DRUGS USED IN HYPERTENSION

Wilsie M. Salas MD

Hypertension
Pathophysiology

VASOMOTOR CENTERS Parasympathetic ANS Sympathetic ANS Baroreceptor Peripheral Contractile Vascular Heart rate forces Resistance

Venous tone

Mean Arterial Pressure

Cardiac output

Stroke volume

Venous return

Blood volume

Aldosterone

Renal blood flow

RENIN

Angiotensin

Sympathetic
maintaining a normal blood pressure stimulation can cause both arteriolar constriction and arteriolar dilatation important in the mediation of short term changes in blood pressure in response to stress and physical exercise

Renin Angiotensin Aldosterone

Renin
Produced in the JG cells of the kidneys Renin is responsible for converting renin substrate (angiotensinogen) to angiotensin I, a physiologically inactive substance which is rapidly converted to angiotensin II in the lungs by angiotensin converting enzyme (ACE). Angiotensin II is potent vasoconstrictor

Renin Angiotensin Aldosterone

Angiotensin II potent vasoconstrictor Additional effect is stimulates the release of aldosterone from the zona glomerulosa of the adrenal gland, which results in a further rise in blood pressure related to sodium and water retention.

ReninAngiotensin Aldosterone System

Strategies for treating HTN

Reduction of blood volume Reduction of sympathetic tone Reduction of vascular smooth muscle tone Reduction of angiotensin effects

VASOMOTOR CENTERS Parasympathetic ANS Sympathetic ANS Baroreceptor` Peripheral Contractile Vascular Heart rate forces Resistance

Venous tone

Mean Arterial Pressure

Cardiac output

Stroke volume

Venous return

Blood volume

Aldosterone

Renal blood flow

RENIN

Angiotensin

Drugs for hypertension

Diuretics Sympathoplegics blockers Vasodilators Angiotensin antagonist

Ganglia

a/b blockers Nerve terminal Calcium blockers

ACE inhibitors

Receptor blockers

CNS sympathetic outflow

Older oral vaodilators

Parenteral vasodilators

DIURETICS
Lower the blood pressure by reduction of blood volume and by direct vascular effects Carbonic anhydrase inhibitors; loop diuretics; Thiazides; K+ sparing diuretics and osmotic diuretics More important: Loop Diuretics (furosemide) thiazide diuretics (hydrochlorthiazide)

Loop Diuretics
Prototype: Furosemide Others: Bumetanide, Torsemide (sulfonamide derivative; ethacrynic acid (phenoxyacetic acid derivative) Action: inhibit the cotransport of Na, K and Chloride at the thick ascending loop of henle Short acting usually 4 hrs Toxicity: hypokalemic metabolic acidosis, ototoxicity

Thiazide diuretics
Prototype: Hydrochlorthiazide Active by oral route duration of action 6-12hrs Action: inhibit the NaCl transport in the early segment of the distal convuluted tubule Toxicity: potassium wasting, uric acid increase

Sympathoplegics
Drugs that interfere with sympathetic blockade The result is reduced in one of the ff:
Vascular tone Heart rate Contractile force Cardiac output Total peripheral resistance

Sympathoplegics
A. CNS Active Agents
Alpha 2 selective agonists (Clonidine, methyldopa) causes a decrease in sympathetic outflow by activation of a2 receptors in the Central Nervous system Methyldopa: prodrug Converted to methylnorepinephrine in the brain

Sympathoplegics
B. Ganglion blocking drugs
Nicotinic blockers acting on the ganglia are very good and efficacious however their adverse effects are severe Hexamethonium and trimetaphan Toxicities: (parasympathetic blockade) blurred vision, constipation, urinary hesitancy, sexual dysfunction (sympathetic blockade) sexual dysfunction, orthostatic hypotension

Sympathoplegics
C. Postganglionic Sympathetic Nerve Terminal Blockade
Drugs that deplete the nerve terminals of its norepinephrine stores that deplete and blocks the release of the stores ( Guanethidine, reserpine) MAO Inhibitors: causes the formation of false transmitter called Octopamine causes diminished vascular & cardiac response

Sympathoplegics
D. Adrenoceptor blockers
Alpha-1-blockers: reduce vascular resistance and venous returns Beta Blockers: initially reduces cardiac output after some time may cause decrease in vascular resistance ( due to the dual action of beta blockers that reduces renin release) Toxicity: elevated lipid levels, glucose and diminished HDL levels

Vasodilator
Dilate blood vessels by acting directly on the smooth muscle through non autonomic mechanism Four major mechanisms:
Release of nitric oxide Opening of Potassium channels Blockade of Calcium channels Activation of Dopamine receptors

Vasodilator
Most commonly used Vasodilators
Hydralazine & Minoxidil Calcium channel blockers Nitroprusside & Diazoxide Fenoldopam

Vasodilator
Hydralazine and Minoxidil
Older vasodilators, orally active suitable for chronic therapy More effect on the arterioles than the veins MOA: release of Nitric oxide from endothelial cells Rarely used at higher dosages due to its toxicities i.e. Tachycardia and salt and water retention (compensatory mechanism)

Vasodilator
Hydralazine and Minoxidil
Minoxidil prodrug; metabolite Monoxidil sulfate is a potassium channel opener that hyperpolarizes the and relaxes smooth muscle

Vasodilator
Calcium channel blocker
Block the L-type calcium channels, causing decrease influx of Calcium during action potential in a frequency and voltage dependent manner thus reducing muscle contractility Effect: relaxation of blood vessels, uterus, bronchii Orally active, chronic use in hypertension Nifedipine, Verapamil & Diltiazem

Vasodilator
Nitroprusside & Diazoxide
Nitroprusside: Release of nitric oxide which stimulates guanylyl cyclase, increasing the release of cGMP (Cyclic guanyl monophosphate) in smooth muscles; short acting few minutes thus given by continuous infusion Diazoxide: opens potassium channels thus causing hyperpolarization and relaxation of smooth muscles; duration of action is several hours given in IV boluses

Vasodilator
Fenoldopam
Dopamine 1 agonist causing marked arteriolar vasodilation IV infusion only short duration of action (10mins) and for hypertensive emergencies

Angiotensin Antagonist
Angiotension converting enzyme inhibitors
Angiotensin I Angiotensin converting enzyme (ACE) Angiotensin II

Inhibition of aldosterone, facilitates the release of kinins that are actually endogenous vasodilators Captopril Angiotensin II receptor blocker
Inhibits Angiotensin II at AT1 receptor site Losartan, valsartan, irbesartan and candesartan

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