Pharmacology and PKPD of Antihypertensives

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