Antihypertensive drugs: Definition, classification, pharmacological actions, dose, indications, contraindications, Etiology of hypertension, Blood pressure mechanism, Hypertension treatment.

Anti-hypertensive drugs

Definition, classification, pharmacological actions, dose, indications, contraindications

The pressure exerted by blood on the arterial wall is called blood pressure. The pressure exerted by blood on the artery wall during cardiac diastole is called diastolic blood pressure. The pressure exerted by blood on the wall of the artery during cardiac systole is called systolic blood pressure. Normal systolic blood pressure is 120 mm of Hg to 139 mm of Hg.

Normal diastolic blood pressure is 80 mm of Hg to 89 mm of Hg. Diastolic blood pressure of more than 90 mm of Hg OR Systolic blood pressure of more than 140 mm of Hg for more than a week is considered hypertension or high blood pressure.

• · Diastolic hypertension is divided into three groups: mild blood pressure, Moderate blood pressure, and Severe blood pressure.

• · Diastolic blood pressure between 90 mm of Hg and 104 mm of Hg is called mild diastolic hypertension. Diastolic blood pressure between 105 mm and 114 mm of Hg is called moderate diastolic hypertension. Diastolic blood pressure above 115 mm of Hg is called severe diastolic hypertension.

• · Systolic hypertension is divided into two classes. Systolic hypertension between 140mm of Hg and 159 mm of Hg with normal diastolic blood pressure is called borderline systolic hypertension. Systolic blood pressure of 160 mm of Hg or more with normal diastolic pressure is called isolated systolic blood pressure.

• · Systolic hypertension or diastolic hypertension can develop congestive heart failure, cerebrovascular damage, myocardial infarction, and renal failure.

Etiology of hypertension:

There are two terms for hypertension. These are primary hypertension and secondary hypertension.

• Primaryhyper tension (essential hypertension)· An increase in blood pressure due to an unknown reason is called primary hypertension. There are various factors to develop primary hypertension eg. chronic stress, high intake of sodium, renal deficiency to excrete sodium, potassium deficiency, increase in body fluid volume, increase in thickness and tone of the blood vessel wall, obesity, lack of physical activity, smoking too much alcohol consumption, intrinsic sympathomimetic effect, decrease in vasodepressor hormone, renin-angiotensin system and heredity.

• secondary hypertension: An increase in blood pressure due to known reasons is called secondary hypertension. Usually, kidney, endocrine glands, cardiovascular disorders, sympathetic nervous system stimulation, or side effects of drugs are the main reasons for secondary hypertension

Blood pressure mechanism:

Baroreflex and Renin-Angiotensin-Aldosteron mechanisms regulate blood pressure.

• 1. The baroreflex or baroreceptor reflex is located on the aortic arch. Baroreceptors are pressure-sensitive receptors. Baroreceptors send an impulse to the cardiovascular center in the spinal cord that stimulates the sympathetic nervous system and calms down the parasympathetic nervous system

Sympathetic nervous system stimulation increases the rate and forces cardiac contraction and vasoconstriction. These effects lead to an increase in cardiac output and an increase in pressure on the arterial wall.

• 2. Renin-Angiotensin-Aldosterone Mechanism: Renin-Angiotensin-Aldosterone system is a hormonal system to regulate blood pressure.

A baroreceptor is also located in the kidney. A decrease in renal arterial blood pressure activates the kidney baroreceptor. This baroreceptor stimulates the conversion of prorenin to rennin in the kidney. Renin enters into blood plasma that converts angiotensinogen to angiotensin–I. Angiotensinogen is released from the liver into the blood. Angiotensin I is converted to angiotensin II by the enzyme angiotensin-converting enzyme (ACE). Angiotensin II is potent vasoconstrictor. Vasoconstriction increases blood pressure.

Angiotensin II also stimulates the adrenal cortex to secrete aldosterone. Aldosterone increases the reabsorption of water and sodium into the blood and the excretion of potassium in the urine. This increases sodium concentration and plasma volume which also increases blood pressure.

Hypertension treatment:

Four groups of drugs are most commonly used to treat hypertension. These are

• A. Diuretics,

• B. B-blockers,

• C. ACE inhibitors and

• D. Calcium channel blockers.

Among these, diuretics and β-blockers are the first choices of drugs. If both fail to control hypertension then a vasodilator is recommended. A combination of drugs is used to minimize the dose of each drug and to decrease the side effects of the drug. Calcium channel blockers, ACE inhibitors, and angiotensin II antagonists

• A. DIURETICS:

Diuretics are preferred as the first choice and most preferred drug to treat hypertension.

1. Thiazides; Thiazides are the first choice among all diuretics to treat uncomplicated mild hypertension. However, they potentiate the effect, reduce the dose, reduce the side effects of other antihypertensive drugs, and reduce tolerance development to other antihypertensive drugs. Hydrochlorothiazide is the most preferred drug among all thiazides.

Mechanism of action: Thiazide diuretics increase sodium ion and water excretion by blocking their reabsorption in the renal tubule. Loss of salts and water decreases plasma volume. This leads to a fall in blood pressure.

Excretion of sodium ions decreases the intracellular concentration of sodium ions in smooth muscles of blood vessels. These leads make the blood vessel wall insensitive to sympathetic nervous system angiotensin II stimuli. There will be no blood vessel constriction. Similar effects can be produced by restricting sodium intake in the diet without using diuretics. Thiazide diuretics will not be much more effective in high sodium intake.

Therapeutic uses: Thiarazide does not develop postural hypotension except in elder patients. Some antihypertensive drugs like β-blockers and ACE inhibitors retain sodium ions. Thus, thiazide diuretics are used with these drugs to avoid sodium retention in the body.

Side effects: Hypokalemia, hyponatremia, hyperglycemia, hyperlipidemia, and hyperuricemia.

• a. Hypokalemia and hyponatremia lead to muscle weakness and arrhythmia.

• b. Hyperglycemia precipitates diabetes and disturbs anti-diabetic drug effects.

• c. Hyperuricemia leads to precipitate gout.

• d. Hyperlipidemia increases cholesterol levels & LDL concentration in the blood.

• 2. Loop diuretics (high ceiling diuretics): They are potent and act very quickly even in a patient suffering from poor renal function. Loop diuretics block the reabsorption of sodium and chloride and increase the excretion of calcium. Loop diuretics are useful in a patient not responding to thiazide or other diuretics.

Frusemide: It is a prototype strong diuretic drug and a weak antihypertensive agent. It produces an antihypertensive effect by reducing plasma volume. It has a shorter duration of action than thiazide diuretics. Its side effect such as hypokalemia and hyperurecemia is similar to thiazzide diuretics. Thus frusemide through the oral route is not better than thiazide. Frusemide is also preferred in renal failure, ineffective thiazide diuretics, CHF, and fluid retention.

3. Potassium Sparing Diuretics (Spironolactone): Potassium sparing diuretics are used in combination with thiazide diuretics. This inhibits the loss of potassium ions. It is useful in the treatment of essential hypertension to prevent potassium ion loss.

B. β ADRENERGIC RECEPTOR BLOCKERS:

β Adrenergic receptor blockers and diuretics are the first choices to control high blood pressure. β Adrenergic receptor blockers are mild antihypertensive drugs to control mild and moderate hypertension. They are used alone or in combination with other antihypertensive agents.

Mechanism of action:

• 1. Sympathetic nervous system: Postganglionic sympathetic nerves release neurotransmitter noradrenaline. Non-selective β Adrenergic receptor blockers block the release of noradrenaline. This decreases heart rate and cardiac output.

• 2. Peripheral vascular resistance: Stimulation of β Adrenergic receptors in the peripheral vascular system causes vasodilation and α Adrenergic receptors in the peripheral vascular system cause vasoconstriction.

β Adrenergic receptor blockers initially produce vasoconstriction by blocking β Adrenergic receptors present in blood vessels. However, continuous use of β Adrenergic receptor blockers produces vasodilation and reduces peripheral blood vessels' resistance to blood flow.

• 3. Renin mechanism: β Adrenergic receptor blockers reduce renin secretion from the kidney. This inhibits the synthesis of angiotensin II and the secretion of aldosterone from the adrenal medulla. This leads to falling blood pressure.

• 4. β Adrenergic receptor blockers promote the biosynthesis of prostacyclin. Prostacyclin is a prostaglandin that dilates blood vessels.

However, the β Adrenergic receptor blockade to reduce cardiac output is the most prominent effect of decreasing blood pressure.

Contraindications: β Adrenergic receptor blockers are contraindicated in variant angina, coronary spasm, CHF and Asthma, and peripheral blood vessel disorder.

β Adrenergic Receptor Blockers Agents

• 1. Propranolol is a prototype β Adrenergic receptor blocker that decreases both systolic and diastolic blood pressure. It produces a satisfactory antihypertensive effect in combination with vasodilators.

• 2. Atenolol and metoprolol are selective β1 Adrenergic receptor blockers. They are the drug of choice to control hypertension in asthmatic patients. Propranolol is contraindicated in asthmatic patients.

Side effects:

• 1. Central nervous system: Fatigue, lethargy, headache, vertigo, depression, hallucination, insomnia.

• 2. Plasma lipid: Lipid metabolism disturbance. Increase in triglyceride and decrease HDL levels.

• 3. Kidney: They decrease the glomerular filtration rate by decreasing renal blood filtration.

• 4. Other effects: Impotency, cardiomyopathy, hypoglycemia, and hypotension.

Drug Withdrawal Effect: Rebound hypertension and arrhythmia after abrupt withdrawal of the drug. Thus their dose should be reduced gradually.

C. VASODILATORS

Direct-acting vasodilators produce blood vessels. That reduces peripheral blood vessel resistance in blood flow. This leads to a decrease in blood pressure. Usually, vasodilators are not preferred to treat hypertension due to their side effects. However, vasodilators are recommended as an antihypertensive agent with diuretics and β-adrenergic receptor blockers. This combination compensates for side effects of each other, eg Hydralazine, minoxidil, and diazoxide

• 1. Hydralazine: Hydrazine with diuretics and β-blockers is used to treat moderate to severe hypertension. β-adrenergic receptor blockers counter the reflex tachycardia effect of hydralazine. Diuretics counter the sodium and water retention effect of hydrazine. These three drugs effectively decrease peripheral blood vessel resistance and reduce blood pressure.

Side effects: Anorexia, Nausea, Vomiting, Diarrhoea, Headache, Tachycardia, Angina Pectoris and Palpitation

• 2. Minoxidil: Pharmacological effects are similar to hydralazine. It is used in severe hypertension and is not controlled by other antihypertensive drugs.

• 3. Sodium nitroprusside: Sodium nitroprusside is the drug of choice to manage a hypertensive emergency. Diastolic blood pressure above 150 mm of Hg or systolic blood pressure above 210 mm of Hg is considered a hypertensive emergency.

Metabolites of sodium nitroprusside are cyanide ions. However, cyanide poisoning is rare during the use of sodium nitroprusside. If cyanide poisoning occurs then it is treated by administering sodium thiosulphate as an intravenous infusion. Sodium thiosulphate converts cyanide ions to sodium thiocyanate. Sodium thiocyanate is less toxic and it is excreted in the urine.

Mechanism of action:

Blood vessel endothelial cells blood corpuscles and other cells of blood convert sodium nitroprusside to nitrous oxide. Nitrous oxide causes blood vessel dilation by relaxing blood vessel smooth muscle.

Vasodilation of all blood vessels reduces peripheral vascular resistance in blood flow, decreases venous return to the heart, decreases cardiac output, and decreases cardiac muscle work and oxygen consumption.

Side effects: Weakness, nervousness, acidosis, vomiting, and abdominal pain.

A. CALCIUM CHANNEL BLOCKERS:

They are indirect vasodilators. Calcium channel blockers are an ideal alternative to first-line drugs. They are preferred if first-line drugs are ineffective or contraindicated. The following three chemical groups of calcium channel blockers are used as antihypertensive agents

• a. Diphenyl alkylamines: Verapamil

• b. Benzothiazine derivatives: Diltiazem

• c. Dihydropyridine: Nifedipine

These three inhibit the entry of calcium ions into cardiac muscle cells and smooth muscle cells. This effect blocks contraction in smooth muscles of blood vessels. It produces vasodilation. Vasodilation causes falls in blood pressure. These drugs also block cardiac muscle contraction.

They are an ideal alternative to diuretics for elderly patients suffering from hypertension. They are an ideal alternative to beta-adrenergic receptor blockers for hypertensive patients also suffering from coronary disease.

• Nifedipine (dihydroxy pyridine compounds): Nifedipine shows more vasodilation effect and low cardiac muscle effect than other calcium channel blockers verapamil & diltiazem. Nifedipine is the most effective antihypertensive agent to treat severe hypertension.

Calcium channel blockers produce natriuresis (Sodium excretion in urine). Thus diuretics are not required with calcium channel blockers to treat hypertension.

Side effects: Constipation, dizziness, headache and fatigue

E. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACE):

Angiotensin-converting enzyme inhibitors are the choice of drug to treat hypertension if diuretics and beta-blockers are ineffective or contraindicated. They are effective in low doses hence there will be low side effects. Angiotensin-converting enzyme inhibitors produce a synergistic effect with diuretics in the treatment of hypertension. Thus a low dose of diuretics will be effective in combination with ACE inhibitors.

Mechanism of action: ACE inhibitors produce an antihypertensive effect by antagonizing the pressure mechanism of the body which is a renin-angiotensin-aldosterone system.

Therapeutic uses

• 1. ACE inhibitors are the most effective antihypertensive agents.

• 2. They are also useful to treat hypertension in a patient also suffering from congestive heart failure.

• 3. They cause arterial dilation that increases renal blood flow. Thus they are effective in treating hypertension in a patient also suffering from renal nephropathy.

• 4. They do not affect carbohydrate metabolism. Thus they can be used to treat hypertension patients with diabetes. They also slow down diabetic nephropathy.

F. ANGIOTENSIN ANTAGONIST:

Angiotensin antagonists such as losartan act by blocking angiotensin II receptors without affecting the formation of angiotensin II. Its pharmacological effects are similar to ACE inhibitors or just opposite to the angiotensin II effect. Such as the relaxation of smooth muscles in a renal artery leading to vasodilation, blocking the secretion of aldosterone leading to the excretion of water and sodium.

They are preferred over ACE inhibitors due to their low side effects. ACE inhibitors develop a dry cough that may force patients to stop the administration of ACE inhibitors. Losartan plasma's half-life is about 2 hours. It is metabolized to active metabolites that are 10 times more effective than losartan. Active metabolite has also more half-life than losartan. Thus losartan is administered once a day.

G. α ADRENERGIC RECEPTOR BLOCKERS:

α1 adrenergic receptors are located in the smooth muscles of blood vessels. α1 adrenergic receptors stimulate and produce contraction in smooth muscles of blood vessels. This leads to vasoconstriction and an increase in blood pressure. α1 adrenergic receptor blockers competitively block α1 adrenergic receptors present on smooth muscles of blood vessels. This leads to the relaxation of these smooth muscles to produce blood vessel dilation. That decreases blood pressure. This vasodilation does not affect normal cardiac output and does not produce reflex tachycardia. These drugs also do not change renal blood flow. They are used alone or in combination with other antihypertensive drugs such as propranolol or diuretics. Combination therapy produces an additive effect.

Prazosin: Prazosin is a prototype α1 adrenergic receptor blocker that selectively blocks α1 adrenergic receptors. α1 adrenergic receptor blockage causes dilation of all blood vessels and decreases blood pressure. The initial dose may develop postural hypotension and loss of consciousness. This is called the first dose effect. But it may persist in elder patients. Long-term use causes water and salt retention.

Advantages

• 1. These drugs reduce low-density lipoprotein (LDL) and triglyceride levels along with an increase in HDL levels. This improves the lipid profile of the patient

• 2. They are suitable for patients suffering from hypertension along with diabetes because they do not adversely affect carbohydrate metabolism

Side Effects: Postural hypotension, headache, blurred vision, drowsiness, lethargy, nausea, palpitation dizziness, nasal blockage, mouth dryness, and rashes

H. CENTRAL SYMPATHETIC DRUGS:

Clonidine: Clonidine has a high affinity for α2 adrenergic receptors in CNS. It stimulates α2 adrenergic receptors in the CNS to decrease sympathetic activity. A decrease in sympathetic activity decreases heart rate (bradycardia) and decreases blood pressure Clonidine is used in mild to moderate hypertension not controlled by diuretics alone. Clonidine does not decrease renal blood flow or glomerular filtration rate. Thus it can be used in hypertension with nephropathy (renal disease).

Side effects: Sedation, mouth dryness, dryness in the nasal cavity, sleep disturbance dryness in the eyes, constipation, impotence, bradycardia, and postural hypotension. Sudden withdrawal of clonidine causes rebound hypertension. Thus drugs should be withdrawn gradually.