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14 Cards in this Set

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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

▪Thiazides are weak organic acids. They are excreted by organic acid secretory system in PT. Compete with uric acid.

▪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)

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)

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).

▪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.)
▪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.

▪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.

▪↓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.

▪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.

▪hyperchloremic metabolic acidosis.
▪Gynecomastia, impotence, BPH. Spironolactone can interact with androgen & progesterone receptors. Eplerenone has 500x lower affinity for these receptors.
▪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.)

▪Prototype Drug: Furosemide
▪Most drugs are sulfonamide derivatives.

▪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.

▪Heart Failure, acute pulmonary edema.
▪Other edamtous conditions.
▪Hyperkalemia, Hypercalcemia.
▪Acute renal failure
▪Anion Overdose (Br, F, I)

-Hypokalemic metabolic alkalosis (↓Na →↑K+/H+ secretion)
▪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.)
DRUG: Acetozolamide

SITE OF ACTION: Proximal Tubule


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.

▪Acetazolamide is a weak diuretic. The kidney can compensate for its role later in the nephron.

▪Urine pH ↑ leading to metabolic acidosis as blood pH ↓
▪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)

▪Captopril (prototype): Fastest acting b/c no active metabolite. Shorter duration-- 2x/day.
▪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%).

▪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)
▪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)

▪Bilateral Renal Artery stenosis/unilateral stenosis if only have 1 kidney.
▪High dose of NSAIDS (can ↓Prostaglandins & counteract antihypertensive effect of ACEI)
▪During Pregnancy

▪Cough (↑bradykinin)
▪Angioneurotic edema (mucous membranes in mouth & airways swell)
▪Hyperkalemia (due to ↓Aldosterone, esp in pts w/ renal insufficiency)
▪Dysgeusia (↓taste)
• 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.
•used in ALLHA Study.
•does not need to be converted to active metabolite.
•t1/2 = 24 hours. Only need to take 1x/day
•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.
Metabolic & CV effects of ACE-I:
Metabolic Alterations
•NO NET CHANGE in Catecholamines (this is why you can use ACE-I as 1st line drug)

Cardiovascular alterations
•↓↓Bloop Pressure
Angiotensin Receptor Blocker
▪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.
Antiotensin I Receptor Blocker
Direct Renin Inhibiting Drug

▪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)