Antihypertensive drugs 2

Lecture-2- Antihypertensive drugsد.رياض الموسوي

Calcium – Channel Blockers :-
Calcium-channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective. They are effective in treating hypertension in patients with angina or diabetes. High doses of short-acting calcium hannel blockers should be avoided because of increased risk of myocardial infarction due to excessive vasodilation and marked reflex cardiac stimulation.

A. Classes of calcium-channel blockers:
The calcium-channel blockers are divided into three chemical classes, each with different pharmacokinetic properties and clinical indications .

Diphenylalkylamines:-Verapail is the least selective of any calcium-channel blocker and has significant effects on both cardiac and vascular smooth muscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and migraine headache.

Benzothiazepines: Like verapamil, diltiazem affects both cardiac and vascular smooth muscle cells; however, it has a less pronounced negative inotropic effect on the heart compared to that of verapamil. Diltiazem has a favorable side-effect profile.

Dihydropyridines: This rapidly expanding class of calcium-channel blockers includes the first-generation nifedipine and five second-generation agents for treating cardiovascular disease: amlodipine, felodipine, isradipine, nicardipine, and nisoldipine . These second-generation calcium-channel blockers differ in pharmacokinetics, approved uses, and drug interactions. All dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart. They are therefore particularly attractive in treating hypertension.
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B. Actions:-
The intracellular concentration of calcium plays an important role in maintaining the tone of smooth muscle and in he contraction of the myocardium. Calcium enters muscle cells through special voltage-sensitive calcium channels. his triggers release of calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level of calcium. Calcium-channel antagonists block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular mooth muscle to relax, dilating mainly arterioles.

C. Therapeutic uses:-
Calcium-channel blockers have an intrinsic natriuretic effect and, therefore, do not usually require the addition of diuretic. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.

D. Pharmacokinetics:-
Most of these agents have short half-lives (8 hours) following an oral dose. Treatment is required three times a day to maintain good control of hypertension. Sustained-release preparations are available and permit less frequent dosing. Amlodipine has a very long half-life and does not required a sustained-release formulation.

E. Adverse effects:-
Constipation occurs in 10 percent of patients treated with verapamil. Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure are more frequent with dihydropyridines. Verapamil should e avoided in patients with congestive heart failure or with atrioventricular block due to its negative inotropic force of cardiac muscle contraction and dromotropic (velocity of conduction) effects.

Vasodilators :-
The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, have traditionally not been used as primary drugs to treat hypertension. Vasodilators act by producing relaxation of vascular smooth muscle, which decreases resistance and, therefore, blood pressure. These agents produce reflex stimulation of the heart, resulting in the competing reflexes of increased myocardial contractility, heart rate, and oxygen consumption. These actions may prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals. Vasodilators also increase plasma renin concentration, resulting in sodium and water retention. These undesirable side effects can be blocked by concomitant use of a diuretic and a ?1-blocker.

A. Hydralazine
This drug causes direct vasodilation, acting primarily on arteries and arterioles. This results in a decreased peripheral resistance, which in turn prompts a reflex elevation in heart rate and cardiac output. Hydralazine is used to treat moderately severe hypertension. It is almost always administered in combination with a ? -blocker, such as propranolol (to balance the reflex tachycardia), and a diuretic (to decrease sodium retention). Together, the three drugs decrease cardiac output, plasma volume, and peripheral vascular resistance. Hydralazine monotherapy is an accepted method of controlling blood pressure in pregnancy-induced hypertension. Adverse effects of hydralazine therapy include headache, tachycardia, nausea, sweating, arrhythmia, and precipitation of angina. A lupus-like syndrome can occur with high dosage, but it is reversible on discontinuation of the drug.

B. Minoxidil
This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). Minoxidil is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs. Reflex tachycardia and fluid retention may be severe and require the concomitant use of a loop diuretic and a - ? - blocker.Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart failure. Minoxidil treatment also causes hypertrichosis (the growth of body hair). This drug is now used topically to treat male pattern baldness.]

Diuretics :-
Diuretics can be used as first-line drug therapy for hypertension unless there are compelling reasons to choose another agent. Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke, myocardial infarction, and congestive heart failure.

A. Thiazide diuretic:-
All oral diuretic drugs are effective in the treatment of hypertension, but the thiazides have found the most widespread use.

Actions:
Thiazide diuretics, such as hydrochlorothiazide, lower blood pressure initially by increasing sodium and water excretion. This causes a decrease in extracellular volume, resulting in a decrease in cardiac output and renal blood flow. With long-term treatment, plasma volume approaches a normal value, but peripheral resistance decreases. Potassium-sparing diuretics are often used combined with thiazides.

Therapeutic uses:
Thiazide diuretics decrease blood pressure in both the supine and standing positions, and postural hypotension is rarely observed except in elderly, volume-depleted patients. These agents counteract the sodium and water retention observed with other agents used in the treatment of hypertension (for example, hydralazine). Thiazides are therefore useful in combination therapy with a variety of other antihypertensive agents, including –?-blockers, ACE inhibitors, angiotensin-receptor blockers, and potassium-sparing diuretics. Thiazide diuretics are particularly useful in the treatment of black or elderly patients. They are not effective in patients with inadequate renal function (creatinine clearance, <50 mL/min). Loop diuretics may be required in these patients.

Pharmacokinetics:
Thiazide diuretics are orally active. Absorption and elimination rates vary considerably, although no clear advantage is present for one agent over another. All thiazides are ligands for the organic acid secretory system of the nephron, and as such, they may compete with uric acid for elimination.

Adverse effects:
Thiazide diuretics induce hypokalemia and hyperuricemia in 70 percent of patients and hyperglycemia in 10 percent of patients. Hypomagnesemia may also occur. Serum potassium levels should be monitored closely in patients who are predisposed to cardiac arrhythmias (particularly individuals with left ventricular hypertrophy, ischemic heart disease, or chronic heart failure) and who are concurrently being treated with both thiazide diuretics and digoxin.

B. Loop diuretics:- bumetanide ethacrynic acid furosemide torsemide
The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics. Loop diuretics cause decreased renal vascular resistance and increased renal blood flow. [Loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease it.]

C. Potassium-sparing diuretics.
Amiloride and triamterene (inhibitors of epithelial sodium transport at the late distal and collecting ducts) as well as spironolactone and eplerenone (aldosterone-receptor antagonists) reduce potassium loss in the urine. Spironolactone has the additional benefit of diminishing the cardiac remodeling that occurs in heart failure.

Drugs Acting on CNS :-

A. Clonidine
This ?2-agonist diminishes central adrenergic outflow. Clonidine is used primarily for the treatment of hypertension that has not responded adequately to treatment with two or more drugs. Clonidine does not decrease renal blood flow or glomerular filtration and, therefore, is useful in the treatment of hypertension complicated by renal disease. Clonidine is absorbed well after oral administration and is excreted by the kidney. Because it may cause sodium and water retention, clonidine may be administered in combination with a diuretic. Adverse effects are generally mild, but the drug can produce sedation and drying of the nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine. The drug should therefore be withdrawn slowly if the clinician wishes to change agents.

C. ?-Methyldopa
This ?2-agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS. This leads to reduced total peripheral resistance and a decreased blood pressure. Cardiac output is not decreased,and blood flow to vital organs is not diminished. Because blood flow to the kidney is not diminished by its use, ?-methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common side effects of ?-methyldopa are sedation and drowsiness. It has been used in hypertensive pregnant patients.

Hypertensive Emergency
Hypertensive emergency is a rare but life-threatening situation in which the DBP is either >150 mm Hg (with SBP>210 mm Hg) in an otherwise healthy person or >130 mm Hg in an individual with preexisting complications, such as encephalopathy, cerebral hemorrhage, left ventricular failure, or aortic stenosis. The therapeutic goal is to rapidly reduce blood pressure.

A. Sodium nitroprusside
Nitroprusside is administered intravenously and causes prompt vasodilation with reflex tachycardia. It is capable of reducing blood pressure in all patients regardless of the cause of hypertension. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. [ Because nitroprusside also acts on the veins, it can reduce cardiac preload.] Nitroprusside is metabolized rapidly (half-life of minutes) and requires continuous infusion to maintain its hypotensive action. Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production. Although cyanide toxicity is rare, it can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys. [Note: Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.] Nitroprusside is light sensitive, and when in solution, it should be protected from light.
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B. Labetalol
Labetalol is both an ?- and a ?-blocker and is given as an intravenous bolus or infusion in hypertensive emergencies. Labetalol does not cause reflex tachycardia. Labetalol carries the contraindications of a nonselective ?-blocker. The major limitation is a longer half-life, which precludes.

C. Fenoldopam
Fenoldopam is a peripheral dopamine-1 receptor agonist that is given as an intravenous infusion. Unlike other parenteral antihypertensive agents, fenoldopam maintains or increases renal perfusion while it lowers blood pressure. Fenoldopam can be safely used in all hypertensive emergencies and may be particularly beneficial in patients with renal insufficiency. The drug is contraindicated in patients with glaucoma.

D. Nicardipine
Nicardipine, a calcium-channel blocker, can be given as an intravenous infusion. The initial dose is 5 mg/h and can be increased to a maximum of 15 mg/h. The major limitation of nicardipine in treating hypertensive emergency is its long half-time (approximately 8 hours).

Hypertension In pregnancy :-

1- ?-methyldopa I preeclapsia
2- Hydralazine in toxemia of pregnancy (eclampsia)
3- ?-blockers may be used, but may causes fetal distress
4- ACEIs + Diuretics should be avoided

British guideline for management of hypertension :-

Step 1 :- ACEI or ARB or ?-blocker.
Step 2 :- one of the above drugs + CCB or Thiazides
Step 3 :- One of step 1 drugs + CCB + Thiazides
Step 4 ( resistant hypertension ) :- Add ?-blocker or spiranolactone or other diuretics.