What is hypertension?
Hypertension is a condition of elevated blood pressure (BP) in the body. Normal BP in our body is 120/80 mm Hg. Clinically, hypertension can be divided into 2 major divisions-
i) Primary hypertension–
Definite cause for rise in BP is not known.
ii) Secondary hypertension–
Secondary to renal disease (polycystic kidneys, pyelonephritis), endocrine disorder (Cushing’s syndrome, pheochromocytoma, primary hyperaldosteronism.
Normally BP is controlled by 2 main system in our body.
i) Adrenergic nervous system– It operates through baroreceptors and is mainly responsible for counteracting acute changes in BP. When one stands up from lying down position, the cardiac output tends to fall due to reduced venous return to heart which may lead to fall in BP and fainting.
ii) Humoral RAAS system (Renin Angiotensin Aldosterone System)– It has slow response and important in long term regulation of BP. It operates through kidneys. Renin, a proteolytic enzyme is produced and stored in kidneys. Its convert serum globulin angiotensin to angiotensin I which is inactive decapeptide. Angiotensin I is converted to Angiotensin II by action of ACE (Angiotensin Converting Enzyme). Angiotensin II is most potent vasoconstrictor agent and it also stimulate synthesis and release of aldosterone from adrenal cortex. Aldosterone cause sodium retention and increase blood volume.
Figure- RAAS system
Drugs used in hypertension (ANTIHYPERTENSIVE DRUGS)
Drugs used to treat hypertension can be broadly classified into following types.
i)Diuretics – e.g. Furosemide, Hydrochlorthiazide, Spirinoloactone
ii) Adrenergic blocker
-α blocker – e.g. Prazosin, Phentolamine
-β blocker- e.g. Atenolol, Propranolol
– α and β blocker –e.g. Labeatolol
iii) ACE (Angiotensin Converting Enzyme) inhibitor– e.g. Captopril, Enalapril
iv) ARBs ( Angiotensin Receptor Blocker)/ ACE-II inhibitor– e.g. Losartan, Telmisartan
v) CCB (Calcium Channel Blocker) – Amlodipine, Verapamil, Nifedipine
vi) Central sympatholytic– e.g. Clonidine, Methyldopa
vii) Vasodilators– e.g. Hydralazine, Minoxidil
i) Diuretics
Diuretics are the drugs which increase rate of urine formation. They are recommended as first-line drug therapy for hypertension.
General mechanism of action
Diuretics act on various parts of nephron and decrease reabsorption of Na+ /H2O and increases urine formation.
Diuretics can be further classified into following types-
i) Osmotic Diuretics –e.g. Mannitol
ii) Thiazide Diuretics- e.g. Hydrochlorthiazide
iii) Carbonic Anhydrase Inhibitors- e.g. Acetazolamide
iv) Loop Diuretics- e.g. Furosemide
v) Aldosterone antagonist- e.g. Spironolactone
i) Osmotic Diuretics
Mannitol is a sugar (polyhydroxy aliphatic alcohol) when given intravenously act on proximal tubule and loop of Henle and decrease reabsorption of sodium and water. They mainly increase water excretion than Na+ excretion.
Pharmacokinetics
It is mostly given by IV route. It is not absorbed orally.
Uses
-In barbiturate poisoning
– In acute renal failure
– Used in cerebral oedema
-During rapid dialysis
– In raised intraocular pressure
Side effects
-Hypersensitivity – Vomiting –Headache – Nausea – Polydipsia
Dose
1-1.5 gm/kg infusion
Contraindication
–In heart failure – Anuria – Cerebral haemorrhage
ii) Thiazide Diuretics
They act on DCT (Distal Convulated Tubule) and inhibit reabsorption of sodium and water. They are most widely used diuretic drugs and are orally effective.
Uses
-As anti-hypertensive drug
– In heart failure
– In diabetes
Side effects
-Hypokalemia – Hyponatraemia – Hypersensitivity
Dose – Hydrochlorthiazide -25-100 mg/day
Contraindication
It should not be given to patients allergic to sulfur.
iii) Carbonic Anhydrase Inhibitors
It inhibit reabsorption of HCO3- ion in PCT (Proximal Convulated Tubule) by inhibiting enzyme carbonic anhydrase.
H2O + CO2 ——- H2CO3
H2CO3 ——— H+ + HCO3 –
The enzyme carbonic anhydrase is present in kidney, gastric mucosa, eyes, pancreas, CNS and RBC. When carbonic anhydrase is inhibited, carbonic acid is not formed which results in unavailability of H+ for Na+ exchange. They are effective orally and effect starts within one hour of administration. They may cause hyperglycemia, hyperuricemia, hyperlipidemia and hypercalcemia.
Uses
-As weak diuretics
– In glaucoma (to reduce elevated intraocular pressure)
– To treat epilepsy
– In mountain sickness
Side effect
-Acidosis – Drowsiness – Hypersensitivity
Contraindication
-In liver disease
Dose – 250 mg OD or BD
iv) Loop Diuretics
It inhibit sodium reabsorption in ascending limb of loop of Henle so known as loop diuretics. It inhibit Na+ -K+-2Cl- symport.
Pharmacokinetics
Orally effective, also given by IV or IM route. It is well absorbed from GI tract.
Uses
-As a very effective, potent and safe diuretic
– In hypertension
– To treat edema
– In barbiturate poisoning
– In acute and chronic renal failure
Side effects
Generally it is well tolerated. Occasionally it can cause ototoxicity, hyperuricemia, hypotension, nausea, vomiting, headache/giddiness.
Dose -20-80 mg OD in morning
v) Aldosterone Antagonist
e.g. Spironolactone
It is structurally similar to aldosterone thus antagonizes the action of aldosterone by binding with aldosterone receptor. It prevents potassium secretion and decrease sodium reabsorption. They are orally effective. They are also known as potassium sparing diuretics as cause increase in sodium excretion and decrease in potassium and hydrogen ion excretion.
Uses
– In hypertension
– To treat CHF
– In hyperaldosteronism
Side effects
No serious side effects have been reported even after long term use. Sometimes it may cause hyperkalemia, drowsiness, nausea, mental confusion, menstrual irregularities.
Dose- 25-50 mg BD or QID
ii) Adrenergic blocker
-α adrenergic blocking agents
e.g. Prazosine. Phentolamine
Phentolamine and Phenoxybenzamine are non selective competitive blocker of alpha receptor. Phentolamine has short duration of action and phenoxybenzamine has longer duration of action. Prazosine is selective alpha-1 receptor blocker.
ADR
Giddiness, drowsiness, headache, tiredness, weakness
–β adrenergic blocking agents
e.g. Atenolol. Propranolol
Mechanism of action
They block β1receptor which lower peripheral resistance and reduce cardiac output. On other hand they also decreases rennin release from kidney which decrease formation of angiotensin II leading to decreased secretion of aldosterone. Both mechanism ultimately lead to decrease in BP.
Pharmacological Action
They reduce elevated BP in hypertensive patients and also protect against stress induced hypertension. They do not impair kidney function.
Pharmacokinetics
Given through oral route. Some drugs may undergo 1st pass metabolism. They are excreted through kidney.
Uses
-Hypertension
– Angina pectoris
– Cardiac arrhythmia
– Anxiety
– Glaucoma
– Pheochromocytoma
Side effects
Generally this drugs are well tolerated and have less ADR. Sometimes it may cause hypotension, bradycardia, insomnia, hallucination, sexual dysfunction etc.
Contraindication
β blockers are contraindicated in bronchial asthma, hyperlipidemia, severe bradycardia, severe depression, complete heart block.
Dose
Propranolol- 80-240 mg/day
Atenolol- 25-100 mg /day
Metoprolol- 100-200 mg/day
-α and β blocker
e.g. Labeatolol
It is non-selective β blocker with selective alpha1 blocking action. When given orally it shows action similar to propranolol. It undergoes extensive 1st pass metabolism. It may cause GI disturbance, dryness of mouth, postural hypotension etc. Mostly used by infusion (1mg/min) to treat hypertensive emergencies.
iii) ACE- Inhibitor (Angiotensin Converting Enzyme- Inhibitor)
e.g. Enalapril, Captopril
Mechanism of action
It inhibit ACE and inhibit conversion of Angiotensin I to Angiotensin II. Inhibition of ACE raises level of bradykinin which is a potent vasodilator. Inhibition of ACE also decrease aldosterone release which decreases Na+ and water retention, Finally BP is decreased.
Pharmacological Action
ACEI decreases both systolic and diastolic BP. They increase the cerebral, renal and coronary blood flow. Also reduce afterload and preload without causing reflex tachycardia. They also increase exercise tolerance and prolong survival of hypertensive patients.
Pharmacokinetics
They are used as pro-drug. Their absorption is reduced by food so given before 1 hour before food. They are excreted through kidney.
Side effects
ACEI are generally well tolerated. Most adverse effects are due to result of specific inhibition of ACE. Most common adverse effect is dry cough (in 30 % cases). They may also cause hyperkalemia, angioedema, first dose syncope, skin rashes, neutropenia, hypotension etc.
Contraindication
Contraindicated in pregnancy and renal artery stenosis, contraction of aorta etc.
Uses
-In hypertension
– In renal insufficiency
– To treat CHF
– In diabetic nephropathy
Dose
Enalapril- 5-20 mg /day od
Captopril- 12.5-50 mg bid
Ramipril- 2.5- 20 mg/day od
iv) ARBs (Angiotensin Receptor Blocker)
e.g. Telmisartan, Losartan
ACEI inhibit ACE which is not a specific enzyme so cause ADR such as cough and angioedema. Thus specific angiotensin receptor blocker are developed.
Mechanism of action
They bind to Angiotensin- II receptor and inhibit binding of Angiotensin to receptor thus antagonizes the action of angiotensin-II.
Uses
-Used in hypertension as a alternative to ACE- inhibitor
Side-effects
-Skin rashes – Insomnia – Depression –Confusion- Nightmares
Contraindication
It can cause fetotoxicity so should be contraindicated during pregnancy.
Dose
Losartan- 25-100 mg/day od or bid
Telmisartan- 20-80 mg/day od
Valsartan- 80-320 mg/day od
v) CCB (Calcium Channel Blocker)
Calcium is responsible for contraction of cardiac and vascular muscle. Calcium transport involve voltage dependent channel, receptor operated channel, sodium-calcium exchange and calcium ATPase. It can be classified into 3 classes-
Phenylalkylamine- e.g. Veraopail
Dihydropyridine- e.g. Amlodipine, Nifedipine
Benzothiazepine- e.g. Diltiazem
Mechansim of action
CCB block L-calcium channel and inhibit entry of calcium into myocardial and vascular smooth muscle thus cause dilation of arteries and arterioles.
Pharmacological Action
CCBs depress myocardial contractility and decrease cardiac workload and oxygen consumption. This effect is beneficial in treatment of angina. They causes coronary artery dilation and decrease oxygen demand of heart due to reduction in systemic vascular resistance and BP.
Pharmacokinetics
They are orally absorbed and metabolized in liver.
Uses
-In hypertension
– In angina
– Also used migraine headache
– In stroke
– To treat raynaud’s syndrome
– In preterm labor
Side effects
These includes headache, tachycardia, leg cramp. hypotension, fatigue, skin rashes etc.
Contraindication
Contraindicated in hypotension, heart block and badycardia.
vi) Central sympatholytics
e.g. Clonidine, Methyldopa
Clonidine –
Mechanism of action
Clonidine acts as central agonist at postsynaptic adrenergic alpha2 receptors in vasomotor center and hypothalamus. Activation of this receptors decrease release of NA and sympathetic outflow which causes lowering of BP. Clonidine produce transient hypertension when given by IV route.
Pharmacokinetics
It is a lipid soluble drug and is well absorbed from gut. It is excreted through urine.
Uses
– In hypertension
-It is used in menopausal hot flushes
– In alcohol and nicotine withdrawl syndrome
Side effects
Commonly causes drowsiness, oral dryness, constipation, impotence, hallucinations etc.
