Pharmacology of HTN

Diuretics

drugs that decrease blood volume

sympatholytics and direct vasodilators

drugs that decrease cardiac output or peripheral vascular resistance

-ACE inhibitors

-Angiotensin II receptor blockers

-Direct Renin Inhibitor

drugs that interfere with the renin-angiotensin system

HTN drugs MOA

allows combination of drugs from 2 or more groups with increased efficacy, and in some cases decreased toxicity

polypharmacy

most pts require 2 or more drugs

-thiazides

-potassium (K+)

Diuretic drug classes:

-alpha and beta blockers

-clonidine

-methyldopa

Sympathetic nervous system depressants (sympatholytics) drugs

-calcium channel blockers

-hydralazine

-minoxidil

Direct vasodilator drugs

-ace inhibitors

-angiotensin II receptor antagonists

-direct renin inhibitor

Inhibitors of the renin-angiotensin system (RAS)

Diuretics MOA

increase excretion of Na+ & water → ReduceBP by reducing blood volume

electrolyte disturbances (hypokalemia) and hypotension

What is the toxicity with diuretics?

10-15 mmHg

How much do diuretics lower BP by?

Thiazides

first choice diuretics

-Thiazides

-Potassium-sparing diuretics (adjuvant)

What are the diuretics used in HTN?

tubular secretion

Thiazide diuretics are secreted into luminal fluid by ______ in PCT.

Thiazide diuretic MOA

Inhibit Na+ reabsorption in the distal convolutedtubule by blocking NCC → ↑ water excretion (↓ CO)

hypokalemia

Thiazide diuretics can cause hyper or hypokalemia?

Hydrochlorothiazide (HCTZ)

DOC for thiazide, dosed every 8-12 hours

Chlorthalidone

-longer DoA (t1/2 50-60h) → more stable effect

-not very lipid-soluble

-less potent than HCTZ, requires large doses

-only thiazide diuretics available IV

-HCTZ

-Chlorthalidone

-Indapamide

-Metolazone

What are thiazide drugs?

Thiazide diuretics AE

-hypotension

-photosensitivity (serious hypersensitivity skin reactions)

-hypokalemia

-hyponatremia

-hypomagesemia

-hyperuricemia

-hyperglycemia

-increase SCr

Potassium-sparing diuretics

-weak diuretics

-adjunctive therapy with other diuretics to help with K+ balance

-prevent K+ excretion at collecting tubules

-hyperkalemia

-interferes with H+ (metabolic acidosis)

Mineralocorticoid Receptor Antagonist (MRAs)

antagonize aldosterone receptors directly

-Spironolactone (Aldactone)

-Eplerenone (Inspra)

What are the mineralcorticoid receptor antagonists (MRAs)?

ENaC blockers

inhibit Na+ flux, which is coupled with K+ secretion

EnaC Blockers

-Amiloride

-Triamterene

Aldosterone Antagonists

-Spironolactone (Aldactone)

-Eplerenone (Inspra)

Spironolactone (Aldatone)

-Competitive aldosterone antagonist→ increased Na+ excretion, water follows; K+ is retained

-Slow onset/offset of action (days before effect, DoA 24-48h)

-Synthetic steroid

-Off-target: Also target & antagonizes androgenreceptors

Spironolactone AE

hyperkalemia, menstrual abnormalities, gynecomastia, ED, headache, GI upset, increased SrCr

Eplerenone (Inspra)

-spironolactone analog

-more selective anti-aldosterone activity (less AE)

-CYP3A4 substrate, caution with strong inhibitors, including grapefruit

Eplerenone (Inspra) AE

mild hyperkalemia, GI, increased SrCr

to decrease sympathetic function (decrease BP)

Why do we choose sympatholytics?

-Clonidine

-Methyldopa

Centrally acting drugs:

Non-selective beta-adrenoreceptor antagonists (beta blockers)

-propranolol

-nadolol

-pindolol

Beta-1 beta-adrenoreptor antagonist (beta blockers)

-metoprolol

-atenolol

-acebutolol

-betaxolol

-nebivolol

-esmolol

mixed alpha and beta blockers

-labetalol

-carvedilol

alpha-adrenoreceptor blocking agents (alpha-1 blockers)

-prazosin

-terazosin

-doxazosin

centrally acting sympatholytic drugs

-less common in practice, but still imp

-likely to cause CNS-related AEs (may produce drowsiness, disturbances of sleep, including nightmares)

-decrease sympathetic outflow from vasomotor center of brainstem

centrally acting sympatholytic drugs

-Clonidine (Catapres)

-Methyldopa

Clonidine MOA

-α2 agonist (α2 >>> α1 selectivity)

-Reduces sympathetic outflow and ↑ parasympathetic outflow from CNS (medulla)

-Decreases catecholamine release via presynaptic α2 receptor agonism inpostganglionic fibers → Reduction of CO (↓ HR and relaxation of capacitance vessels)and ↓ PVR.

-Decreases plasma NE concentration

Clonidine AE

dry mouth, sedation, bradycardia, orthostatic, hypotension, sudden withdrawal syndrome (rebound HTN)

Methyldopa

-primarily for HTN during pregnancy

-lowers BP mostly by reducing PVR with variable reduction in HR and CO

-analog of L-DOPA