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 as contributing to the development of hypertension. The heritability of essential hypertension is estimated to be about 30%.
Classification of hypertension on the basis of blood pressure
Systolic and Diastolic Pressure mmHg Category
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 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.
Baroreflexes mediated by autonomic nerves (combination with humoral mechanisms, including the renin-angiotensin-aldosterone system)
Local release of vasoactive substances
Classification of Antihypertensive agents
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:
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:
8. α Adrenergic blockers:
Prazosin, Terazosin, Doxazosin, Phentolamine, Phenoxybenzamine
9. Central sympatholytics:
Arteriolar: Hydralazine, Minoxidil, Diazoxide
Arteriolar + venous: Sodium nitroprusside
Adrenergic neurone blockers (Reserpine, Guanethidine, etc.), Ganglion blockers (Pentolinium, etc.)
Sites of action of the major classes of anti-hypertensive drugs
, 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.
Inhibitors of epithelial sodium transport at the late distal and collecting ducts (furosemide, and ethacrynic acid) or antagonizing aldosterone receptor (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.
potassium-sparing diuretics (spironolactone, and eplerenone) are competitive antagonists that either compete with aldosterone, or directly block epithelial sodium channel (amiloride).
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 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, feeling of weakness and CNS effects
Safety in asthmatics, diabetics and peripheral vascular disease patients
Long-term ACE inhibitor therapy has the potential to reduce incidence of type 2 diabetes in high risk subjects
No rebound hypertension on withdrawal
No hyperuricaemia, 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
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 respond to monotherapy with ACE inhibitors and majority of the rest to their combination with diuretics or beta blockers.
2. Congestive Heart Failure (CHF):
ACE inhibitors cause both arteriolar and venodilatation 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 improved 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 reducing proteinuria by decreasing pressure gradient across glomerular capillaries as well as by altering membrane permeability.
7. Scleroderma crisis:
The marked rise in BP and deterioration of renal function in 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 daily dose is kept below 150 mg.
Hypotension: An initial sharp fall in BP occurs especially in diuretic treated and CHF patients
Headache, dizziness, nausea and bowel upset
Granulocytopenia and proteinuria (rare ADR)
Acute renal failure
Angiotensin antagonists (ARBs)
losartan, candesartan, valsartan, telmisartan, olmesartan and irbesartan.
Their 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. Aliskiren 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 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 is a first β blocker showed 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 the treatment of hypertension.
Metoprolol is atenolol is 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, & 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 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.
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-adrenoceptorblocking agents
phentolamine (reversible nonselective α-adrenergic antagonist) and phenoxybenzamine (non-selective, irreversible alpha blocker) are useful in diagnosis and treatment of pheochromocytoma.
Centrally acting adrenergic drugs
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.
It is an α2 agonist that is converted to methylnorepinephrine centrally to diminish adrenergic outflow from the CNS.
It is mainly used for management of hypertension in pregnancy, where it has a record of safety.
Hydralazine/Dihydralazine and minoxidil 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
Anti-hypertensive Drugs Notes PDF