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Anti-hypertensive Drugs

Etiology of Hypertension

A specific cause of hypertension established in only 10–15% of patients.

Patients in whom no specific cause of hypertension are said to have essential or primary hypertension.

Patients with a specific etiology are said to have secondary hypertension.

Genetic factors, psychological stress, and environmental and dietary factors contribute to the development of hypertension. The heritability of essential hypertension is estimated to be about 30%.

Classification of hypertension based on blood pressure

Systolic and Diastolic Pressure mmHg Category

<120/80 Normal

120-135/80-89 Pre-Hypertension

>140/90 Hypertension

140-159/90-99 Stage 1

>160/100 Stage 2

Normal Regulation of Blood Pressure

According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to the passage of blood through precapillary arterioles (peripheral vascular resistance, PVR)

BP = CO × PVR

Blood pressure is maintained by

Moment-to-moment regulation of cardiac output and peripheral vascular resistance exerted at three anatomic sites arterioles, postcapillary venules (capacitance vessels), and heart.

Kidney

Baroreflexes mediated by autonomic nerves (in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system)

Local release of vasoactive substances

Anti-hypertensive Drugs

Anti-hypertensive drugs are medications used to treat high blood pressure, also known as hypertension. These drugs work by various mechanisms to lower blood pressure and reduce the risk of complications associated with hypertension.

Classification of Antihypertensive agents

1. Diuretics

Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide

High ceiling: Furosemide, Torsemide, ethacrynic acid.

K+ Sparing: Spironolactone, Amiloride

2. ACE inhibitors

Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril, etc.

3. Angiotensin (AT1 receptor) blockers:

Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan

4. Direct renin inhibitor:

Aliskiren

5. β Adrenergic blockers:

Propranolol, Metoprolol, Atenolol, etc.

6. Calcium channel blockers:

Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine, etc.

7. β + α Adrenergic blockers:

Labetalol, Carvedilol

8. α Adrenergic blockers:

Prazosin, Terazosin, Doxazosin, Phentolamine, Phenoxybenzamine

9. Central sympatholytics:

Clonidine, Methyldopa

10. Vasodilators

Arteriolar: Hydralazine, Minoxidil, Diazoxide

Arteriolar + venous: Sodium nitroprusside

11. Others:

Adrenergic neuron blockers (Reserpine, Guanethidine, etc.), Ganglion blockers (Pentolinium, etc.)

Sites of action of the major classes of anti-hypertensive drugs

Diuretics

Thiazide diuretics:

Thiazide diuretics, such as hydrochlorothiazide and chlorthalidone, lower blood pressure initially by increasing sodium and water excretion.

Thiazide diuretics can induce hypokalemia, hyperuricemia, and, to a lesser extent, hyperglycemia in some patients.

Loop diuretics:

Inhibitors of epithelial sodium transport at the late distal and collecting ducts (furosemide, and ethacrynic acid) or antagonizing aldosterone receptors (spironolactone, and eplerenone) and reduce potassium loss in the urine.

Aldosterone antagonists have the additional benefit of diminishing the cardiac remodeling that occurs in heart failure.

The loop diuretics act promptly by blocking sodium and chloride reabsorption in the kidneys, even in patients with poor renal function or those who have not responded to thiazide diuretics.

Loop diuretics cause decreased renal vascular resistance and increased renal blood flow.

K+ Sparing:

potassium-sparing diuretics (spironolactone, and eplerenone) are competitive antagonists that either compete with aldosterone or directly block epithelial sodium channels (amiloride).

ACE inhibitors

The ACE inhibitors are recommended as first-line treatment of hypertension in patients with a variety of compelling indications, including high coronary disease risk or history of diabetes, stroke, heart failure, myocardial infarction, or chronic kidney disease.

ACE is also responsible for the breakdown of bradykinin, a peptide that increases the production of nitric oxide and prostacyclin by the blood vessels. Both nitric oxide and prostacyclin are potent vasodilators.

ACE inhibitors decrease angiotensin II and increase bradykinin levels. Vasodilation is the result of decreased vasoconstriction (from diminished levels of angiotensin II) and enhanced vasodilation (from increased bradykinin).

By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention.

ACE inhibitors reduce both cardiac preload and afterload, thereby decreasing cardiac work.

Advantages of ACE inhibitor:

Free of postural hypotension, electrolyte disturbances, feelings of weakness, and CNS effects

Safety in asthmatics, diabetics, and peripheral vascular disease patients

Long-term ACE inhibitor therapy has the potential to reduce the incidence of type 2 diabetes in high-risk subjects

No rebound hypertension on withdrawal

No hyperuricemia, no deleterious effect on plasma lipid profile

ACE inhibitors are the most effective drugs for preventing sudden cardiac death in post-infarction patients.

However, they are less effective for primary prophylaxis of MI and for preventing left ventricular hypertrophy.

Uses of ACE inhibitors

1. Hypertension:

The ACE inhibitors are first-line drugs in all grades of hypertension, but the angiotensin receptor blockers (ARBs) have now surpassed them in popularity.

Essential hypertension responds to monotherapy with ACE inhibitors and the majority of the rest to their combination with diuretics or beta blockers.

2. Congestive Heart Failure (CHF):

ACE inhibitors cause both arteriolar and vasodilatation in CHF patients; reduce afterload as well as preload.

3. Myocardial infarction:

Long-term ACE inhibitor therapy reduces recurrent MI.

4. Prophylaxis in high cardiovascular risk subjects:

ACE inhibitors are protective in high cardiovascular-risk subjects even when there is no associated hypertension or left ventricular dysfunction. ACE inhibitors may improve endothelial function.

5. Diabetic nephropathy:

Prolonged ACE inhibitor therapy has been found to prevent or delay end-stage renal disease in type I as well as type II diabetics.

6. Nondiabetic nephropathy:

ACE inhibitors reduce proteinuria by decreasing the pressure gradient across glomerular capillaries and altering membrane permeability.

7. Scleroderma crisis:

The marked rise in BP and deterioration of renal function in the scleroderma crisis is mediated by Ang II.

ACE inhibitors produce improvement and are life-saving in this condition.

Adverse effects of ACE inhibitors:

The adverse effect profile of all ACE inhibitors is similar.

Captopril is well tolerated by most patients, especially if the daily dose is kept below 150 mg.

Hypotension: An initial sharp fall in BP occurs especially in diuretic-treated and CHF patients

Hyperkalaemia

Cough

Rashes, urticaria

Angioedema

Dysgeusia/ parageusia

Foetopathic

Headache, dizziness, nausea, and bowel upset

Granulocytopenia and proteinuria (rare ADR)

Acute renal failure

Angiotensin antagonists (ARBs)

losartan, candesartan, valsartan, telmisartan, olmesartan and irbesartan.

The pharmacologic effects of ARBs are similar to those of ACE inhibitors.

ARBs 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 may be used as first-line agents for the treatment of hypertension, especially in patients with a compelling indication of diabetes, heart failure, or chronic kidney disease.

Direct renin inhibitor

A selective renin inhibitor, aliskiren directly inhibits renin and, thus, acts earlier in the renin–angiotensin–aldosterone system than ACE inhibitors or ARBs.

It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. Aliskirens should not be routinely combined with an ACE inhibitor or ARBs.

Aliskiren can cause diarrhea, especially at higher doses, and can also cause cough and angioedema, but probably less often than ACE inhibitors.

Aliskiren is contraindicated during pregnancy.

β-adrenergic blockers

β-adrenergic blockers are mild antihypertensives and do not significantly lower BP in normotensives.

In stage 1 cases of hypertensive patients (30 – 40%), β- adrenergic blockers are used alone.

Propranolol

Propranolol is the first β blocker shown to be effective in hypertension and ischemic heart disease.

Propranolol has now been largely replaced by cardioselective β blockers such as metoprolol and atenolol.

All β-adrenoceptor-blocking agents are useful for lowering blood pressure in mild to moderate hypertension.

In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators.

Metoprolol & Atenolol

Metoprolol and atenolol, which are cardioselective, are the most widely used β blockers in treating hypertension.

Metoprolol is atenolol inhibiting stimulation of β1 adrenoceptors.

Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure.

Atenolol is reported to be less effective than metoprolol in preventing the complications of hypertension.

Other beta blockers

Nadolol and carteolol, nonselective β-receptor antagonists

Betaxolol and bisoprolol are β1-selective blockers

Pindolol, acebutolol, and penbutolol are partial agonists, ie, β blockers with some intrinsic sympathomimetic activity.

These drugs are particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease.

Labetalol, Carvedilol, and nebivolol have both β- blocking and vasodilating effects.

Esmolol is a β1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases.

Esmolol is used for the management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure.

α-Adrenergic blockers

Prazosin, terazosin, and doxazosin

Prazosin is a prototype α1-adrenergic blocking agent.

Terazosin and doxazosin are long-acting congeners of Prozosin.

Alpha-blockers reduce arterial pressure by dilating both resistance and capacitance vessels.

Other alpha-adrenoceptor blocking agents

phentolamine (reversible nonselective α-adrenergic antagonist) and phenoxybenzamine (a non-selective, irreversible alpha-blocker) are useful in the diagnosis and treatment of pheochromocytoma.

Centrally-acting adrenergic drugs

Clonidine

Clonidine acts centrally as an α2 agonist to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery.

This leads to reduced total peripheral resistance and decreased blood pressure.

At present, it is occasionally used in combination with a diuretic.

Methyldopa

It is an α2 agonist converted to methyl norepinephrine centrally to diminish adrenergic outflow from the CNS.

It is mainly used for the management of hypertension in pregnancy, where it has a record of safety.

Vasodilators

Hydralazine/Dihydralazine and minoxidil are not used as primary drugs to treat hypertension.

These vasodilators act by producing relaxation of vascular smooth muscle, primarily in arteries and arterioles.

This results in decreased peripheral resistance.

Both agents produce reflex stimulation of the heart, resulting in the competing reflexes of increased myocardial contractility, heart rate, and oxygen consumption.

Hydralazine is an accepted medication for controlling blood pressure in pregnancy-induced hypertension. This drug is used topically to treat male pattern baldness.

Treatment of hypertension

FAQs

How quickly do anti-hypertensive drugs work? Anti-hypertensive drugs may start showing effects within a few hours to days, but the full impact may take weeks.
Can lifestyle changes alone manage hypertension? While lifestyle changes are crucial, some individuals may require medication for optimal blood pressure control.
Are there natural alternatives to anti-hypertensive drugs? While lifestyle modifications can complement treatment, they may not replace the need for medication in severe cases.
What should I do if I experience side effects from my medication? Consult your healthcare provider immediately; they can adjust your medication or suggest alternative options.
Is it safe to combine different types of anti-hypertensive drugs? Combining drugs can be safe and effective, but it should be done under the guidance of a healthcare professional.