FARMAKOLOGI IFARMAKOLOGI I

THABRANI PUTRA, dr.THABRANI PUTRA, dr.

DEPARTMENT OF FARMAKOLOGIDEPARTMENT OF FARMAKOLOGIFAKULTAS KEDOKTERAN UNIVERSITAS MALAHAYATIFAKULTAS KEDOKTERAN UNIVERSITAS MALAHAYATI

BANDAR LAMPUNGBANDAR LAMPUNG

ANTIHIPERTENSIANTIHIPERTENSI

PENDAHULUANPENDAHULUAN

Hipertensi adalah peningkatan tekanan darah Hipertensi adalah peningkatan tekanan darah (sistole > 140 mmHg, diastole > 90 mmHg).(sistole > 140 mmHg, diastole > 90 mmHg).

Klasifikasi berdasarkan JNC VII, 2003.Klasifikasi berdasarkan JNC VII, 2003. TD ditentukan oleh : cardiac output dan TD ditentukan oleh : cardiac output dan

peripheral vascular resistance.peripheral vascular resistance. Organ yang berpengaruh : jantung, pembuluh Organ yang berpengaruh : jantung, pembuluh

darah, ginjal.darah, ginjal.

Drugs used in hypertensionDrugs used in hypertension

The four major groups of antihypertension drugs :The four major groups of antihypertension drugs :

1.1. DiureticsDiuretics

2.2. SympathoplegicsSympathoplegics

3.3. VasodilatorVasodilator

4.4. Angiotensin antagonisAngiotensin antagonis

DiureticsDiuretics

These drugs lower Blood Pressure (BP) by These drugs lower Blood Pressure (BP) by reduction of Blood volume (BV).reduction of Blood volume (BV).

The most important diuretics for hypertension The most important diuretics for hypertension therapy are therapy are The Thiazides and The loop diuretics.The Thiazides and The loop diuretics.

The Thiazides The Thiazides adequate in mild hypertension. adequate in mild hypertension. The Loop diuretics The Loop diuretics adequate in moderate, severe adequate in moderate, severe

& malignant hypertension.& malignant hypertension.

SympathoplegicsSympathoplegics Sympathoplegics Sympathoplegics sympathetic nerve function in sympathetic nerve function in

several waysseveral ways Effects Effects : reduction of venous tone, Heart rate (HR), : reduction of venous tone, Heart rate (HR),

contractile force of the heart, Cardiac Output (CO) & contractile force of the heart, Cardiac Output (CO) & total peripheral resistancetotal peripheral resistance

Compensatory responses & adverse effects are markedCompensatory responses & adverse effects are marked ClassificationClassification : :

- Baroreceptor-sensitizing agents- Baroreceptor-sensitizing agents- CNS-active agents- CNS-active agents- Ganglion-blocking drugs- Ganglion-blocking drugs- Postganglionic Sympathetic nerve terminal blockers- Postganglionic Sympathetic nerve terminal blockers- Adrenoceptor blockers- Adrenoceptor blockers

Baroreceptor-sensitizing agentsBaroreceptor-sensitizing agents

Effects Effects : : reducing sympathetic outflow and reducing sympathetic outflow and increasing parasympathetic outflowincreasing parasympathetic outflow

No currently available drugs act at this site .No currently available drugs act at this site .

CNS-Active AgentsCNS-Active Agents Prototype : AlphaPrototype : Alpha22-selective agonists (-selective agonists (clonidine, clonidine,

methildopamethildopa)) Effects : reducing sympathetic outflow by activation of Effects : reducing sympathetic outflow by activation of

22 receptors in the receptors in the CNSCNS The drugs readily enters the CNS when given orallyThe drugs readily enters the CNS when given orally MethildopaMethildopa is prodrug; it is converted to is prodrug; it is converted to

methilepinephrine in the brain.methilepinephrine in the brain. ToxTox : salt retention, rebound hypertension (sudden : salt retention, rebound hypertension (sudden

dicontinuation of clonidine), hematologic dicontinuation of clonidine), hematologic immunotoxicity-hemolytic anemia (methyldopa), immunotoxicity-hemolytic anemia (methyldopa), sedation (both drugs) sedation (both drugs)

Ganglion-blocking drugsGanglion-blocking drugs

Prototype : nicotinic blockers (Prototype : nicotinic blockers (trimetaphan, trimetaphan, hexamethoniumhexamethonium))

EffectsEffects : extremely powerful BP-lowering : extremely powerful BP-lowering ToxTox : :

- salt retention.- salt retention.- blurred vision, constipation, urinary hesitancy,- blurred vision, constipation, urinary hesitancy, sexual dysfunctionsexual dysfunction..- sexual disfunction, orthostatic hypotension- sexual disfunction, orthostatic hypotension

Postganglionic sympathetic nerve Postganglionic sympathetic nerve terminal blockersterminal blockers

Prototype & mechanism of action: Prototype & mechanism of action: ReserpineReserpine (deplete the adrenergic nerve terminal of (deplete the adrenergic nerve terminal of

its NE stores).its NE stores). GuanethidineGuanethidine (block release of the stores). (block release of the stores).

In high dose these drugs are very efficacious but In high dose these drugs are very efficacious but produce a high incidence of adverse effects.produce a high incidence of adverse effects.

Have long duration action.Have long duration action. ToxicityToxicity : : behavioral depression (discontinuation of behavioral depression (discontinuation of

reserpin), orthostatic hypotension & sexual reserpin), orthostatic hypotension & sexual dysfunction(guanethidine).dysfunction(guanethidine).

Adrenoceptor BlockersAdrenoceptor Blockers

Prototype : Prototype : -blockers (-blockers (prazosinprazosin-a selective agent, -a selective agent, phentolamine, phenoxybenzaminephentolamine, phenoxybenzamine), ), ββ-blockers -blockers ((propanololpropanolol))

Mechanism of action : Mechanism of action : Reduce vasc resistance & venous return (alpha-Reduce vasc resistance & venous return (alpha-

blocker).blocker). Reduce CO, decrease vasc resistance, reduce Reduce CO, decrease vasc resistance, reduce

angiotensin levelsangiotensin levels The non-selective The non-selective -blockers are of no value in -blockers are of no value in

chronic hypertension because of excessive chronic hypertension because of excessive compensatory responses, especially tachycardiacompensatory responses, especially tachycardia

VasodilatorVasodilator

Drugs that dilate blood vessels by acting Drugs that dilate blood vessels by acting directly on smooth muscle cells.directly on smooth muscle cells.

Four major mechanism :Four major mechanism :- release of nitric oxide.- release of nitric oxide.- opening of potassium channels.- opening of potassium channels.- blockade of calcium channels.- blockade of calcium channels.

VasodilatorVasodilator

Hydralazine & MinoxidilHydralazine & Minoxidil They have more effects on arterioles than on venous.They have more effects on arterioles than on venous. Orally active & suitable for chronic therapy.Orally active & suitable for chronic therapy. Mechanism of actionMechanism of action : :

release of nitric oxide from endothelial cells release of nitric oxide from endothelial cells (hydralazine)(hydralazine)

potassium channel opener (minoxidil)potassium channel opener (minoxidil) ToxicityToxicity : :

tachycardia, salt&water retention, drug-induced tachycardia, salt&water retention, drug-induced lupus erythematosus (hydralazine)lupus erythematosus (hydralazine)

severe compensatory response, hirsuitisme, severe compensatory response, hirsuitisme, pericardial abnormality (Minoxidil)pericardial abnormality (Minoxidil)

VasodilatorVasodilator

Ca-channel BlockerCa-channel Blocker Prototype : Prototype : nifedipine, verapamil, diltiazemnifedipine, verapamil, diltiazem They are effective venodilator because they are They are effective venodilator because they are

orally active, suitable for chronic hypertension orally active, suitable for chronic hypertension of any severity.of any severity.

They produce fewer compensatory response.They produce fewer compensatory response.

VasodilatorVasodilatorNitroprusside & DiazoxideNitroprusside & Diazoxide Mechanism of action : Mechanism of action :

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

smooth musclesmooth muscle These drugs given parenterally, used in hypertensive emergenciesThese drugs given parenterally, used in hypertensive emergencies Toxicity Toxicity : :

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

salt&water retentionsalt&water retention

FenolopamFenolopam Mechanism of action : D1 receptor activation (arteriolar Mechanism of action : D1 receptor activation (arteriolar

vasodiation)vasodiation) Given by IV infusion, used in hypertensive emergenciesGiven by IV infusion, used in hypertensive emergencies

Angiotensin AntagonistsAngiotensin Antagonists The groups :The groups :

Angiotensin Converting Enzyme (ACE) inhibitor (Angiotensin Converting Enzyme (ACE) inhibitor (captoprilcaptopril).). angiotensin II receptor blockers (angiotensin II receptor blockers (losartan, valsartan, losartan, valsartan,

irbosartan, candesartanirbosartan, candesartan). ). These drugs are given by oral administrationThese drugs are given by oral administration

Effects : Effects : ACE-inhibitor : a reduction in blood levels of angiotensin II ACE-inhibitor : a reduction in blood levels of angiotensin II

and aldosterone, probably an increase endogenous and aldosterone, probably an increase endogenous vasodilators of the kinin familyvasodilators of the kinin family

Toxicity : Toxicity : ACE inhibitor : cough, renal damage in patient with ACE inhibitor : cough, renal damage in patient with

preexisting renal vasc disease, renal damage in the fetus.preexisting renal vasc disease, renal damage in the fetus. Angiotensin II receptor blockers : fetal renal toxicity, Angiotensin II receptor blockers : fetal renal toxicity,

potassium retentionpotassium retention These drugs are absolutely contraindicated in pregnancy These drugs are absolutely contraindicated in pregnancy