Drugs Affecting the Cardiovascular System

Ion Channels Blockers Antihypertension Drugs The Treatment of Congestive Heart Failure Antiarrhythmic Drugs Antianginal Drugs Antihyperlipidemic Drugs and Anti-artherosclerosis Drugs

Antihypertensive Drugs
OVERVIEW
Hypertension is defined as a sustained diastolic blood pressure greater than 90 mmHg (mercury) accompanied by an elevated systolic blood pressure(>140 mmHg). Hypertension results from increased peripheral vascular smooth muscle tone, which leads to increased arteriolar resistance and reduced capacitance of the venous system. Elevated blood pressure is an extremely common disorder, affecting approximately 10-15% of the population. Although many of these individuals have no symptoms, chronic hypertensioneither systolic or diastolic can lead to congestive heart failure, myocardial infarction, renal damage, and cerebrovascular accidents. The incidence of morbidity and mortality significantly decreases when hypertension is diagnosed early and is properly treated.

 ETIOLOGY OF HYPERTENSION
Essential/primary hypertension: more than 90% of patients
have essential hypertension, a disorder of unknown origin affecting the blood pressure-regulating mechanism. A family history of hypertension in creases the likelihood that an individual will develop hypertensive disease. Essential hypertension occurs more often among middle-aged males than among middle-aged females. Environmental factors such as a stressful lifestyle, high dietary intake of sodium, obesity, and smoking all further predispose an individual to the occurrence of hypertension.

 ETIOLOGY OF HYPERTENSION
Secondary hypertension: occurs in 5-10% of patients. The cause is usually one of the following: Renal disease which activates the ReninAngiotensin-Aldosterone System (RAAS) Endocrine disease, steroid-secreting turmour of the adrenal cortex, adrenaline-secreting tumour of the adrenal medulla.

MECHANISMS FOR CONTROLLING BLOOD PRESSURE Arterial blood pressure is regulated within a narrow range to provide adequate perfusion of the tissues without causing damage to the vascular system, particularly the arterial intima. Arterial blood pressure is directly proportional to the product of the blood volume, cardiac output and the peripheral vascular resistance. In both normal and hypertensive individuals, blood volume cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms: the baroreflexes mediated by the sympathetic nervous system, and the renin-angiotensin-aldosterone system (RAAS). Most antihypertensive drugs lower blood pressure by reducing cardiac output and /or decreasing peripheral resistance.

Classification of Antihypertension I. Sympatholytic drugs

II. Vasodilators
III. Inhibitors of RAS IV. Diuretics

Classification I Sympatholytic drugs (drugs

that alter sympathetic nervous system function) 1.central antihypertensive drugs Clonidine, Methyldopa 2.ganglion-blocking agents( ganglionic blocking drugs) Mecamylamine 3.adrenergic neuron blocking agents( antipostganglionic sympathetic neurons) reserpine, guanethidine

4.adrenoceptor antagonists (adrenergic receptor blocking agents) -adrenoceptor-blocking agents propranolol -adrenoceptor-blocking agents prazosin and -blockers labetalol

Classification II Vasodilators
1. direct vasodilators hydralazine sodium nitroprusside 2. calcium channel blockers( calcium antagonists) nifedipine nitrendipine 3. potassium channel openers minoxide diazoxide pinacidil

Classification III Inhibitors of RAS

1.angiotensin converting enzyme inhibitors. ACEI captopril enalapril 2.angiotensin receptor-blocking agents losartan valsartan 3. renin inhibitors: Enalkiren , Remikiren

Classification VI Diuretics
hydrochlorothiazide indapamide

Classification I. Sympatholytic drugs Subtype 1. Central antihypertensive drugs Normal regulation of blood pressure in CNS:
Vasomotor centers Inhibiting neurons:2 receptor resulting in blood pressure lowering bradycardia vasodilatation Exciting neurons: receptors resulting in blood pressure enhancing tachycardia

Center nervous system controls peripheral sympathetic activity in brain stem

 Clonidine and Methyldopa may stimulate inhibiting neurons of central adrenoceptors-2 receptor, resulting in vasodilation, blood pressure lowers.

Drug 1. Clonidine
2- imidazoline derivation Pharmacokinetics: Lipid-soluble, rapid absorption by oral administration F, 75% t1/2 8~12 hours 30%~ 50% metabolisms in liver Others are eliminated unchanged in urine

Mechanism of action:
1.stimulating postsynaptic 2 adrenoceptors in brain stem peripheral sympathetic activity blood pressure producing sedation 2.stimulating 1-imidazoline receptor in rostral ventrolateral medulla oblongata (RVLM)peripheral sympathetic activity lowering 3.stimulating opium receptor relieving abstinence syndrome

Pharmacodynamics:
1. Relaxation of arterial vessels reduction in peripheral vascular resistance blood pressure lowers 2. Contracting force of cardiac muscule reduction of cardiac output heart rate decreases 3. Decreased renal vascular resistance and maintenance of renal blood flow 4. Inhibiting movement and secretion of gastrointestinal tract hypertensive patients with ulcer is the better

Adverse reaction: 1.dry mouth/ xerostomia (dry nasal mucosa, dry eyes), nausea, dizziness, sedation, parotid gland swelling and pain, sleep disturbances with vivid dreams or nightmares 2.water and sodium (Na+) retention 3.withdrawal syndrome headache apprehension, tremors, abdominal pain, sweating, tachycardia treatment: -adrenergic blocker (phentolamine) continuative administration clonidine

Drug 2. Methyldopa
1.center antihypertension drug 2.treatment: mild to moderately severe hypertension with renal failure 3.reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output 4.no decreasing renal blood flow and glomerular filtration rate

Clinical uses: 1.moderate hypertensive disease 2.iv drop, therapy of hypertensive crisis 3.controlling abstinence syndrome of opium

Subtype 2. ganglion-blocking agents( ganglionic blocking drugs)

Drug: Mecamylamine

Subtype 3. Adrenergic neuronblocking agents

Drug 1. Reserpine
Pharmacological action: 1. lower blood pressure, with long-term therapy with reserpine cardiac output peripheral vascular resistance heart rate rennin secretion falls salt and water are retained 2. sedative and neuroleptic effect reserpine depletes catecholamine and 5hydroxytryptamine (5-HT)

Mechanism of action: Reserpine can remain bound to amine pump of vesicular membranes in central and peripheral adrenergic neurons for prolonged periods of time. The storage vesicles are destroyed as a result of their interaction with reserpine and nerve endings lose their ability to concentrate and store norepinephrine and dopamine.

 Catecholamines leak into the cytoplasm, where they are destroyed by intraneruronal monoamine oxidase (MAO), depressing the ability to uptake norepinephrine
Reserpine -induced depletion of biogenic amines correlates with evidence of sympathetic dysfunction and antihypertensive effects.

 Recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks after discontinuation of the drug, so effect of reserpine is slow and persistent. Clinical uses: Mild hypertension Cooperative administration

Adverse effects: Sedation and inability to concentrate or perform complex tasks are the most common adverse effects.
More serious is the occasional psychotic depression.

Drug 2. Guanethidine

Mechanism and sites of action: Guanethidine inhibits the release of norepinephrine from sympathetic nerve endings. Guanethidine nerve concentration in transmitter vesicles replaces norepinephrine causes gradual depletion of norepinephrine stores in the nerve ending

Subtype 4. adrenoceptor antagonists (adrenergic receptor blocking agents)

-adrenoceptor-blocking agents propranolol -adrenoceptor-blocking agents prazosin and -blockers labetalol

Drug1.-adrenoceptor-blocking agents
1.Mechanism and sites of action blocking -receptor in heart, decreasing cardiac output depressing secretion of rennin, inhibiting the renninangiotensin-aldosterone system, decreasing level of angiotersin in plasm -blockers may also block -receptor of presynaptic membrane in peripheral prejunctional to reduce sympathetic vasoconstrictor nerve activity decreasing secretion of norepinephrine in never center, affecting sympathetic regulation changing sensitivity of baroreceptor increasing synthesis of prostaglandin

Drugs

propranolol 1 2 metoprolol 1 intrinsic sympathetic mimetic activity atenolol 1 intrinsic sympathetic mimetic activity

Clinical uses: Moderate hypertension or severe hypertension of therapeutic ineffective with other antihypertensive drugs. Adverse reaction: Postural hypotension, dizziness, nausea, vomiting, diarrhea Contraindications: Severe diseases accompanied heart, brain, kidney, arteriosclerosis, dysfunction of circulation

Drug 2. 1-adrenoceptor-blocking agents 1. Mechanism: 1). blocking selectively postsynaptic 1 receptors in arterioles and venules 2). dilating both resistance and capacitance vessels 2. Drugs: 1). prazosin 2). terazosin 3). urapidil

Drug 3. and adrenoceptor -blocking agents

1.Mechanism: Blocking 1 and receptors Blocking action of R> blocking action of 1 R 2.Drugs: labetalol

Classification II. Vasodilators

Summary of the Action and Mechanism 1. Dilating directly arterioles but no veins, lowering blood pressure, relaxing smooth muscle of arterioles. 2. Eliciting compensatory responses, mediated by baroreceptors and the sympathetic nervous system, as well as rennin, angiotension and aldosterone opposing the antihypertensive effect of vasodilator such astachycardia; cardiac output; plasma rennin activity; retention of salt and fluid. 3. Vasodilators are used common by combination with other antihypertensive drugs that oppose the compensatory cardiovascular response.

Subtype1. direct vasodilators

Drugs: 1.hydralazine Action: relaxing smooth muscle in arterioles via release of nitric oxide (NO) in vascular interfere with Ca2+ entering into cell 2.sodium nitroprusside .treating hypertensive emergencies and severe cardiac failure, crisis .dilating both arterial and venous vessels decreasing cardiac preload and afteroad

Subtype 2. Calcium channel blockers

Action:
Antianginal effects Antiarrhythmic effects Dilating peripheral arterioles
Reducing blood pressure

Mechanism of action: inhibiting calcium influx

into arterial smooth muscle cells

Drugs: 1.Nifedipine,Verapamil,Diltiazem 2. Dihydropyridine family: amlodipine, felodipine, isradipine, nicardipine, nifedipine, misolipine, more selective as vasodilators treating selectively angina or coronary spasm prolong effect, slow, persist, smoother, reflex sympathetic activation with slight antiarteriosclerosis

Subtype 3. potassium channel openers

Drugs:
minoxide diazoxide

pinacidil

Classification III. Inhibitors of RAS

NO

PGI2

ACEI and AT blocker

bradykinin

aldosterone

Subtype I. Angiotensin converting enzyme inhibitors ACEI Drugs: Captopril

Mechanism of action: 1.inhibiting ACE angiotensin------angiotensin ACE (-) inhibitors 2.inhibiting RAS( rennin- angiotensin system) in local tissue 3.inhibiting the kalliurein-kini system

4.Accelerating release of prostacyclin(PGI2) vasodilatations decreased peripheral vascular resistance decreased blood pressure

5.accelerating release of nitric oxide (NO) 6.improving myocardial hypertrophy of left ventricle, inhibiting hyperplasia of vascular smooth muscles. decreasing formation of Ang, inhibiting remodeling of myocadia and vascular smooth muscles. 7.cleansing free radical, protecting tissue ischemia and reperfusion injury 8.affecting metabolism decreasing cholesterol and triglyceride increasing HDL (high density lipoprotein)

Subtype II. Antagonist of Angiotensin II Receptor (Angiotensin II Receptor Blockers

Drugs: Losatan Valsartan

Subtype III. renin inhibitors:

Drugs:

Enalkiren, Remikiren

Classification VI Diuretics hydrochlorothiazide

indapamide

 TREATMENT STRATEGIES
Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any of four drugs depending on the individual patient: a diuretic, a b-blocker, an ACE inhibitor, or a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is added. A bblocker is usually added if the initial drug was a diuretic, or a diuretic is added if the first drug was a b-blocker. A vasodilator can be added as a third step for those patients who still fail to respond.

Drugs Affecting the Cardiovascular System

Antihypertension Drugs The Treatment of Congestive Heart Failure Antiarrhythmic Drugs Antianginal Drugs Ion Channels Blockers Antihyperlipidemic Drugs