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How do diuretics work to lower BP?
Lower BP by depleting the body of sodium and reducing blood volume
How do antihypertensives that block RAAS lower BP?
Reduce total vascular resistance and may reduce blood volume
How do direct vasodilators lower BP?
Relaxing vascular smooth muscle leads to arterial vasodilation. Decreasing systemic vascular resistance.
How do sympatholytic agents work to lower bp?
Decrease BP by decreasing sympathetic input and/or increase parasympathetic input
Examples of diuretic drug classes:
Thiazide diuretics, loop diuretics, mineralocorticoid (aldosterone) receptor antagonists, potassium-sparing diuretics
Examples of drug classifications that block RAAS:
ACEi, ARB, direct renin inhibitors
Examples of direct vasodilators:
Calcium channel blockers, hydralazine, minoxidil
Examples of sympatholytic agents:
Beta-blockers, clonidine
What drug classes are first-line antihypertensives?
Thiazide diuretics, ACEi, ARB, calcium channel blockers
How much can diuretics lower BP?
Can lower BP up to 10-15 mmHg in most patients
Are diuretics used as monotherapy?
Can be used as monotherapy for mild hypertension, but are often used in combination with other agents
Brand name of Chlorthalidone?
Hygroton, Thalitone
Brand name of Indapamide?
Lozol
Brand name of Metolazone?
Zaroxolyn
Indication for thiazide diuretics?
First-line antihypertensive
MOA for thiazide diuretics:
Increases sodium (and therefore water) and chloride excretion by blocking reabsorption in the distal convoluted tubule of the nephron by blocking the Na+/Cl- transporter (NCC)
CI for thiazide diuretics
Hypersensitivity to sulfonamides (low risk of cross-reactivity with antibiotics), anuria
ADRs for thiazide diuretics
Dizziness, hyperuricemia, other electrolyte abnormalities (hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia), pancreatitis
Key PKPD for thiazide diuretics
Secreted by the organic acid secretory system in the proximal tubule which completes with secretion of uric acid which can elevate levels of uric acid
Pearls for thiazide diuretics
Not as effective if CrCl < 30 mL/min (prefer chlorthalidone)
Brand name of furosemide
Lasix
Indication for loop diuretics
Edema due to heart failure, hypertension
MOA for loop diuretics
Actively secreted via the nonspecific organic acid transport system into the lumen of the thick ascending limb of Henle’s loop, where it decreases sodium reabsorption by competing for the chloride site on the Na+-K+-2Cl- cotransporter
CI for loop diuretics
Anuria (no urine)
ADRs for loop diuretics
Hyperuricemia, hypokalemia, hypomagnesemia, dizziness, acute kidney injury (AKI), ototoxicity
DDI for loop diuretics
increased risk of ototoxicity if used with aminoglycosides
Pearls for loop diuretics
Most efficacious diuretics (causes most fluid removal)
BBW for loop diuretics:
Potent diuretic, at high doses can lead to profound fluid and electrolyte loss
Bioavailability of furosemide?
~40-70%
Duration for furosemide?
4-8 hours
Half-life for furosemide?
1-2 hours
Elimination of furosemide
mainly renal
Bioavailability for torsemide
~90%
Duration of torsemide
8-12 hours
Half-life of torsemide
3.5 hours
Elimination of torsemide
mainly hepatic
Bioavailability of bumetanide
~90%
Duration of bumetanide
3-6 hours
Half-life of bumetanide
1-1.5 hours
Elimination of bumetanide
50% renal and 50% hepatic
Bioavailability of ethacrynic acid
100%
Duration for ethacrynic acid
IV: 2-4 hours
PO: 12 hours
Half-life of ethacrynic acid
2-4 hours
Elimination of ethacrynic acid
renal
Brand name of torsemide
Demadex
Brand name of bumetanide?
Bumex
Brand name of spironolactone
Aldactone, CaroSpir
Brand name of eplerenone
Inspra
Indication for MRAs?
Heart failure, HTN
MOA for MRAs?
Competes with aldosterone for receptor sites in the distal renal tubules, increasing sodium chloride and water excretion while conserving potassium and hydrogen ions; may block the effect of aldosterone on arteriolar smooth muscle as well.
CI for MRAs?
Anuria (no urine) and hyperkalemia
ADRs for MRAs?
Dehydration, hyperkalemia, hyponatremia, dizziness, cardiac arrhythmias due to electrolyte abnormalities
Specific ADRs for spironolactone:
Gynecomastia, breast tenderness, impotence
Specific ADRs for eplereone?
increased triglycerides
Key PKPD for MRAs?
Spironolactone binds with high affinity to the androgen receptor which is the source of ADRs like gynecomastia and decreased libido.
Eplerenone has a much greater selectivity for mineralocorticoid receptor
DDI for MRAs?
Eplerenone: strong CYP3A4 inhibitors will increase concentrations
Pearls of MRAs?
Minimally efficacious blood pressure control when used as monotherapy
What are MRAs also known as?
Aldosterone antagonists (‘aldo’)
Examples of potassium-sparing diuretics:
Triamterene, amiloride
Indication for potassium-sparing diuretics
Hypertension
MOA for potassium-sparing diuretics
Competitive inhibition of epithelial sodium channel (ENaC) in the collecting duct of the nephron —→ decrease sodium reabsorption and increase potassium reabsorption.
CI for potassium-sparing diuretics
Hypersensitivity to sulfonamides (low risk of cross-reactivity with antibiotics), anuria
ADRs for potassium sparing diuretics
Hyperkalemia, hypotension, dizziness, headache, gout, SJS
Key PKPD for potassium sparing diuretics
Amiloride has longer duration of action than triamterene (24 hours vs 8 hours)
Pearls of potassium-sparing diuretics
Almost always in a combination tablet to decrease rates of hypokalemia with thiazide diuretics
Brand name of lisinopril
Prinivil, Zestril
Indication for ACEi
First-line antihypertensive
Other: MI, heart failure with reduced ejection fraction (HFrEF)
MOA for ACEi
Competitive angiotensin converting enzyme inhibitor (ACEi). This prevents stimulation of the angiotensin II receptor. The angiotensin II receptor is responsible for vasoconstriction, aldosterone secretion, sympathetic outflow, and stimulation of renal sodium reabsorption
CI for ACEi
History of ACEi-induced, hereditary, or idiopathic angioedema, pregnancy
ADRs for ACEi
Hyperkalemia, Acute kidney Injury (AKI), dizziness, dry cough, angioedema, liver failure
Key PKPD for ACEi
Almost all ACEi are renally eliminated.
By inhibiting peptidyl dipeptidase (hydrolyzes angiotensin I —> II), the breakdown of bradykinin is also inhibited —→ ADRs such as dry cough and angioedema
DDI for ACEi
Increased risk of hyperkalemia and/or angioedema in combination with other RAAS inhibitors
Pearls of ACEi
If side effects like dry cough develop, try and ARB instead
ACEi examples:
Lisinopril, enalapril, ramipril, quinapril, benazepril, fosinopril
Brand name of valsartan
Diovan
Indication for ARBs
First-line antihypertensive
Other: MI, heart failure with reduced ejection fraction (HFrEF)
MOA for ARBs
Selective, reversible competitive antagonist of angiotensin II receptor. The angiotensin II receptor is responsible for vasoconstriction, aldosterone secretion, sympathetic outflow, and stimulation of renal sodium reabsorption.
CI for ARBs
Pregnancy
ADRs for ARBs
hyperkalemia, AKI, dizziness, angioedema, rhabdomyolysis,
Key PKPD parameters for ARBs
Since they do not impact bradykinin breakdown, no incidence of dry cough, and a very low risk of angioedema
DDI for ARBs
Increased risk of hyperkalemia and/or angioedema in combination with other RAAS inhibitors
Pearls for ARBs
May use first if trying to prevent side effects like dry cough
ARB examples:
valsartan, irbesartan, losartan, candesartan, Olmesartan, telmisartan
Brand name of amlodipine
Norvasc
Brand name of nifedipine
Procardia
Examples of DHP CCBs?
Amlodipine, felodipine, and nifedipine
Indication for DHP CCBs
first-line antihypertensives
Others: anti-anginal
MOA for DHP CCBs
Inhibits calcium ions from entering slow channels of vascular smooth muscle during depolarization leading to vascular smooth muscle relaxation (vasodilation)
ADRs for DHP CCBs
Peripheral edema, pulmonary edema, hepatotoxicity, thrombocytopenia
Key PKPD for DHP CCBs
May cause reflex sympathetic activation —→ slight tachycardia and increase in cardiac output.
Amlodipine may take up to one week to see full BP lowering effects (half-life of 30-50 hours)
DDI for DHP CCBs
Major substrate of CYP3A4
Key counseling points for DHP CCBs
Immediate release nifedipine has an increased risk of MI and mortality. ONLY USE EXTENDED RELEASE
Brand name of diltiazem
Cardizem
Brand name of verapamil
Calan
Examples of Non-DHP CCBs
Diltiazem, Verapamil
Indication for Non-DHP CCBs
first-line antihypertensive
Other: angina, atrial arrhythmia
MOA of Non-DHP CCB
Inhibits calcium ions from entering slow channels of vascular smooth muscle and myocardium during depolarization leading to vascular smooth muscle relaxation (vasodilation) and slows automaticity of AV node (decreases HR)
CI for Non-DHP CCBs
2nd or 3rd degree heart block
ADRs for Non-DHP CCBs
Peripheral edema, pulmonary edema, headache, heart failure, heart block, hepatotoxicity
Key PKPD for Non-DHP CCBs
Verapamil has the greatest depressant effect on the sympathetic nervous system (HR/CO)
Diltiazem has modest effects