Anti-hypertensive Drugs (2) PDF

‫ميحرلا نمحرلا هللا مسب‬ Anti-hypertensive Drugs (2) Mohammed Ali Khalifa Assistant Professor of Pharmacology November 2024 Antihypertensive drugs Vasodilators ACEIs and ARBs Vasodilators Mechanism & Sites of Action This class of drugs includes...

‫ميحرلا نمحرلا هللا مسب‬ Anti-hypertensive Drugs (2) Mohammed Ali Khalifa Assistant Professor of Pharmacology November 2024 Antihypertensive drugs Vasodilators ACEIs and ARBs Vasodilators Mechanism & Sites of Action This class of drugs includes the oral vasodilators, hydralazine and minoxidil, which are used for long-term outpatient therapy of hypertension; the parenteral vasodilators, nitroprusside, diazoxide, and fenoldopam, which are used to treat hypertensive emergencies; the calcium channel blockers, which are used in both circumstances; and the nitrates, which are used mainly in angina. Mechanism of vasodilators Compensatory response to vasodilators HYDRALAZINE Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. SODIUM NITROPRUSSIDE Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. MINOXIDIL Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. CALCIUM CHANNEL BLOCKERS In addition to their antianginal, and antiarrhythmic effects, calcium channel blockers also reduce peripheral resistance and blood pressure. The mechanism of action in hypertension (and, in part, in angina) is inhibition of calcium influx into arterial smooth muscle cells. CALCIUM CHANNEL BLOCKERS Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine) are all equally effective in lowering blood pressure, and many formulations are currently approved for this use in the USA. Clevidipine is a newer member of this group that is formulated for intravenous use only. CALCIUM CHANNEL BLOCKERS Hemodynamic differences among calcium channel blockers may influence the choice of a particular agent. Nifedipine and the other dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem. Reflex sympathetic activation with slight tachycardia main ADRs. CALCIUM CHANNEL BLOCKERS Doses of calcium channel blockers used in treating hypertension are similar to those used in treating angina. Some epidemiologic studies reported an increased risk of myocardial infarction or mortality in patients receiving short-acting nifedipine for hypertension. It is therefore recommended that short-acting oral dihydropyridines not be used for hypertension. INHIBITORS OF ANGIOTENSIN Renin, angiotensin, and aldosterone play important roles in at least some people with essential hypertension. Blood pressure of patients with high-renin hypertension responds well to drugs that interfere with the system, supporting a role for excess renin and angiotensin in this population INHIBITORS OF ANGIOTENSIN Mechanism & Sites of Action Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and reduced sodium delivery or increased sodium concentration at the distal renal tubule. Renin acts upon angiotensinogen to split off the inactive precursor decapeptide angiotensin I. INHIBITORS OF ANGIOTENSIN Angiotensin I is then converted, primarily by endothelial ACE, to the arterial vasoconstrictor octapeptide angiotensin II, which is in turn converted in the adrenal gland to angiotensin III. Angiotensin II has vasoconstrictor and sodium-retaining activity. Angiotensin II and III both stimulate aldosterone release. INHIBITORS OF ANGIOTENSIN Three classes of drugs act specifically on the renin-angiotensin system: ACE inhibitors; the competitive inhibitors of angiotensin at its receptors, including losartan and other nonpeptide antagonists; and aliskiren, an orally active renin antagonist. A fourth group of drugs, the aldosterone receptor inhibitors (eg, spironolactone, eplerenone) are discussed with the diuretics. ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS Captopril and other drugs in this class inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent vasodilator, which works at least in part by stimulating release of nitric oxide and prostacyclin. The hypotensive activity of captopril results both from an inhibitory action on the renin-angiotensin system and a stimulating action on the kallikrein. ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver. ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance. Cardiac output and heart rate are not significantly changed. Unlike direct vasodilators, these agents do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease. ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS ACE inhibitors have a particularly useful role in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure). This effect is particularly valuable in diabetes, and these drugs are now recommended in diabetes even in the absence of hypertension. ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS These benefits probably result from improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure. ACE inhibitors have also proved to be extremely useful in the treatment of heart failure, and after myocardial infarction, and there is recent evidence that ACE inhibitors reduce the incidence of diabetes in patients with high cardiovascular risk. Pharmacokinetics & Dosage Peak concentrations of enalaprilat, the active metabolite of enalapril, occur 3– 4 hours after dosing with enalapril. The half-life of enalaprilat is about 11 hours. Typical doses of enalapril are 10–20 mg once or twice daily. Lisinopril has a half-life of 12 hours. Pharmacokinetics & Dosage Doses of 10– 80 mg once daily are effective in most patients. All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys; doses of these drugs should be reduced in patients with renal insufficiency. Toxicity Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic as a result of diuretics, salt restriction, or gastrointestinal fluid loss. Other adverse effects common to all ACE inhibitors include acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney), hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema. Toxicity Bradykinin and substance P seem to be responsible for the cough and angioedema seen with ACE inhibition. ACE inhibitors are contraindicated during the second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death. Drug Interactions Important drug interactions include those with potassium supplements or potassium-sparing diuretics, which can result in hyperkalemia. Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking bradykinin-mediated vasodilation, which is at least in part, prostaglandin mediated. ANGIOTENSIN RECEPTOR–BLOCKING AGENTS Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. Candesartan, eprosartan, irbesartan, telmisartan, and olmesartan are also available. They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors. ANGIOTENSIN RECEPTOR–BLOCKING AGENTS They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II. ANGIOTENSIN RECEPTOR–BLOCKING AGENTS Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with heart failure and chronic kidney disease. The adverse effects are similar to those described for ACE inhibitors, including the hazard of use during pregnancy. Cough and angioedema can occur but are less common with angiotensin receptor blockers than with ACE inhibitors. CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS Outpatient therapy of hypertension: The initial step in treating hypertension may be nonpharmacologic. As discussed previously, sodium restriction may be effective treatment for many patients with mild hypertension. The average American diet contains about 200 mEq of sodium per day. CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS Outpatient therapy of hypertension: Weight reduction even without sodium restriction has been shown to normalize blood pressure in up to 75% of overweight patients with mild to moderate hypertension. Regular exercise has been shown in some but not all studies to lower blood pressure in hypertensive patients. CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS Outpatient therapy of hypertension: For pharmacologic management of mild hypertension, blood pressure can be normalized in many patients with a single drug. However, most patients with hypertension require two or more antihypertensive. Thiazide diuretics, beta blockers, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers have all been shown to reduce complications of hypertension and may be used for initial drug therapy. CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS Outpatient therapy of hypertension: The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. For example, drugs that inhibit the renin-angiotensin system are particularly useful in patients with diabetes or evidence of chronic kidney disease with proteinuria. CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS Outpatient therapy of hypertension: Beta blockers or calcium channel blockers are useful in patients who also have angina. Diuretics, ACE inhibitors, angiotensin receptor blockers, beta blockers or hydralazine combined with nitrates in patients who also have heart failure. And alpha1 blockers in men who have benign prostatic hyperplasia. Race may also affect drug selection. CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS Management of hypertensive emergencies. Management of hypertensive urgencies. Resistant hypertension & polypharmacy. Recommended References