FARMAKOLOGI I

THABRANI PUTRA, dr.

DEPARTMENT OF FARMAKOLOGI
FAKULTAS KEDOKTERAN UNIVERSITAS MALAHAYATI BANDAR LAMPUNG

ANTIHIPERTENSI

PENDAHULUAN

Hipertensi adalah peningkatan tekanan darah (sistole > 140 mmHg, diastole > 90 mmHg). Klasifikasi berdasarkan JNC VII, 2003. TD ditentukan oleh : cardiac output dan peripheral vascular resistance. Organ yang berpengaruh : jantung, pembuluh darah, ginjal.

Drugs used in hypertension

The four major groups of antihypertension drugs :
1. 2. 3.

4.

Diuretics Sympathoplegics Vasodilator Angiotensin antagonis

Diuretics

These drugs lower Blood Pressure (BP) by reduction of Blood volume (BV). The most important diuretics for hypertension therapy are The Thiazides and The loop diuretics. The Thiazides adequate in mild hypertension. The Loop diuretics adequate in moderate, severe & malignant hypertension.

Sympathoplegics

Sympathoplegics sympathetic nerve function in several ways Effects : reduction of venous tone, Heart rate (HR), contractile force of the heart, Cardiac Output (CO) & total peripheral resistance Compensatory responses & adverse effects are marked Classification : - Baroreceptor-sensitizing agents - CNS-active agents - Ganglion-blocking drugs - Postganglionic Sympathetic nerve terminal blockers - Adrenoceptor blockers

Baroreceptor-sensitizing agents

Effects : reducing sympathetic outflow and increasing parasympathetic outflow No currently available drugs act at this site .

CNS-Active Agents

Prototype : Alpha2-selective agonists (clonidine, methildopa) Effects : reducing sympathetic outflow by activation of 2 receptors in the CNS The drugs readily enters the CNS when given orally Methildopa is prodrug; it is converted to methilepinephrine in the brain. Tox : salt retention, rebound hypertension (sudden dicontinuation of clonidine), hematologic immunotoxicity-hemolytic anemia (methyldopa), sedation (both drugs)

Ganglion-blocking drugs

Prototype : nicotinic blockers (trimetaphan, hexamethonium) Effects : extremely powerful BP-lowering Tox : - salt retention. - blurred vision, constipation, urinary hesitancy, sexual dysfunction. - sexual disfunction, orthostatic hypotension

Postganglionic sympathetic nerve terminal blockers

Prototype & mechanism of action: Reserpine (deplete the adrenergic nerve terminal of its NE stores). Guanethidine (block release of the stores). In high dose these drugs are very efficacious but produce a high incidence of adverse effects. Have long duration action. Toxicity : behavioral depression (discontinuation of reserpin), orthostatic hypotension & sexual dysfunction(guanethidine).

Adrenoceptor Blockers

Prototype : -blockers (prazosin-a selective agent, phentolamine, phenoxybenzamine), -blockers (propanolol) Mechanism of action : Reduce vasc resistance & venous return (alphablocker). Reduce CO, decrease vasc resistance, reduce angiotensin levels The non-selective -blockers are of no value in chronic hypertension because of excessive compensatory responses, especially tachycardia

Vasodilator

Drugs that dilate blood vessels by acting directly on smooth muscle cells. Four major mechanism : - release of nitric oxide. - opening of potassium channels. - blockade of calcium channels.

Vasodilator
Hydralazine & Minoxidil They have more effects on arterioles than on venous. Orally active & suitable for chronic therapy. Mechanism of action : release of nitric oxide from endothelial cells (hydralazine) potassium channel opener (minoxidil) Toxicity : tachycardia, salt&water retention, drug-induced lupus erythematosus (hydralazine) severe compensatory response, hirsuitisme, pericardial abnormality (Minoxidil)

Vasodilator
Ca-channel Blocker Prototype : nifedipine, verapamil, diltiazem They are effective venodilator because they are orally active, suitable for chronic hypertension of any severity. They produce fewer compensatory response.

Vasodilator
Nitroprusside & Diazoxide Mechanism of action :

nitroprussid release of nitric oxide. diazoxide opens potassium channels, thus hyperpolarizing and relaxing smooth muscle

These drugs given parenterally, used in hypertensive emergencies Toxicity :

excessive hypotension, tachycardia, cyanide toxicity (nitroprusside). hypotension, hyperglycemia (because this drug reduces insulin release), salt&water retention

Fenolopam Mechanism of action : D1 receptor activation (arteriolar vasodiation) Given by IV infusion, used in hypertensive emergencies

Angiotensin Antagonists

The groups : Angiotensin Converting Enzyme (ACE) inhibitor (captopril). angiotensin II receptor blockers (losartan, valsartan, irbosartan, candesartan). These drugs are given by oral administration Effects : ACE-inhibitor : a reduction in blood levels of angiotensin II and aldosterone, probably an increase endogenous vasodilators of the kinin family Toxicity : ACE inhibitor : cough, renal damage in patient with preexisting renal vasc disease, renal damage in the fetus. Angiotensin II receptor blockers : fetal renal toxicity, potassium retention These drugs are absolutely contraindicated in pregnancy