18.antihypertensives

Antihypertensive drugs

• Primary or essential hypertension (95%)

No specific underlying cause

• Secondary hypertension (5%)Due to specific disease or drug

Blood Pressure

• Systolic blood pressure (SBP) : maximum pressure recorded during ventricular systole

• Diastolic blood pressure (DBP) : minimum pressure recorded during ventricular diastole

• Pulse pressure (PP) : SBP - DBP

• Mean arterial pressure : DBP + 1/3 PP

Classification of BP for adults

Category SBP (mmHg) DBP (mmHg)

Normal < 120 < 80

Prehypertension 120 - 139 80 - 89

Hypertension

Stage 1 (mild) 140 - 159 90 - 99

Stage 2 (moderate) 160 - 179 100 - 109

Stage 3 (severe) ≥ 180 ≥ 110

Classification:

1.Angiotensin Converting Enzyme inhibitors (ACEIs) :

Captopril, enalapril, lisinopril

2. Angiotensin-II receptor blockers (ARBs) : Losartan, candesartan, irbesartan

3. Calcium channel blockers (CCBs) : Verapamil, diltiazem, nifedipine, nimodipine amlodipine, felodipine

4. Diuretics : a) Thiazides & related agents –

Hydrochlorothiazide chlorthalidone b) Loop diuretics – Furosemide, bumetanide c) Potassium sparing diuretics – Amiloride triamterene spironolactone

5. Sympatholytic drugs: a) Centrally acting agents – Clonidine, α-

methyldopa b) Ganglion blockers – Trimethaphan c) Neuronal blockers – Reserpine

d) α-Adrenergic blockers: (i) Non-selective: Phenoxybenzamine phentolamine (ii) Selective: Prazosin, terazosin e) β-Adrenergic blockers: (i) Non-selective: Propranolol, timolol (ii) Selective: Atenolol, metoprolol

6. Vasodilators: a) Arteriolar – Hydralazine, minoxidil, diazoxide b) Arterial and venodilator – Sodium

nitroprusside

I. ACEIs : 1st line agents

Renin

ACE

(vasoconstriction)

BP

ACEIs

Bradykinin PG

Vasodilation

Blood vessel Aldosterone release

Cardiac hypertrophy & remodelling

Angiotensinogen

Angiotensin I

Angiotensin II

PVR Na+ & H2O retention

Inactive

Mechanism of action:• Inhibit the generation of angiotensin II – a potent

vasoconstrictor

• Inhibit the degradation of bradykinin – a potent vasodilator

• Stimulate the synthesis of PGs

• Reduce sympathetic nervous system activity

• Reduce aldosterone production

• Dilates both arteries & veins – afterload and preload

Therapeutic uses:

Hypertension

Congestive cardiac failure (CCF)

Myocardial infarction

Diabetic nephropathy

Scleroderma renal crisis

Adverse effects:• Dry cough & angioedema

• Taste alteration, proteinuria

• Teratogenicity – growth retardation & neonatal death

• Severe hypotension, neutropenia

• Hyperkalaemia

Drug interactions :

• ACEI x Potassium sparing diuretics – hyperkalaemia

• ACEI x Lithium – Li toxicityContraindicated in pregnancyPreferred drug in younger age group,

diabetics – delay or prevent the progression of renal complications

II. ARBs : MOA : competitevely inhibits the binding of angiotensin II to AT1 receptors

- do not affect bradykinin production

Therapeutic uses:• Hypertension• Diabetic nephropathy• CCF

Adverse effects: • Dry cough & angioedema - less

III. Diuretics:Thiazide diuretics –MOA:

On chronic therapy

ThiazidesInhibit Na+-Cl- symport in the

early distal tubule

Promote Na+, H2O excretion

CO

BP

Na+ concentration inthe vascular smooth vessels

PVR

Advantages:• Long duration of action• Cheaper• Well tolerated in elderly patients• Decreases the incidence of fracture in elderly

patients by reducing urinary calcium excretion

Can not be given in patients with gout and hyperlipidaemia

Loop diuretics: Furosemide – not preferred in uncomplicated primary HT because of shorter duration of action

- used in presence of renal failure, CCF or hypertensive emergency

IV. CCBs:• Dihydropyridines (DHPs) – preferred among CCBs -

more selective action on blood vessels• Particularly useful in elderly patients and also in

patients with angina, asthma, pvd, migraine, hyperlipidaemia, diabetes and renal dysfunction

DHPsRelaxes

vascular smooth muscle

PVR

BP

V. Sympatholytics :

a) β-adrenergic blockers – often used as 1st line agents in mild to moderate

hypertension blocks β1 receptors on heart –

HR,

FOC, CO - BP

β-blockers blocks β1 receptors on kidney –

renin release - BP sympathetic outflow - BP

β-adrenergic blockers are mainly useful in –

• Young hypertensives with high renin levels

• Patients with associated conditions such as angina, post MI, migraine and psychosomatic disorders

• Patients receiving vasodilatorsAvoided in pts with asthma, pvd,

diabetes, hyperlipidaemia

b) Centrally acting agents: Clonidine –

MOA:

to

Heart

Blood vessel

HR, COPVR

BP

Clonidine stimulates α2A

receptors in VMC sympathetic

outflow

from VMC

Adverse effects:

Dryness of mouth & eyes Sedation, depression, nausea, dizziness Bradycardia, impotence, pain Swelling of parotid gland

Sudden stoppage after prolonged use - withdrawal syndrome –

headache, nervousness, tachycardia, sweating, tremors, palpitation & rebound hypertension

α-Methyldopa:MOA – α-methyldopa

α-methyldopamine

α-methylnoradrenaline (false NT)

stimulates α2-VMC

sympathetic outflow

HR,PVR

BP

• Preferred antihypertensive during pregnancy

Adverse effects:

• Nasal stuffiness, dryness of mouth • Headache, sedation, mental depression• Bradycardia, EPS• Impotence, gynaecomastia

c) α-Adrenergic blockers:

α-blockers

Nonselective blockers Selective blockers

Block both α1 & α2- receptors Block selectively α1-

in the blood vessels vascular receptors

Vasodilation & fall in BP Arterial & venodilation(due to α1-blockade)

Noradrenaline release Fall in BP(due to presynaptic α2-blockade)

Reflex tachycardia

Non-selective drugs – not preferred for essential hypertension

Used in special conditions –• Pheochromocytoma• Clonidine withdrawal• Cheese reaction

Prazosin – first dose phenomenon – postural

hypotension after the 1st dose

VI. Vasodilators :

activates

MinoxidilDiazoxide

K+ channel (K+ channel openers)

K+ efflux

Hyperpolarization of vascular smooth

muscle

Vasodilatation

BP

Minoxidil:• Use – promote hair growth in male-type baldness

• AE – reflex tachycardia, Na+ & H2O retention with

edema

Diazoxide:• Use – treatment of hypertensive emergencies

• AE - reflex tachycardia, Na+ & H2O retention,

hyperglycaemia

Sodium nitroprusside:• A powerful arteriolar & venodilator

MOA: Sodium nitroprusside

generates nitric oxide (NO)

relaxes vascular smooth muscles

Vasodilation

CO, BP

myocardial work

O2 demand

Uses : Hypertensive crisis CCF Acute aortic dissection

AE: anorexia, nausea, vomiting, fatigue, disorientation,

toxic psychosis

Treatment of Hypertension

Non-pharmacological approaches:• Weight reduction• Sodium restriction• Alcohol restriction• Aerobic exercises• Mental relaxation• Smoking cessation• Consumption of potassium-rich diet

Selection of antihypertensive drugs in individual patients depends on:

• Comorbidity• Associated complications• Age• Sex• Cost of the drug• Concomitant drugs

Combination therapy

• Hydralazine/ DHPs & beta blockers• ACEI/ ARBs & Diuretics• Vasodilators & diuretics• ACEI & clonidine/ beta blocker• CCB + ACEI + Diuretic• CCB + beta blocker + diuretic• ACEI + beta blocker + diureticUsed for severe / non responsive / malignant

HT

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