Antihypertensive drugs 1

د.رياض الموسوي Lec – 1 -

Antihypertensive Drugs

Hypertension is defined as either a sustained systolic blood pressure (SBP) of greater than 140 mm Hg or a sustained diastolic blood pressure (DBP) of greater than 90 mm Hg

Etiology of Hypertension:

Although hypertension may occur secondary to other disease processes, like pheochromocytoma, cushings syndrome, renal artery thrombosis more than 90 percent of patients have essential hypertension, a disorder of unknown origin affecting the blood pressure regulating mechanism. A family history of hypertension increases the likelihood that an individual will develop hypertensive disease, and its prevalence increases with age and obesity. Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, and smoking, further predispose an individual to the occurrence of hypertension.

Classification of Antihypertensive drugs :-

1- Adrenergic blocker agents ( B1 , alpha 1 blockers & mixed blocker )
2- ACE inhibitors
3- AR inhibitors
4- Renin inhibitors
5- Ca++ channel blockers
6- Diuretics
7- Vasodilators
8- Drugs acting on CNS

1- Adrenergic blockers :
a- ? blockers

?-Blockers are currently recommended as first-line drug therapy for hypertension when concomitant disease is present for example, with heart failure. These drugs are efficacious but have some contraindications.

A. Actions:-

The ?-blockers reduce blood pressure primarily by decreasing cardiac output . They may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin from the kidneys, thus decreasing the formation of angiotensin II and the secretion of aldosterone. The prototype I²-blocker is propranolol, which acts at both ?1 and ?2 receptors. Selective blockers of ?1 receptors, such as metoprolol and atenolol , are among the most commonly prescribed ?1blockers. The selective ?1-blockers may be administered cautiously to hypertensive patients who also have asthma, for which propranolol is contraindicated due to its blockade of ?2-mediated bronchodilation.). The – ?-blockers should be employed cautiously in the treatment of patients with acute heart failure or peripheral vascular disease.

B. Therapeutic uses:-

Subsets of the hypertensive population: The – ?-blockers are more effective for treating hypertension in white than in black patients and in young compared to elderly patients. [Note: Conditions that discourage the use of ?-blockers (for example, severe chronic obstructive lung disease, chronic congestive heart failure, or severe symptomatic occlusive peripheral vascular disease) are more commonly found in the elderly and in diabetics.]
Hypertensive patients with concomitant diseases: The – ?-blockers are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, chronic heart failure, and migraine headache.

C. Pharmacokinetics:-

The ?-blockers are orally active. Propranolol undergoes extensive and highly variable first-pass metabolism. The ?-blockers may take several weeks to develop their full effects.




D. Adverse effects:

1- Common effects: The – ?-blockers may cause bradycardia and CNS side effects such as fatigue, lethargy, insomnia, and hallucinations; these drugs can also cause hypotension . The – ?-blockers may
decrease libido and cause impotence. [Note: Drug-induced sexual dysfunction can severely reduce patient compliance.]

2- Alterations in serum lipid patterns: The – ?-blockers may disturb lipid metabolism, decreasing high-density lipoprotein cholesterol and increasing plasma triacylglycerol.

3- Drug withdrawal: Abrupt withdrawal may induce angina, myocardial infarction, or even sudden death in patients with ischemic heart disease. Therefore, the dose of these drugs must be tapered over 2 to 3 weeks in patients with hypertension and ischemic heart disease.

b- ?1 blocking agents :-
?1-Adrenoceptor Blocking Agents:

Prazosin , doxazosin , and terazosin produce a competitive block of ? 1-adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Therefore, long-term tachycardia does not occur, but salt and water retention does. Postural hypotension may occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects. Reflex tachycardia and first-dose syncope are almost universal adverse effects. Concomitant use of a - ? blocker may be necessary to blunt the short-term effect of reflex tachycardia. An increased rate of congestive heart failure occurs
in patients taking doxazosin alone compared to those taking a thiazide diuretic alone. Because of the side-effect profile, development of tolerance, and the advent of safer antihypertensives, ?1 blockers are seldom used in the treatment of hypertension. Tamsulosin, an bloc ? 1ker with greater selectivity for prostate muscle, has been used in the treatment of prostate hyperplasia ( BPH).

c- ? & ? blocking agents :

Labetalol and carvedilol block both ?1- and ?1- and ?2- receptors. Carvedilol, although an effective antihypertensive, is mainly used in the treatment of heart failure. Carvedilol has been shown to reduce mortality associated with heart failure.

2- ACE inhibitors :-

ACE Inhibitors:

The ACE inhibitors, such as enalapril or lisinopril , are recommended when the preferred first-line agents (diuretics or ?-blockers) are contraindicated or ineffective. Despite their widespread use, it is not clear if antihypertensive therapy with ACE inhibitors increases the risk of other major diseases.

A. Actions:

The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexively increasing cardiac output, rate, or contractility. These drugs block the ACE that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. The converting enzyme is also responsible for the breakdown of bradykinin. ACE inhibitors decrease angiotensin II and increase bradykinin levels. Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention.

B. Therapeutic uses:

ACE inhibitors are most effective in hypertensive patients who are white and young. However,
when used in combination with a diuretic, the effectiveness of ACE inhibitors is similar in white and black patients with hypertension. Along with the angiotensin-receptor blockers, ACE inhibitors slow the progression of diabetic nephropathy and decrease albuminuria. ACE inhibitors are also effective in the management of patients with chronic heart failure. ACE inhibitors are a standard in the care of a patient following a myocardial infarction. Therapy is started 24 hours after the end of the infarction.

C. Side effects:

Common side effects include dry cough, rash, fever, altered taste, hypotension (in hypovolemic states), and hyperkalemia . The dry cough, which occurs in about 10 percent of patients, is thought to be due to increased levels of bradykinin in the pulmonary tree. Potassium levels must be monitored, and potassium supplements (or a high postasium diets) or potassium-sparing diuretics are contraindicated. Angioedema is a rare but potentially life-threatening reaction and may also be due to increased levels of bradykinin. Because of the risk of angioedema and first-dose syncope, ACE inhibitors may be first administered in the physician s office with closeobservation. Reversible renal failure can occur in patients with severe bilateral renal artery stenosis. ACE inhibitors are fetotoxic and should not be used by women who are pregnant.

ARBs :-

The angiotensin II ( AT2) receptor blockers (ARBs) are alternatives to the ACE inhibitors. These drugs block the AT1 receptors. Losartan, is the prototypic ARB; currently, there are six additional ARBs( Candisartan, telmisartan, ondasartan) . Their pharmacologic effects are similar to those of ACE inhibitors in that they produce arteriolar and venous dilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention. ARBs do not increase bradykinin levels. ARBs decrease the nephrotoxicity of diabetes, making them an attractive therapy in hypertensive diabetics. Their adverse effects are similar to those of ACE inhibitors, although the risks of cough and angioedema are significantly decreased. ARBs are also fetotoxic.



Renin Inhibitors :-

A selective renin inhibitor, aliskiren has been released for the treatment of hypertension. Aliskiren directly inhibits renin and, thus, acts earlier in the renin-angiotensin-aldosterone system. It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. It can also be combined other antihypertensives, such diuretics, ACE inhibitors, ARBs, or calcium-channel blockers. Aliskiren can cause diarrhea, especially at the higher doses. Aliskiren can also cause cough and angioedema but probably less often than ACE inhibitors. The drug is contraindicated during pregnancy.