Antihypertensive Agents Antihypertensive Agents Determinants of BP Peripheral
Antihypertensive Agents
Antihypertensive Agents Determinants of BP: ⦿ � Peripheral Vascular Resistance � Cardiac Output. � Blood Volume and viscosity. Why do we treat hypertension? * Munir Gharaibeh MD, Ph. D, MHPE 2
Benefits of Lowering BP Antihypertensive therapy has been associated with reduction of incidence of: ⦿ Stroke. ⦿ Myocardial infarction. ⦿ Heart failure. * Munir Gharaibeh MD, Ph. D, MHPE 3
* Average 14 readings: two per session, taken morning and evening for 7 days. Munir Gharaibeh MD, Ph. D, MHPE 4
Autonomic and Hormonal Control of Cardiovascular Function * Munir Gharaibeh MD, Ph. D, MHPE 5
Sites of Action of Classes of Antihypertensive Drugs. * Munir Gharaibeh MD, Ph. D, MHPE 6
* Munir Gharaibeh MD, Ph. D, MHPE 7
Diuretics ⦿ Widely recommended as first-line therapy, especially in the elderly, and the obese. ⦿ Inexpensive. ⦿ Can be well combined with others. ⦿ When used in low doses, with sodium restriction, will cause few metabolic side effects, but retain antihypertensive activity. * Munir Gharaibeh MD, Ph. D, MHPE 8
Diuretics ⦿ Weak Diuretics: �Thiazides ⦿ Potent Diuretics: �Loop Diuretics: e. g. Furosemide. ⦿ Diuretics differ in their diuretic activity but not in their antihypertensive activity. * Munir Gharaibeh MD, Ph. D, MHPE 9
Diuretics ⦿ Early Effects (3 -4 days): Decrease Blood Volume ⦿ Late Effects (3 -4 weeks): Decrease Na+ & Cl- in blood vessel walls leading to vasodilation. ⦿ Have * side effects. Munir Gharaibeh MD, Ph. D, MHPE 10
VASODILATORS ⦿ Work directly on blood vessels. ⦿ Reduce peripheral resistance, without impairing autonomic reflexes. ⦿ Work to reduce the availability of intracellular calcium in blood vessel walls. * Munir Gharaibeh MD, Ph. D, MHPE 11
VASODILATORS Cause Tolerance. So, almost always combined with diuretics and/or beta blockers. * Munir Gharaibeh MD, Ph. D, MHPE 12
Compensatory Responses to Vasodilators * Munir Gharaibeh MD, Ph. D, MHPE 13
VASODILATORS Hydralazine: Oldest vasodilator, was withdrawn and then came back. ⦿ Arterial dilator. ⦿ Activates baroreceptor reflex. ⦿ Can cause drug-induced lupus syndrome. ⦿ * Munir Gharaibeh MD, Ph. D, MHPE 14
VASODILATORS Diazoxide: ⦿ Arterial dilator. ⦿ Causes excessive hypotension. ⦿ Used in emergencies by rapid I. V. bolus injection. ⦿ Rapidly bound to albumin. ⦿ Onset 10 -30 seconds. ⦿ Duration 2 -4 hours. ⦿ Does not require constant monitoring. * Munir Gharaibeh MD, Ph. D, MHPE 15
VASODILATORS Sodium Nitroprusside: ⦿ Cyanide-containing molecule. ⦿ Relaxes both arterial and venous smooth muscle. ⦿ No excessive reflex increase in cardiac output. ⦿ Might increase C. O. if there is failure. * Munir Gharaibeh MD, Ph. D, MHPE 16
VASODILATORS Sodium Nitroprusside: ⦿ Short half life. ⦿ Action is immediate, requires constant monitoring in ICU. ⦿ Useful in emergencies, surgery and heart failure. ⦿ Drug is light sensitive. ⦿ Poisoning: High thiocyanate levels and acidbase balance causing weakness, nausea, tinnitus, flushing, lactic acidosis and anoxia. * Munir Gharaibeh MD, Ph. D, MHPE 17
VASODILATORS Minoxidil: ⦿ K+ channel-opener: increases K+ efflux. ⦿ Prolonged arterial relaxation. ⦿ Superior to hydralazine. ⦿ For severe hypertension, usually in combination with a diuretic and β blocker. ⦿ Hypertrichosis(hair growth), so now used mainly in the treatment of baldness. * Munir Gharaibeh MD, Ph. D, MHPE 18
Calcium Channel Blockers Block calcium entry into cells. More effective than others in protection against stroke. Primarily act to reduce peripheral resistance. Effective in the elderly. Cause no metabolic disturbances. * Munir Gharaibeh MD, Ph. D, MHPE 19
Calcium Channel Blockers ⦿ Nifedipine PVR --- ⦿ Diltiazem -- - ⦿ Verapamil -- -- * HR +++ (Reflexly) Munir Gharaibeh MD, Ph. D, MHPE 20
* Munir Gharaibeh MD, Ph. D, MHPE 21
Angiotensin - Converting Enzyme Inhibitors (ACEI) ⦿ Inhibit ACE in the lungs. ⦿ Also inhibit kinin metabolism. * Munir Gharaibeh MD, Ph. D, MHPE 22
Sites of action of drugs that interfere with the reninangiotensin-aldosterone system. * Munir Gharaibeh MD, Ph. D, MHPE 23
Angiotensin - Converting Enzyme Inhibitors (ACEI) Angiotensin II: ⦿ Potent vasoconstrictor by itself. ⦿ Facilitates release of NE. ⦿ Central actions to increase BP. ⦿ Promotes release of aldosterone. ⦿ Regulates intra-renal blood flow. * Munir Gharaibeh MD, Ph. D, MHPE 24
Angiotensin - Converting Enzyme Inhibitors (ACEI) ⦿ Captopril -----Prototype. ⦿ Enalapril ⦿ Quinalapril ⦿ Lisinopril. ⦿ Many others ⦿ All are similarly effective ⦿ Might differ in toxicity * Munir Gharaibeh MD, Ph. D, MHPE 25
Angiotensin - Converting Enzyme Inhibitors (ACEI) Therapeutic Benefits: ⦿ ⦿ ⦿ ⦿ Especially effective in High-rennin hypertension. Useful in HF and Ischemic Heart Disease. Do not increase HR. In diabetic Nephropathy, dilate efferent arterioles which reduces intraglomerular pressure and consequently protects against progressive glomerulosclerosis. No need for a diuretic but a diuretic can be added. No metabolic effects. * Contraindicated in pregnancy and established renal failure. * Munir Gharaibeh MD, Ph. D, MHPE 26
Angiotensin - Converting Enzyme Inhibitors (ACEI) Side Effects: Captopril is very toxic, others are safe drugs. Hypotension( First Dose Phenomena) especially with renovascular hypertension. ⦿ K+ retention, especially in the presence of renal dysfunction or when combined with K+ sparing diuretics or ARBs. ⦿ Unexplained dry cough(10% of patients). * Munir Gharaibeh MD, Ph. D, MHPE 27
Angiotensin II Receptor Blockers (AT 1) ⦿ Newest group, very costly. ⦿ May be only indicated when ACEI are intolerable. ⦿ Fastest growing class of antihypertensive drugs. ⦿ Free of side effects, especially cough. * Munir Gharaibeh MD, Ph. D, MHPE 28
Angiotensin II Receptor Blockers (AT 1) ⦿ Losartan. ⦿ Valsartan. ⦿ Candesartan. ⦿ Irbesartan. ⦿ Telmisartan ⦿ Eprosartan. ⦿ Many * others Munir Gharaibeh MD, Ph. D, MHPE 29
α 1 -selective Alpha Adrenergic Antagonists Prazosin Terazocin Doxazosin ⦿ Good in Moderate Hypertension ⦿ Also effective in Benign Prostatic Hypertrophy All are free of metabolic effects, but can cause drowsiness, postural hypotension (First - Dose Phenomenon), tachycardia, and tolerance due to fluid retention. * Munir Gharaibeh MD, Ph. D, MHPE 30
Beta Adrenergic Blockers Antihypertensive Mechanisms: ⦿ 1. Decrease HR, SV, and consequently C. O ⦿ 2. Decrease Renin Release ⦿ 3. Central Action * Munir Gharaibeh MD, Ph. D, MHPE 31
Beta Adrenergic Blockers Preparations: Propranolol: ⦿ Timolol ⦿ Nadolol ⦿ Pindolol ⦿ Acebutelol ⦿ Esmolol ⦿ Metoprolol ⦿ Atenolol ⦿ Betaxolol ⦿ Bisoprolol ⦿ * 30 1957, Prototype, Lipophilic Long acting Short half life β 1 selective. Munir Gharaibeh MD, Ph. D, MHPE 32
Beta Adrenergic Blockers Therapeutic Features: ⦿ Effect is not immediate. ⦿ Effective in high - renin hypertension ⦿ Used in combination or as monotherapy. ⦿ Useful in Hyperkinetic hearts. ⦿ Used in other cardiovascular conditions(IHD, Arrhythmia, HF, migraine). ⦿ No postural hypotension. * Munir Gharaibeh MD, Ph. D, MHPE 33
Beta Adrenergic Blockers Side Effects: ⦿ ⦿ ⦿ ⦿ * Bronchospasm Heart Failure? With high doses CNS: fatigue, depression, impotence. . etc Impair lipid and glucose metabolism Mask hypoglycemia !!! Claudication If stopped abruptly, can result in withdrawal syndrome due to upregulation of receptors. Munir Gharaibeh MD, Ph. D, MHPE 34
Vasodilating Beta Adrenergic Blockers ⦿ Labetalol: � � ⦿ β, α 1 antagonist & β 2 partial agonist. Useful for emergencies. Carvedilol: �β, α 1 antagonist. ⦿ Esmolol: �β 1 selective, short acting, rapidly metabolized. �Used by continuous IV infusion. ⦿ Nebivolol * Munir Gharaibeh MD, Ph. D, MHPE 35
Centrally Acting Antihypertensive Drugs 1. Propranolol 2. Reserpine: Old fashioned, depletes NE from vesicles. Slow onset and offset, very cheap. 3. α- Methyl Dopa: Central α agonist. α MD---- α MDA ---- α MNE. Mainly used in hypertensive pregnant ladies. Can cause lactation. * Munir Gharaibeh MD, Ph. D, MHPE 36
Centrally Acting Antihypertensive Drugs 4. Clonidine: ⦿ Imidazoline derivative------- used as nasal decongestants. ⦿ I. V: Biphasic Effect: peripheral and central. ⦿ Oral. ⦿ Transdermal Patch(7 days). * Munir Gharaibeh MD, Ph. D, MHPE 37
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