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14 Cards in this Set
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THIAZIDE DIURETICS
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▪1st line drugs w/ few exceptions
▪Inhibit NaCl transport in DT. ▪prototype: hydrochlorothiazide ▪Best drug: Chlorthalidone (has 2x effect at ½ dose. Has long half life) ▪Dose Response: Doubling does NOT increase effects 2x. It only ↑↑ side effects. ▪Not as strong as loop diuretics (Furosemide), but stronger than those which work at Collecting Duct (AA, K+ sparing) CHEMISTRY: unsubstituted sulfonamide PHARMACOKINETICS: ▪Thiazides are weak organic acids. They are excreted by organic acid secretory system in PT. Compete with uric acid. PHARMACODYNAMICS: ▪Act on luminal site of epithelial cells in DCT. Block Na/Cl transporter. ▪Blocks Na/Cl symport on luminal surface → ↓ [Na] intracellularly ▪Enhance Ca2+ reabsorption in DCT due to ↑ Na/Ca exchange basolaterally. → ↑[Ca] in blood (good for osteoporosis) ▪↑Na/K ATPase → hypokalemia ▪MOA: ↓Na ultimately leads to ↓TPR -> 4 wks for max effect. Diets low in Na mimic this effect. CLINICAL INDICATIONS: Hypertension, mild heart failure, kidney stones (b/c of hypercalciuria), Diabetes insipidus (paradoxical effect) INTERACTIONS: LITHIUM: increases reabsorption in Proximal Tubule. May need smaller dose of Thiazides. QUINIDINE (antiarrhythmic) increases chances of Torsade de Pointes DIGITALIS (for HF) Binds Na/K ATPase. Dec. K+ allows more digitalis to bind & could lead to toxicity. NSAIDS (↓ PG → ↓thiazide effects) TOXICITY: 1) Hypokalemia metabolic alkalosis (↑ excretion →↑Aldosterone → ↑K+/H+ excretion → hypokalemic alkalosis) (2) Hyperuricemia (→gout) (3) Impaired glucose tolerance (impaired insulin release & decreased tissue glucose utilization) (4) Hyperlipidemia (transient inc. in serum cholesterol & LDL) (5) Hyponatremia (due to hypovolemia-induced elevation of ADH). DRUGS: ▪Chlorthalidone: best. Longest half life. ▪Hydrochlorothiazide: most used. ▪Metolazone: unlike other thiazides can be used in pts. With renal impairment (other thiazides cannot reach their site of action when kidney is impaired.) |
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POTASSIUM SPARING DIURETICS
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POTASSIUM-SPARING DIURETICS
▪DRUGS: act in Principle cells of the Collecting Duct Amiloride & Triamterene block luminal Na+ channel so that K+ is not secreted into lumen → not excreted. Spironolactone & Eplerenone are Aldosterone Antagonists (AA) that block the Aldosterone receptor (on the basolateral membrane) → block Aldosterone from enhancing the Na+ reabsorption (@ luminal membrane) & Na/K ATPase (@ basolateral) CHEM: Spironolactone & Eplerenone are synthetic steroids. Triamterene & Amiloride are organic. PHARMACOKINETICS: ▪Spironolactone is slowly activated. Eplerenone is faster. Both are eliminated by the liver. ▪Triamterene is metabolized in the liver and excreted in the urine. ▪Amiloride is excreted in the urine. PHARMACODYNAMICS: ▪↓Na+ reabsorption in the collecting dugs by: (1) (A&T) blocking Na+ channel (on principle cells) (2) (S&E) blocking Aldosterone receptor on basolateral membrane (on principal cells) (3) ↓Na+/H+ exchange by the intercalated cells of the Collecting duct. (This can lead to metabolic acidosis). ▪MOA: In Principal Cell of Collecting Tubule. -Triamterene & Amiloride directly interfere with Na+ entry through Na+ selective ion channel channels on the luminal membrane. Since K+ secretion is coupled to Na+ exit (into the blood) @ the basolateral membrane, these drugs are K+ sparing. -Spironolactone & Eplerenone bind to Aldosterone receptors & prevent Aldosterone activation of luminal Na+ channel & basolateral Na+/K+ channel. CLINICAL INDICATIONS: ▪S & E effective as Hypertension monotherapy. ▪T&A have less efficacy than AA & are used in combination w/ thiazide diuretics to spare K+. Possibility of interaction w/ Triamterene & Spironolactone & NSAID since these drugs may depend on Prostaglandin production (blocked by NSAIDs). ▪Conn’s Syndrome: mineralocorticoid excess. TOXICITY: ▪hyperkalemia ▪hyperchloremic metabolic acidosis. ▪Gynecomastia, impotence, BPH. Spironolactone can interact with androgen & progesterone receptors. Eplerenone has 500x lower affinity for these receptors. |
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LOOP DIURETICS
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LOOP DIURETICS:
INTRO: ▪Selectively inhibit NaCl reabsorption in the thick ascending limb of the Loop of Henle. ▪Inhibit the hypertonicity of the medullary interstitium. ▪Inhibit the Na/K/2Cl cotransporter of the macula densa cells (if MD cells sense ↓ NaCL, they release ↑ Prostaglandins → ↑renin release) (If MD cells sense ↑NaCl → Adenosine released → ↓renin. But since Furosemide is blocking NaCl, this latter action is not happening. Therefore, Furosemide INCREASES PG release.) CHEM: ▪Prototype Drug: Furosemide ▪Most drugs are sulfonamide derivatives. PHARMACODYNAMICS: ▪MOA: Inhibition of Na/K/2Cl transport in thick ascending limb of LOH→ ↓lumen K+ potential which is needed to drive Mg2+ & Ca2+ reabsorption paracellularly. ▪↑Prostaglandins synthesis. (NSAIDS may interfere with Loop diuretics) ▪Furosemide & Ethacrynic acid produce venodilation. CLINICAL INDICATIONS: ▪Heart Failure, acute pulmonary edema. ▪Other edamtous conditions. ▪Hyperkalemia, Hypercalcemia. ▪Acute renal failure ▪Anion Overdose (Br, F, I) TOXICITY: -Hypokalemic metabolic alkalosis (↓Na →↑K+/H+ secretion) ▪Ototoxicity ▪Hyperuricemia (caused by hypovolemia-associated ↑of uric acid reabsorption. ▪Hypomagnesemia (even though Ca2+ reabsorption is blocked as well, Calcium can be reabsorpbed in the DCT, so its loss is not as severe.) |
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CARBONIC ACID INHIBITORS
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CARBONIC ACID INHIBITORS
DRUG: Acetozolamide SITE OF ACTION: Proximal Tubule INDICATION: Glaucoma MOA: Na+ is reabsorbed via Na+/H+ exchanger on luminal membrane. This can only work if H+ is present. The H+ is provided by Carbonic Anhydrase. Acetozolamide blocks Carbonic Anhydrase. NOTE: ▪Acetazolamide is a weak diuretic. The kidney can compensate for its role later in the nephron. SIDE EFFECT ▪Urine pH ↑ leading to metabolic acidosis as blood pH ↓ |
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ACE INHIBITORS
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ACE INHIBITORS
▪Drugs targeting the renin/angiotensin system are important for the treatment of HTN & HF. ▪Renin secretion is controlled by: (1) local baroreceptors in the afferent arteriole (↓blood volume promotes ↑ renin from JGA cells) (2) MD sensing Na/Cl in the distal tubule (↑[Cl] sensed by MD cells → secrete adensosine→ inhibits renin release from JGA; ↓[Cl]→ MD secrete prostaglandins → ↑reniin) (3) NE release from postganglionic SNS onto β1 receptors JGA → ↑ renin secretion. ▪Angiotensinogen →(renin)→Angiotensin I →(ACE)→Angiotensin II ▪Angiotensin II causes: aldosterone secretion, SNS stimulation, thirst, ADH secretion, direct renal reabsorption at the proximal tubule (Na+/H+), negative feedback on JGA cells to ↓renin, excites SNS via multiple mechanisms (stimulates SNS ganglia, NE release, catecholamine secretion by Adrenal Medulla, Inhibits NE reuptake, Crosses into CNS via postrema to stimulate SNS outflow) DRUGS: ▪Captopril (prototype): Fastest acting b/c no active metabolite. Shorter duration-- 2x/day. ▪Enalopril ▪Ramipril (used in HOPE trial. Study observed 20%↓ in acute MI, stroke, & death by CV causes by Ramipril vs. placebo. ↓Incidence of Type II Diabetes.Mech: ACE-I have anti-athersclerotic effect.) ▪Lisinopril (used in ALLHAT study: thiazides were better) ▪Most are given as prodrugs and have similar bioavailability (except Captopril, which is rapidly absorbed & has bioavailability of about 75%). MOA: ▪Metabolic Changes produced by ACEI: ↓↓Aldosterone, ↑Bradykinin, ↑↑Renin, ↑K+, no net change in catechnolamines (can use ACEI as first line drug) ▪Cardiovascular changes produced by ACEI: ↓TPR, ↓↓BP, No Net change in HR (Angi II stimulates SNS, so w/ ACEIs you would predict ↑HR & ↓catecholamine levels, but ↓BP activates Baroreceptors reflex to ↑HR & Catecholamines. Result: NO NET effect). ▪ACEI DO NOT AFFECT VEINS, so BP is about the same standing or lying down (i.e. NO orthostatic hypotension). ▪ACEI are most effective when renin levels are high (ppl on low Na/Cl diet). ▪ACEI are NOT 1st line drugs for older African Americans w/ HTN) |
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ACE INHIBITORS (#2)
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CLINICAL INDICATIONS:
▪Hypertension in pts w diabetes. (If monotherapy ok, use thiazide) ▪HTN w/ diabetes w/ proteinuria (ACEIs ↓decreasing constriction of Efferent arteriole, →intraglomerular pressure→↓GFR→↓protein filtration). ▪Pts without HTN but with Diabetes & Microalbuminuria ▪Congestive Heart Failure/Left Ventricular Hypertrophy (Angiotensin II is a growth/trophic factor. Blocking ANGII→↓LVH) CONTRAINDICATIONS ▪Bilateral Renal Artery stenosis/unilateral stenosis if only have 1 kidney. ▪High dose of NSAIDS (can ↓Prostaglandins & counteract antihypertensive effect of ACEI) ▪During Pregnancy SIDE EFFECTS/TOXICITY ▪Cough (↑bradykinin) ▪Rash ▪Angioneurotic edema (mucous membranes in mouth & airways swell) ▪Hyperkalemia (due to ↓Aldosterone, esp in pts w/ renal insufficiency) ▪Dysgeusia (↓taste) |
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Capropril
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• ACE InhibitorFastest acting drug b/c it does not have to be converted into active metabolite.
• Peak effect in only a few hours. • Shorter duration of action relative to other ACE-I. Patient may need to take 2x/day. |
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Lisinopril
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•ACE-I
•used in ALLHA Study. •does not need to be converted to active metabolite. |
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Enalapril
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•ACE-Inhibitor
•Prodrug •t1/2 = 24 hours. Only need to take 1x/day |
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Ramipril
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•Ace-Inhibitor
•Prodrug •t1/2 = 24 hours. Patient only needs to take 1x/day. •Used in HOPE TRIAL: -Study gave either Ramipril or placebo to pateitns at risk for CV disease (CAD, high cholesterol, diabetes) & followed them for 4 yrs. -Observed 20% Decrease in acute MI infarction, stroke, & death by CV causes. Mechanism: pehaps ACE-I have an anti-atherosclerotic effect. |
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Metabolic & CV effects of ACE-I:
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Metabolic Alterations
•↓↓Aldosterone •↑Bradykinin •↑↑Renin •↑K+ •NO NET CHANGE in Catecholamines (this is why you can use ACE-I as 1st line drug) Cardiovascular alterations •↓TPR •↓↓Bloop Pressure •NO NET CHANGE IN HR |
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Angiotensin Receptor Blocker
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▪Better than ACEIs because they block the effects of Angiotensin II & counteract the alternative/chymase pathway for Angiotensin II synthesis.
▪Selectively block AT1 receptor, leaving AT2 open. ▪Prototype Drug: Losartan ▪INDICATIONS: When ACEIs do not work (similar to it) ▪Contraindications: Pregnancy ▪Side Effects: Similar to ACEI, but no cough or angioedema. --> Side effects are: Rash, Hyperkalemia, Dysgeuisia ▪AT1 is inhibited. AT1 (working through a G protein receptor coupled to PLC →IP3 →↑Ca) causes: vasoconstriction, ↑ Aldosterone, ↑Na reabsorption, cardiac growth, vascular smooth muscle growth, ↑SNS, ↑ADH, ↓Q of renal blood, Inhibits renal renin release. ▪AT2: stimulates apoptosis, antiproliferative, embryonic differentiation/development (why ACEI are contraindicated during pregnancy), Endothelial cell growth, vasodilation. |
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Losartan
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Antiotensin I Receptor Blocker
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Direct Renin Inhibiting Drug
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▪Aliskiren
▪Direct Renin Inhibiting Drug. ▪MOA: unknown. Decreases Aldosterone, Angiotensin I, Angiotensin II levels. Renin Plasma levels are not increased because Aliskiren binds renin. (This is different from ARBs & ACEIs, which block the receptor & ACE respectively and cause positive feedback to increase plasma renin levels) ▪Majority is excreted in feces, 25% excreted in kidney. ▪Aliskiren is reabsorbed through the biliary system, which is why its half life is so long (t ½ = 20 hrs) |