Drugs Used inHypertension Haitham M. Al-Wali Ph.D Pharmacology & Therapeutics Al-Nahrain college of Pharmacy
Hypertension is defined as: either a sustained systolic blood pressure >140 mm Hg or a sustained diastolic blood pressure >90 mm Hg • Hypertension results from: ↑↑peripheral vascular arteriolar smooth muscle tone→ ↑↑arteriolar resistance and ↓↓capacitance of the venous system. • Hypertension affecting 15 % of the population of the United States (74 million people). • Chronic hypertension can lead to cerebrovascular accidents (strokes), congestive heart failure, myocardial infarction, and renal damage
Hypertension is classified into four categories for the purpose of treatment management
ETIOLOGY OF HYPERTENSION • >90 % of patients have idiopathic, also called “primary” or “essential” hypertension • ˂10% of cases of hypertension are due to (“secondary”to) factors that can be clearly defined and corrected. This type of hypertension is associated with pheochromocytoma, coarctationof the aorta, renal vascular disease, adrenal cortical tumors
ETIOLOGY OF HYPERTENSION • A family history of hypertension • Race:The incidence of is four-fold more frequent among blacks than among whites. • Sex: It occurs more among middle-aged males than middle-aged females • It’s prevalence increases with age and obesity. • Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, and smoking
The strategies for treating idiopathic hypertension include: 1-↓ of blood volume. 2- ↓sympathetic effects 3- ↓vascular smooth muscle tension. 4- ↓angiotensin effects. Unfortunately, the baroreceptor reflex and the renin response in primary hypertension are reset to maintain the higher blood pressure. As a result, they respond to a therapeutically lowered blood pressure with compensatory homeostatic responses.
TREATMENT STRATEGIES The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality 1. Current recommendations are to initiate therapy with a thiazide diuretic. 2. If blood pressure is inadequately controlled, Aβ-blocker may be added 3. Avasodilator can be added as a third drug for those patients who still fail to achieve goal blood pressure. • When angiotensin II–converting enzyme inhibitors orangiotensin II–AT1 receptor blockers are used to initiate therapy, adiuretic is the most common second drug added.
Individualized care • Black patients respond well to diuretics and calcium-channel blockers, but monotherapy with β-blockers or ACE inhibitors is often less effective. • Similarly,β-blockersand diuretics are favored for treatment of hypertension in elderly patients(ACEs are less effective). • Patient compliance in antihypertensive therapy β-blockers can decrease libido and induce erectile dysfunction in males, may prompt the patient to discontinue therapy. Combining two or three drug classes in a single pill.
DIURETICS Diuretics can be used as first-line drug therapy for hypertension safe, inexpensive, and effective in preventing stroke, MI, and congestive HF. lower blood pressure by reduction of blood volume and probably also by a direct vascular effect? Thiazide diuretics (eg, chlorthalidone, hydrochlorothiazide) and the loop diuretics (eg, furosemide). Thiazides may be adequate in mild and moderate hypertension, but the loop agents are used in severe hypertension and in hypertensive emergencies.
SYMPATHOPLEGICS drugs interfere with sympathetic (SANS) control of cardiovascular function. The result is a reduction of one or more of the following: venous tone, heart rate, contractile force of the heart, cardiac output, and total peripheral resistance
SympathoplegicsThat Act in the CNS Alpha2-selective agonists (eg, clonidine, methyldopa) cause a decrease in sympathetic outflow by activation of α2 receptors in the CNS. These drugs enter the CNS when given orally. • Methyldopa is a prodrug; it is transported into the brain and then converted to methylnorepinephrine. • Clonidineand methyldopa reduce blood pressure by reducing cardiac output, vascular resistance, or both. The major compensatory response is salt retention.
Sudden discontinuation of clonidine causes rebound hypertension, which may be severe. This rebound increase in blood pressure can be controlled by reinstitution of clonidine therapy or administration of α blockers such as phentolamine. • Methyldopaoccasionally causes hematologic immunotoxicity, and in some patients progressing to hemolytic anemia. • Both drugs may cause sedation—methyldopa more so at therapeutic dosage. • Early studies suggested that methyldopaprotected kidney function and was safe in pregnancy.
Ganglion-Blocking Drugs Nicotinic blockers that act in the ganglia are very efficacious, but because their adverse effects are severe, they are now considered obsolete. Eg. Hexamethonium and trimethaphan
Postganglionic Sympathetic Nerve Terminal Blockers • Reserpine depletes the adrenergic nerve terminal of its norepinephrine stores. • Guanethidinedeplete and block release of the stores of norepinephrine. produce severe adverse effects and are now considered obsolete for hypertension.
AdrenoceptorBlockers • Alpha1-selective agents (eg, prazosin, doxazosin, terazosin) • Alpha blockers reduce vascular resistance and venous return. • The nonselective α blockers (phentolamine, phenoxybenzamine) are of no value in chronic hypertension because of excessive tachycardia. • Alpha1- selective adrenoceptorblockers relax smooth muscle in the prostate, which is useful in benign prostatic hyperplasia.
Beta blockers • are used very heavily in the treatment of hypertension. • Propranolol is the prototype, and atenolol, metoprolol, and carvedilol are among the most popular. • They initially reduce cardiac output, but in chronic use may include a decrease in vascular resistance. The latter effect may result from reduced angiotensin levels (β blockers reduce renin release from the kidney).
Nebivolol is a newer β blocker with some direct vasodilator action caused by nitric oxide release. β1-selective blockers with fewer CNS effects may have some advantages over the nonselective and more lipid-soluble agents. • The β-blockers are useful in treating conditions that may coexist with hypertension such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, and chronic heart failure. β-Blockers are also used to prevent migraine
VASODILATORS Drugs that dilate blood vessels by acting directly on smooth muscle cells through nonautonomic mechanisms Vasodilators act by four major mechanisms:
A. Calcium Channel-Blocking Agents (eg, nifedipine, verapamil, diltiazem) • Because they are moderately efficacious and orally active, these drugs are suitable for chronic use in hypertension of any severity. • Verapamiland diltiazem also reduce cardiac output in most patients. • Nifedipineis the prototype dihydropyridine, and many other dihydropyridines are available (amlodipine, felodipine, isradipine, etc).
B. Hydralazine and Minoxidil • have more effect on arterioles than on veins. They are orally active and suitable for chronic therapy. • Hydralazine apparently acts through the release of nitric oxide from endothelial cells. • must be combined with other drugs, usually diuretics and β blockers. However, it is rarely used at high dosage because of its toxicity. • Hydralazine induced lupus erythematosus is reversible upon stopping the drug.
Minoxidil is a prodrug; its metabolite, minoxidil sulfate, is a potassium channel opener that hyperpolarizes and relaxes vascular smooth muscle. • Because it can cause hirsutism, minoxidilis also available as a topical agent for the treatment of baldness.
C. Nitroprusside, Diazoxide, and Fenoldopam • These parenteral vasodilators are used in hypertensive emergencies. • Nitroprussideis short-acting agent (duration of action is a few minutes) that must be infused continuously. • The release of nitric oxide (from the drug molecule itself) stimulates guanylylcyclase and increases cyclic guanine monophosphate (cGMP) concentration and relaxation in vascular smooth muscle.
Diazoxide is a thiazide derivative but lacks diuretic properties. • It is given as intravenous boluses or as an infusion and has several hours’ duration of action. • Diazoxideopens potassium channels, thus hyperpolarizing and relaxing smooth muscle cells. • also reduces insulin release and can be used to treat hypoglycemia caused by insulin-producing tumors. • Dopamine D1 receptor activation by fenoldopamcauses marked arteriolar vasodilation. • This drug is given by intravenous infusion. It has a short duration of action (10 min) and, like nitroprusside and diazoxide, is used for hypertensive emergencies.
ANGIOTENSIN ANTAGONISTS • The two primary groups are: • The angiotensin-converting enzyme (ACE) inhibitors and • the angiotensin II receptor blockers (ARBs). ACE inhibitors (eg, captopril), which inhibit the enzyme variously known as angiotensin- converting enzyme, kininase II, and peptidyldipeptidase, • cause a reduction in blood levels of angiotensin II and aldosterone and an increase in endogenous vasodilators of the kinin
The ACE inhibitors are useful in heart failure and diabetes as well as in hypertension. • The toxicities of ACE inhibitors include: cough (up to 30% of patients), hyperkalemia, angioedemaand renal damage in occasional patients with preexisting renal vascular disease (although they protect the diabetic kidney). • They cause major renal damage in the fetus and are absolutely contraindicated in pregnancy.
The angiotensin receptor blockers (ARBs), is represented by the orally active agents losartan , telmisartan, valsartan, irbesartan , candesartan, and other ARBs, which competitively inhibit angiotensin II at its AT1 receptor site. • ARBs appear to be as effective in lowering blood pressure as the ACE inhibitors and have the advantage of a lower incidence of cough, although they do cause hyperkalemia. • Like the ACE inhibitors, they cause fetal renal toxicity and are thus contraindicated in pregnancy.
Aliskirenis a newer drug in the antihypertensive group inhibits renin’s action on its substrate, angiotensinogen • thus reduces the formation of angiotensin I and, in consequence, angiotensin II. • Toxicities include headache and diarrhea. It does not appear to cause cough , contraindicated in pregnancy • Angiotensin antagonists and renin inhibitors reduce aldosterone levels (angiotensin II is a major stimulant of aldosterone release) and cause potassium retention.
Hypertensive emergency (formerly called malignant hypertension) • is an accelerated form of severe hypertension associated with rising blood pressure and rapidly progressing damage to vessels and end organs. • Management carried out on an urgent basis in the hospital. • Powerful vasodilators (nitroprusside, fenoldopam, or diazoxide) are combined with diuretics(furosemide) and β blockers • to lower blood pressure to the 140–160/90–110 mm Hg range promptly (within a few hours). Further reduction is then followed more slowly.