ANTI-HYPERTENSIVE AGENTS: Vasodilators

PHCL-L3-Cardiopharm-lecture09

Classification of Vasodilators
(according to mechanism and Site of Action)
Directly acting Vasodilators Act directly on Vascular smooth muscles Organic nitrates Drugs acting on K channels Calcium Channel Blockers, Indirectly acting Vasodilators Inhibit action of endogenous constrictors Those that inhibit sympathetically mediated vasocontriction Those that inhibit renin-angistensin system
2

Effects of Vasodilators
Vasodilators act:
To increase total tissue blood flow To reduce arterial pressure To reduce central venous pressure

Net effect:
Reduction of cardiac preload (reduced filling pressure) and after-load (reduced vascular resistance), hence reduction in cardiac work.
3

Vasodilators
Uses:
Angina pectoris
(Ca antagonists,organic nitrates)

Cardiac failure
(ACE inhibitors, organic nitrates)

Hypertension
(-antagonists)

Hypertensive crisis
(nitroprusside, hydralazine, diazoxide)
4

Activators of NO/guanylate cyclase pathway

a1 Adrenoreceptor
antagonists Prazosin

Hydralazine ? Nitroprusside Nitroglycerin

NO

Ca2+ - channel blockers Dihydropiridines Verapamil Diltiazem

Ca2+

VSMCs

Ang II receptor antagonists Losartan

K+
K+ - channels activators Minoxidile Diazoxide

Peripheral
Vasodilators
5

Mechanism of action and pharmacologic effects of Organic Nitrates

Mechanism of Action:
Relax smooth muscles by intracellular

conversion of nitrates to Nitric Oxide (NO) NO activates guanylate cyclase and increases the cells cyclic GMP Elevated cGMP dephosphorylate myosin light chain, resulting in vascular smooth muscle relaxation

Pharmacologic effects:
Relieving coronary vasospasm redistributing myocardial blood flow to ischaemic areas of the myocardium Tolerance can develop rapidly to the effects of

nitrate therapy

Common Adverse Drug Reactions of organic nitrates

Headache
Increase dose slowly

Hypotension
GLYCERYL TRINITRATE causes syncope

Peripheral Vasodilators

Vasodilators (for use in Hypertension)

Hydralazine Minoxidil Sodium Nitroprusside Diazoxide
***

Vasodilators (for use in Angina)

GLYCERYL TRINITRATE (GTN), ISOSORBIDE MONONITRATE ISOSORBIDE DINITRATE

Sodium nitroprusside
Sodium nitroprusside
short-acting agent (few minutes) administrated by infusion in hypertensive emergencies
(hypertensive encephalopathy, shock, cardiac dysfunction) for max 24 hours (risk of cumulation of cyanide toxicity)

+ NO CN ++ Fe CN CN CN CN -

Releases NO the stock solution should be diluted and covered with foil to prevent photodeactivation adverse effects:
too rapid reduction of BP, nausea, palpitation, dizziness cyanide metabolite accumulation tachycardia, hyperventilation, arrhythmias, acidosis

Peripheral Vasodilators for Hypertension.

Hydralazine:

Minoxidil:

rapidly and fairly absorbed after oral administration useful for hypertensive crisis during pregnancy Adverse effects: Na+ and water retention, systemic lupus erythematosus

Last choice for treatment of hypertension: therapy of severe

hypertension resistant to other drugs

prodrug

channel opener ( repolarization + relaxation of vascular smooth muscle)

more effect on arterioles than on veins orally active

its metabolite (minoxidil sulfate) is a potassium

Adverse effects:

Na+ and water retention coadministration with beta-vlocker and diuretic is

mandatory for this drug, oedemas, hypertrichosis, breast tenderness, Headache, sweating
10

Topical minoxidil (Rogaine) used for correction of baldness.

Nitrovasodilators for Angina

GLYCERYL TRINITRATE (GTN)
Sublingual (To avoid first pass metabolism ), buccal, transdermal

ISOSORBIDE MONONITRATE
Sustained release formulation, tablets

ISOSORBIDE DINITRATE (RISORDAN)

Sustained release formulation, tablets

11

Specific Uses of Nitrates

GLYCERYL TRINITRATE (Nitriderm)
Used for the rapid treatment of angina pain. To avoid first pass metabolism is given by the sublingual route. May be used frequently and prophylactically

Oral Nitrates
Commonly given as a once a day sustained release formulation Used for prophylaxis

12

Vasodilators: K channels activators

Cause vasodilation by activating K channels
Eg: Diazoxide
given by rapid iv. injection (less than 30 seconds)* in hypertensive emergencies -it is a potassium channel opener Adv effects:

glucose intolerance due to reduced insulin secretion (used in patients with inoperable insulinoma) Na+ and water retention, hyperglycaemia, hirsutism

used for treating hypertensive emergencies but diazoxide may rarely be used if accurate infusion pumps are not available and/or close monitoring of blood pressure is not available
13

Why do we have to combine vasodilators with b-blockers and diuretics?