Antihypertensive Drugs

Presented byAbhaya S S

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Contents▪ Introduction▪ ACE Inhibitors▪ ARBs▪ Beta Adrenergic blockers▪ Alpha Adrenergic blockers▪ Calcium channel blockers▪ Vasodilators▪ Central Sympatholytics▪ Beta + Alpha Adrenergic blockers▪ Selection of drug

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Introduction

HyertensionSystolic Blood

Pressure (SBP)

>140 mm Hg

Diastolic Blood

Pressure (DBP)

>90 mm Hg

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Classification of DrugsAce Inhibitors Captopril, enalapril, lisinopril,

perindopril, ramipril.

Angiotensin antagonists

Losartan, irbesartan, candesartan

Calcium channel blockers

Verapamil, diltiazam, nifedipine, felodipine, amlodipine, lacidipine

Diuretics Thiazide=hydrochlorothiazide, chlorthalidone. indapamideHigh ceiling = furosemideK+ sparing = spironolactone.amiloride,

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Classification of Drugsß - Adrenergic blockers

Propranolol, metaprolol, atenolol.

+ß Adrenergic blockers

Labetalol, carvedilol. sodium

- Adrenergic blockers

prazosin., terazosin, phentolamine

Central Sympatholytic

Clonidine, methyldopa

Vasodilators Hydralazine, minoxidil

Renin inhibitors Aliskiren

1. ACE InhibitorsWhat is Renin - Angiotensin? Physiology

Angiotensin Converting Enzyme

Renin

Angiotensinogen

Angiotensin I

Angiotensin II

Binds to ZG and cell surface receptor Angiotensin III

Aldosterone Production (Adrena cortex)

Renal Arterial Pressure

[Na*] in Renal Tubular Fluid

Renal Sympathetic Nerve Activity

Na+ & Water Retention

Vasocontriction

Rise in BP

Increased Blood Volume

Kidney

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ACE Inhibitors▪ Captopril▪ lisinopril▪ enalapril ▪ ramipril ▪ fosinopril

Angiotensin Converting Enzyme inhibitors

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Mechanism of action

This group of drugs inhibit the enzyme kininase II or ACE. So these drugs decreases the activity of RAAS and also potentiate the vasodilatory action of bradykinin.

Angiotensin Converting Enzyme inhibitors

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Adverse effects▪ Cough – persistent brassy cough in 20% cases –

inhibition of bradykinin and substanceP breakdown in lungs

▪Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level)

▪Hypotension (in hypovolemic states) – sharp fall may occur – 1st dose

▪ Acute renal failure- CHF and bilateral renal artery stenosis

▪ Angioedema - swelling of lips, mouth, nose etc.

▪ Rashes, urticaria etc

▪Dysgeusia - loss or alteration of taste

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Adverse effects▪ Foetopathic - hypoplasia of organs, growth

retardation etc

▪Neutropenia▪ Contraindications - Pregnancy, bilateral

renal artery stenosis, hypersensitivity and hyperkalaemia

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2.ARBs▪ Losartan▪ Candesartan▪ Irbesartan▪ Valsartan▪ Telmisartan

Angiotension receptor blockers

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Mechanism of action Angiotension receptor blockers

Angiotensiogen

Angiotensiogen I

Angiotensiogen II

AT2 receptorAT1 receptor

Renin

ACE

ARBS

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Mechanism of action

These drugs act by antagonizing the action of angiotensin II at AT1 receptors. Theses drugs do not increase bradykinin and thus have less chances for causing cough and angioedema

Angiotensin receptor blockers

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ADR

▪ Headache , hypotension, weakness, rashes, nausea, vomiting and teratogenic effects.

▪ They may cause hyperkalemia in patients with renal failure or in patients on potassium sparing diuretics.

Angiotension receptor blockers

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3.Renin inhibitors

▪ Aliskiren , remikiren and enalkiren are the drugs that inhibit the enzyme renin.

▪ Thus these drugs decrease the activity of RAAS causing fall in BP.

▪ ADR

▪ Aliskerin can cause diarrhea at higher doses

▪ Aliskerin can also cause cough and angioedema but probably less often than ACE inhibitors.

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4.Beta-adrenergic blockers▪ Selective blockers (block only 1)

▪ Atenolol , metoprolol, esmolol, betaxolol etc

▪ Nonselective beta blockers (block both 1 and 2)▪ propranolol and timolol.

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Mechanism of action

Inhibition of beta 1 receptors leading to decreased cardiac output.

Decrease in renin release due to inhibition of  β1 receptors in JG cells of kidney , along with this inhibit AT-II and aldosterone production, and lower peripheral resistance

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Contd.

Inhibition of central and peripheral sympathetic outflow due to inhibition of presynaptic stimulatory β receptors on adrenergic neurons.

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Advantages of cardio-selective over non-selective:

▪ In asthma▪ In diabetes mellitus▪ In peripheral vascular disease

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ADR

▪ Fatigue, lethargy – decreased work capacity

▪ Loss of libido – impotence

▪ Cognitive defects – forgetfulness

▪ Difficult to stop suddenly- withdrawal syndrome.

▪ Can precipitate CHF and bronchospasm in susceptible individuals.

▪ Therefore cardio-selective drugs are preferred now

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5.-Adrenergic Blockers▪ Prazosin▪ Terazosin▪ Doxazosin▪ Phentolamine▪ Phenoxybenzamine

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Mechanism of action

These drugs produce a competative block of alpha 1 adrenoceptors. They decrease PVR and lowers arterial BP by causing relaxation of both arterial and venous smooth muscle.

Therefore long term tachycardia does not occur but salt and water retention does.

-Adrenergic Blockers

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-Adrenergic Blockers

▪ Non selective alpha blockers are not used in chronic essential hypertension (phenoxybenzamine, phentolamine), only used sometimes as in phaechromocytoma

▪ Specific alpha-1 blockers like prazosin, terazosin and doxazosine are used

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ADR

▪ Prazosin causes postural hypotension – start 0.5 mg at bed time with increasing dose and upto10 mg daily

▪ Fluid retention in monotherapy

▪ Headache, dry mouth, weakness, dry mouth, blurred vision, rash, drowsiness and failure of ejaculation in males.

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6.α-β Adrenoceptor blocking agents▪ Labetalol and carvedilol are two drugs

having antagonistic activity at both adrenergic receptors (i.e block both α1 and β1 and β2 receptors).

▪ They are mainly used for controlling hypertension in pheochromocytoma.

▪ Carvedilol due to its antioxidant and antimitogenic property is also useful in CHF.

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7 .Calcium Channel Blockers Classification

Calcium Channel blockers

Diphenylalkylamines Verapamil

Benzothiazepines Diltiazem

Dihydropyridines

1st generatio

nNifedipine

2nd generatio

n

Isradipine

Nicardipine

Felodipine

3rd generatio

nAmlodipine

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Mechanism of action

▪ CCBs block the inward movement of calcium by binding to L type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature.

▪ This causes vascular smooth muscle to relax ,dilating mainly arterioles.

Calcium Channel Blockers

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ADR

▪ Constipations occur in 10% of patients

treated with Verapamil.▪ Dizziness , headache, and feeling of

fatigue caused by decrease in BP are most frequent with

dihydropyridines.

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7. Vasodilators

▪Arteriolar = Hydralazine, minoxidil, diazoxide.

▪Arteriolar + Venous = Sodium nitroprusside.

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Mechanism of actionHydralazine molecules combine with receptors in the endothelium of arterioles – NO release – relaxation of vascular smooth muscle – fall in BP

Subsequent fall in BP – stimulation of adrenergic system leading to Cardiac stimulation producing palpitation and rise in CO even in IHD and patients – anginal attack▪ Tachycardia

Arteriolar vasodilators

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Contd.

Increased Renin secretion – Na+ retention

These effects are countered by administration of beta blockers and diuretics

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Mechanism of actionMinoxidilPowerful vasodilator, mainly 2 major uses – antihypertensive and alopeciaProdrug and converted to an active metabolite which acts by hyperpolarization of smooth muscles and thereby relaxation of SM – leading to hydralazine like effects

Arteriolar vasodilators

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ADRHydralazineHeadache, tachycardia, nausea, sweating, arrhythmia and precipitation of angina. A lupus like syndrome can occur with high dosage but it is reversible on discontinuation of the drug.

MinoxidilThis drug causes serious sodium and water retention leading to volume overload ,edema and CHF.

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Sodium Nitroprusside▪ Rapidly and consistently acting

vasodilator

▪ Relaxes both resistance and capacitance vessels and reduces PVR and CO (decrease in venous return)

▪ Unlike hydralazine it produces decrease in cardiac work and no reflex tachycardia.

▪ Improves ventricular function in heart failure by reducing preload

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Mechanism of actionIn the body it functions as a prodrug, reacting with sulfhydryl groups on erythrocytes, albumin, and other proteins to release NO.

NO, or endothelium derived relaxing factor, stimulates guanyl cyclase to produce cyclic GMP, sequestering calcium and inhibiting cellular contraction.

Sodium Nitroprusside

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Contd.

Uses: Hypertensive Emergencies, 50 mg is added to 500 ml of saline/glucose and infused slowly with 0.02 mg/min initially and later on titrated with response (wrap with black paper)

Adverse effects: ADRs are due to release of cyanides (“thiocyanate” which is a metabolic outcome of nitroprusside) – palpitation, pain abdomen, disorientation, psychosis, weakness and lactic acidosis.

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8. Centrally acting sympatholytics▪Clonidine▪Alpha methyldopa

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Mechanism of actionClonidine binds α2-AR with higher affinity than α1-AR. The α2-agonistic activity contributes to its BP-lowering effect due to negative feedback at the presynaptic neurons.

When given i.v., clonidine induces a brief rise of BP, which is followed by prolonged hypotension.

Clonidine

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Mechanism of action▪ The metabolite, α-methylnorepinephrine,

is stored in neurosecretory vesicle in place of NE.

▪ When released, α-methyl-NE is a potent α-AR agonist and in PNS is a vasoconstrictor.

▪ Its CNS effect is mediated by α2-AR, resulting in reduced adrenergic outflow from the CNS and an overall reduced total peripheral resistance.

Alpha methyldopa

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ADRClonidineDryness of mouth and eyes, sedation ,depression, bradycardia, impotence, nausea, dizziness, parotid gland swelling, and pain. Postural hypotension may occur in some case.Sudden stoppage of clonidine after prolonged use may cause withdrawal syndrome- headache, nervousness, tachycardia, sweating, tremors, palpitation and rebound hypertension

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ADRAlpha methyldopaNasal stuffiness, headache, sedation, depression, dryness of mouth, bradycardia, impotence, gynaecomastia, hepatitis and rarely haemolytic anaemia.

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Selection of Antihypertensive DrugsSelection of anti hypertensive drugs in individual patients depends on 1. Comorbidity2. Associated complications3. Age 4. Sex 5. Cost of the drug6. Concomitant drugs

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Selection of Antihypertensive DrugsPreferred drugs for initial treatment of

hypertension: ACE inhibitors, ARBs, CCBs and thiazides.

Therapy usually started with a single agent.

Combination therapy is used in patients who do not respond to single drug, can be used as initial therapy in patients with high BP.

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References▪ Lippincott’s illustrated reviews▪ K D Tripathi essentials of medical

pharmacology

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