), K+ wasting
Events in the Loop of Henle (thick ascending limb)
Water removal (from lumen) occurs in descending limb as a result of hypertonic osmotic forces generated in interstitial spaces; H2O removal opposed if impermeable solutes present (HCO3-, glucose, osmotic diuretics)….. Ascending limb is impermeable to H2O, but active NaCl reabsorption occurs in ascending limb via Na+-K+-2Cl- cotransporter (NKCC2 on the luminal side)
Action of NKCC2 (Na+-K+-2Cl- cotransporter)
Cotransporter itself is electrically neutral, but its action leads to excess intracellular K+ which then back diffuses into lumen —> lumen positive potential —> drives reabsorption of cations Mg++ and Ca++
Loop of Henle Agents (High Ceiling Diuretics) – Pharmacodynamics (Actions)
Inhibit NaCl transport (Na+-K+-2Cl–transporter) in thick ascending limb of loop of Henle
Effects of Loop of Henle Agents (High Ceiling Diuretics)
Loop diuretics have greatest diuretic effect b/c of the large capacity of this segment…. Associated with: 1. Increased Mg++, Ca++ excretion (diminish lumen-positive potential)…. 2. Increased renal blood flow (via effect on RAAS & PGs systems) ….. 3. Retain substantial diuretic effect even if renal function is compromised.
Pharmacokinetics of Loop of Henle Agents
Rapid oral absorption; Extremely rapid IV diuretic response (IV may be required initially in some HF pts due to congestion-related interference w/ oral absorption); Handled by renal secretion and filtration; Duration of effect 2-3 hrs for furosemide, 4-6 hrs for torsemide, 6 hours for bumetanide
Clinical Uses of Loop Diuretics
- Congestive heart failure - Preferred diuretic class b/c of greater efficacy – 1. HF w/ volume overload (to eliminate signs of fluid retention - pulmonary congestion & peripheral edema)….. 2. Acute pulmonary edema ….. 3. Refractory edema (Loops used if no response to Na+ restriction or thiazide diuretic; esp. if renal disease & fluid overload present) ….. 4. Hypercalcemia given w/saline infusion (to prevent extracellular fluid (ECF) volume depletion)
Efficacy of loop diuretics is enhanced by…
salt restriction (< 2 g/day)
Furosemide vs. Other Loop diuretics
Most commonly used loop diuretic; If lack of response, can increase dose or can switch to bumetanide or torsemide (both are more reliable bioavailability; torsemide has longer duration)
Diuretic response in HF Patients
Reduced diuretic response related to decreased drug delivery to kidney due to decreased RBF & hypoperfusion activation of RAAS and SNS
Diuretics for Refractory edema in HF
Can add a thiazide (metolazone) to therapy if loop diuretic produces insufficient dieresis
Action of Thiazide Diuretics
Block distal tubule Na+ reabsorption —> can counter loop-induced increases in Na+ delivery & reabsorption at that segment
To moniter in Thiazides
Thiazides can add to loop-induced hypokalemia so careful monitoring of serum potassium is warranted with initiation of therapy.
Aldosterone antagonist + Loop diuretics
Aldosterone antagonists (like spironolactone) are recommended in some pts w/systolic HF to improve survival….Its actions at collecting tubule will also enhance diuresis & ameliorate the potassium wasting.
Loop diuretics - Adverse Reactions / Toxicities
- Hypokalemic metabolic alkalosis via enhanced secretion of K+ and H+ (More pronounced than w/thiazides), which predisposes patients to ectopic pacemakers and arrhythmias….. 2. Ototoxicity (usually reversible), especially for ethacrynic acid as well as with concomitant use of aminoglycoside antibiotics, and if diminished renal function present….. 3. Hyperuricemia / hyperglycemia….. 4. Hypomagnesemia….. 4. Overdose (Rapid blood volume depletion dizziness, headache, orthostatic hypotension)
Events in the Convoluted tubules
Relatively impermeable to H2O…… NaCl reabsorption occurs via electrically neutral Na+/Cl- cotransporter (pharmacologically distinct from Loop cotransporter)….. Site of active Ca++ reabsorption via a Na+/Ca++ exchanger, which is regulated by parathyroid hormone (PTH); This exchanger is not present at the loop of Henle —> important differences in Ca2+ excretion effects between diuretic classes.
Thiazide Diuretics – Pharmacodynamics (Actions)
Inhibit the Na+/Cl- cotransporter & increasing urinary excretion of NaCl (modest diuretic effect, only 5-10% of filtered Na+ is reabsorbed here)…. In contrast to loop diuretics, thiazides increase reabsorption of Ca++ (lower intracellular Na+ drives Ca++ exchanger OR decreased blood volume increases absorption at PCT)
Pharmacokinetics of Thiazide diuretics – absorption & timing
All absorbed well orally (if GI upset, can take with food or milk); best to take early in day
Pharmacokinetics of Thiazide diuretics – Differences in metabolism / excretion:
Hydrochlorothiazide (Hydrodiuril): Prototype thiazide, BID; Chlorthalidone - Metolazone: longer durations once daily dosing….. All secreted by organic acid secretory system; competition w/uric acid secretion may precipitate a gout attack
Clinical Uses of Thiazide diuretics
- HF (but usually require higher doses or more efficacious diuretics [loop] than in HTN)…. 2. Synergistic diuretic effect w/loop diuretics (esp. metolazone) useful in refractory edema; ….. 3. HTN: 1st line for mild HTN (esp., blacks, elderly, obese);….. 4. Hypercalcuria: Reduced urinary excretion of Ca++ decreases incidence of kidney stones
Thiazides - Adverse Reactions / Toxicities
- Hypokalemia —> weakness, paresthesias, cardiac sensitization (predisposition to ectopic pacemakers, thus use not advisable in pts w/arrhythmias, Hx of MI, pre-infarction angina]….. 2. Volume contraction may lead to secondary hyperaldosteronism….. 3. Impaired carbohydrate tolerance (dose-related): hyperglycemia, glucosuria….. 4. Hyperuricemia (avoid in pts w/gout)….. 5. Hyperlipidemia (if used long-term)….. 6. Allergic rxns (skin rashes & some cross-allergenicity, related to sulfonamide component)
Events in the Collecting Tubules
Site of regulation by the mineralocorticoid aldosterone; Only 2-5% of NaCl reabsorption occurs at this site (thus only weak diuretic action possible), but as the most distal site it has important role in determining final urinary Na+ (and ultimately K+ & H+) concentration
Na+ & K+ transport in the Collecting Tubules
Na+ (& H2O) and K+ transport occurs in principal cells via separate channels that exclude anions….Driving force for Na+ entry into cell exceeds that for K+ exit so lumen becomes negative —> droves Cl- into cells & K+ into urine……Thus, K+ excretion is coupled to Na+ reabsorption & ALL diuretics that cause a greater delivery of Na+ (& greater tubular flow) to this site will enhance K+ excretion.
Aldosterone in the Collecting Tubules
Effects gene transcription to increases number & activity of both Na+ (ENaC) and K+ membrane channels and the Na+-K+-ATPase
Diuretic action in the Collecting Tubules
Block the Na+ channel (triamterene & amiloride) or antagonize the aldosterone receptor (spironolactone & eplerenone) —> decrease Na+ reabsorption & decrease K+ excretion (known as “potassium-sparing” diuretics)
Types of K+-Sparing Diuretics
Aldosterone Antagonists & Na+-channel Blockers
Aldosterone Antagonists (MRAs) –Pharmacodynamics (Actions)
Only mild diuresis possible if used alone; Competitive antagonist at aldosterone receptor: binds to cytosolic receptor, blocking it & preventing aldosterone’s effects in enhancement of protein synthesis at the collecting tubule —> Na+ is NOT reabsorbed, lumen-potential becomes more positive, and thus LESS K+ and H+ ions move into urine….Promotes only moderate increase in Na+ excretion
Types of Aldosterone Antagonists (MRAs) & Differences between them
Spironolactone / Eplerenone… Eplerenone reported to have lower affinity for androgen & progesterone receptors (fewer side effects, esp. gynecomastia).
Na+ Channel Blockers – Examples & Action
EX: Triamterene / Amiloride…..Direct effect to block Na+-channels on collecting duct lumen to decrease Na+ reabsorption (and thus decreases coupled K+ secretion)
Pharmacokinetics of Spironolactone vs. Eplerenone (Aldosterone Antagonists/MRAs)
Spironolactone (Aldactone): 1-2 doses/day, Poor oral absorption, Slow onset of action….. Eplerenone (Inspra): Dosed 1-2 times/day orally, metabolized by CYP3A4
Pharmacokinetics of Triamterene (Dyrenium) & Amiloride (Midamor):
Triamterene metabolized in liver; Amiloride excreted unchanged (thus given less frequently)…. Effect in 2-4 hrs, but 1-3 days to max effect.
Clinical Uses of Aldosterone Antagonists (MRAs)
- HF ….. 2. Primary hyperaldosteronism ….. 3. Hirsutism of polycystic ovary syndrome via block of androgen receptor (spironolactone)….. 4. HTN (in combo w/thiazides; also can use Na+ channel blocker Triamterene + HCTZ)
Aldosterone antagonists actions in HF
Survival benefits; Block aldosterone receptors on heart rather than kidney; Anti-remodeling action (block aldosterone effects on heart cardiac which lead to hypertrophy & fibrosis); Additional benefits from raising serum K+ to counter risk of hypokalemia-induced arrhythmias from K+-wasting diuretics
Adverse Reactions of Aldosterone Antagonists (MRAs) and Na+ channel blockers
- Hyperkalemia ( EKG changes, conduction abnormalities, arrhythmias; risks increased by age, underlying renal dysfunction, higher doses, combined use w/ACEI/ARB or NSAIDs)….. 2. Endocrine abnormalities (gynecomastia) w/spironolactone via block of androgen receptor ( 10%) – NOT seen w/ eplerenone which is more selective for aldosterone receptors…… Mild effects: GI upset, drowsiness
Diuretic Efficacy (in order from least to most efficacious class)
Carbonic Anhydrase Inhibitors = Aldosterone Antagonists/Na+ Channel Blockers < Thiazide < Loop < Loop+Thiazide
Potassium effects of Diuretics (in order from least to most potassium-sparing)
Loop+Thiazide (most K+ lost in urine) < Loop < Thiazides = Carbonic Anhydrase Inhibitors < Aldosterone Antagonists / Na+ channel blockers (Potassium sparing; least K+ lost in urine)
H+ effects of Diuretics (in order from least to most H+ lost in urine)
CA-I’s and Aldosterone Antagonists/Na+ channel blockers = No effect….. Thiazides (lose least H+ via urine) < Loop < Loop+Thiazide (loose most H+ via urine)
Ca2+ effects of Diuretics
CA-I’s and Aldosterone Antagonists/Na+ channel blockers = No effect….. Thiazides increase plasma Ca2+ levels (decrease amouth lost in urine)….. Loop agents lose more via urine (less Ca2+ in plasma)….. Loops+Thiazides may either lose in urine or increase plasma levels (may increase or decrease plasma levels)
Mg2+ effects of Diuretics
Loop agents decrease plasma Mg2+ levels (lost via urine)
HCO3- effects of Diuretics
Carbonic Anhydrase Inhibitors decrease plasma HCO3- levels (lost in urine)
Uric acid effects of Diuretics
Loop, Thiazides, and Loop+Thiazide all increase uric acid levels in the blood (avoid in gout pts!)
Angiotensin-Converting Enzyme Inhibitors [ACEIs] – Examples
Lisinopril (Zestril, Prinivil), Captopril (Capoten), Enalapril (Vasotec)
ACE-I’s: Mechanism of Action in HF
Inhibits ACE conversion of Ang I to Ang II, blocking Ang II-induced vasoconstriction —> decreased preload & afterload….. However, other vasodilators have less survival benefits than ACEIs, suggesting ACEIs work by other mechanisms
Primary mechanism of ACE-I action in HF
Decrease of Ang II-induced release of aldosterone which moderates the myocardial hypertrophy & remodeling response to aldosterone
Other mechanisms of ACE-I action in HF
- Decreases bradykinin inactivation —> vasodilator action….. 2. Enhances NO action to improve endothelial function ….. 3. Reduces sympathetic activity
Other Uses for ACE-I’s (besides in heart failure)
- HTN - first-line therapy….. 2. Delay progression of diabetic nephropathy
Pharmacokinetics and Dosing Considerations of ACE-I’s
Well absorbed orally (reduced absorption for most if taken w/food)…. All ACEIs, except lisinopril & captopril, are prodrugs that are converted to active metabolite by de-esterification in the liver….. Active metabolites are primarily eliminated by the kidneys (exceptions: moexipril & fosinopril) requiring dosage reduction in patients w/renal insufficiency….. Duration of action generally sufficient to allow once-daily dosing for most agents.
Side Effects of ACE-I’s
- Contraindicated in pregnancy (Category C/D in 2nd/3rd trimester)….. 2. Dry cough….. 3. HYPERkalemia….. 4. Severe HYPOtension (if hypovolemic), acute renal failure (esp. w/renal artery stenosis), angioedema….. 5. Neutropenia & proteinuria w/high doses of captopril (but rare w/newer agents)….. 6. Minor effects include altered taste sense, skin rashes
Angiotensin II Receptor (AT1) Antagonists [ARBs] – Examples
Losartan (Cozaar), Valsartan (Diovan)
ARBs - Mechanism of Action in Heart Failure
Selective inhibition of Angiotensin II receptor AT1; Similar to ACEIs, ARBs prevent remodeling & reduce sympathetic activity
Advantage of ARBs vs ACEIs
Potential for more complete inhibition of angiotensin action since alternative pathways (chymase) exist to form Angiotensin II that are NOT blocked by ACEIs….. No side effects mediated by increased bradykinin levels (i.e., NO cough, angioedema)
Disadvantage of ARBs vs ACEIs
Loss of increased bradykinin actions (vasodilation) that result from ACE inhibition….. Block only Ang II actions at AT-1 receptors, while decreased Ang II synthesis by ACEIs will block actions mediated by both AT-1 & AT-2 receptors
Other Uses for ARBs (besides HF)
Alternative in conditions that respond to ACE inhibitors, but ACEIs not tolerated (HTN, diabetic nephropathy delay)
ARBs - Dosing Considerations
All agents are effective orally w/once daily dosing except for losartan (twice daily)…. Decreased losartan dose necessary in hepatic dysfunction.
ARBs - Side Effects
Similar to ACEI, contraindicated in pregnancy, but NO angioedema or cough
