Anti-hypertensive drugs

Diuretics:

Thiazides: Hydrochlorothiazides, Chlorothalidone

High ceiling: Furosemide

K+ sparing: Spironolactone, Triamterene & Amiloride

MOA: Acts on kidneys to excretion of Na & H2O in blood volume blood pressure

Adverse effect

Hypokalaemia muscle pain & fatigue

Hyperglycemia : inhibition of insulin release due to K+ depletion (proinsulin to insulin) precipitation of diabetes

Hyperlipidemia : rise in total LDL level risk of stroke

Hyperurecaemia : inhibition of urate excretion

Sudden cardiac death tosades depointes (hypokalaemia)

All the above metabolic side effects ~ higher doses (50-100mg per day); but, its observed that these adverse effects are minimal with low doses
(12.5 25mg). Average fall in blood pressure is 10mm Hg

Angiontensin-converting Enzyme (ACE) inhibitors:

Captopril, Lisinopril, Enalapril, Ramipril & Fosinopril

MOA: Inhibits synthesis of Angiotensin II - in peripheral resistance & blood volume

Angiontensin I (AT-I) inhibitors:

Lasortan, Candesartan, Valsartan & Telmisartan

MOA: Blocks binding of AT-II to its receptors

Centrally acting:

Clonidine, Methyldopa

MOA: Act on central a 2A receptors to sympathetic outflow fall in blood pressure

Alpha-Methyldopa (prodrug) ~ precursor of Dopamine & NA

MOA: Converted to (alpha) methyl noradrenaline which acts on -2 receptors in brain & causes inhibiton of adrenergic discharge in
medulla fall in PVR (peripheral vessel resistance) & fall in blood pressure

Adverse effect

Cognitive impairment, postural hypotension, +ve Coombs test, etc (not used therapeutically now except in hypertesion in pregnancy)

Clonidine: Imidazoline derivative, partial agonist of central -2 receptors (not frequently used now because of tolerance &
withdrawal hypertension)

-adrenergic blockers:

Aiman Tymer 2012

 Non-selective: Propanolol [others: Hadolol, Timolol, Pindolol, Labetolol]

Cardioselective: Metoprollol [others: Atenolol, Esmolol, Betaxolol]

MOA: Bind to -adrenergic receptors & blocks the activity

K+ channel activators:

Diazoxide, Minoxidil & Nicorandil

MOA: Leaking of K+ due to opening hyperpolarization of smooth muscle cells relaxation of smooth muscle cells

Vasodilators:

o Arteriolar: Hydralazine (also Calcium Channel Blockers & K+ channel activators)

o Arterio-venular: Sodium Nitroprusside

Calcium Channel Blockers ~ blocks influx of Ca2+ in smooth muscle cells relaxation of smooth muscle cells - blood pressure

MOA: 3 types Ca2+ channels in smooth muscles voltage sensitive, receptor operated & leak channel

1. Voltage sensitive 3 types (L-typer, T-typer, N-type)

Normally, L-typer of channels admit Ca2+ & causes depolarization excitation-contraction coupling through phosphorylation of myosin light chain
contraction of vascular smooth muscle elevation of blood pressure

Calcium Channel Blocker L-type:

Smooth muscle relaxation

-ve chronotropic, ionotropic, chronotropic effects in heart

DHPs have highest smooth muscle relaxation & vasodilator action followed by Verapamil & Diltiazem; Other action: DHPs have diuretic
action

Advantage

Unlike diuretics, no adverse metabolic effetcs but mild adverse effect like ~ dizziness, fatigue, etc

Do not compromise haemodynamics= no impairment of work capacity

No sedation / CNS effect

Can be given to asthma, angina & PVD patients

No renal & male sexual function impairment

No adverse fetal effects & can be given in pregnancy

Minimal effect on quality of life

Contraindication

Unstable angina

Heart failure

Hypotension

Aiman Tymer 2012

 Post infarct cases

Severe aortic stenosis

Vasodilators:

o Arteriolar: Hydralazine (also Calcium Channel Blockers & K+ channel activators)

o Arterio-venular: Sodium Nitroprusside

Directly acting vasodilators:

MOA: Hydralazine molecules combine with receptor in endothelium of arterioles NO release relaxation of vascular smoth muscle fall
in BP

Subsequently fall in blood pressure stimulation of adrenergic sys leading to cardiac stimulation producing palpitation & cardiac output
even in IHD & patients anginal attack; Tachycardia; renin secretion Na+ retention (these effects are encoutered by administration of
blockers & diuretics, however many do not agree to this theory)

Uses

I. Moderate hypertension when 1st line fails with -blocker & diuretics

II. Hypertension in pregnancy

Treatment of hypertension General Principles

1) Stage 1

Start with a single most appropriate drug with a low dose, preferably start with Thiazides, others like -blockers, Calcium
Channel Blockers (CCB), ARBs & Angiotensin-converting Enzyme (ACE) inhibitors may also be considered. CCB in case of elderly
& stroke prevention. If required dose moderately.

Partial response / no response add from another group of drug, but remember it should be a low dose combination.

If not controlled change to another low dose combination

In case of side effects lower dose / substitute with other group

2) Stage 2

Start with 2 drug combination one should diuretic

3) In clinical practice a large number of patient require combination therapy the combination should rational & from different patterns of
haemodynamic effects

Sympathetic inhibitors (not -blockers) & vasodilators + diuretics

Diuretics, CCB, ACE inhibitors & vasodilators + -blockers (block renin release)

Hydralazine & CCB + -blockers (tachycardia countered)

ACE inhibitors + diuretics

4) 3 drugs combination: CCB + ACE / ARB + diuretics; CCB + -blockers + diuretic; ACE / ARB + -blockers + diuretic

5) Never combine:

Aiman Tymer 2012

 / - blocker & Clonidine antagonist

Nifedepine & diuretic synergism

Hydralazine with DHP / Prazosin same type of action

Ditiazem & Verapamil with -blocker bradycardia

Methyldopa & Clonidine

6) Hypertension & pregnancy

No drug is safe during pregnancy

Avoid diuretics, Propranolol, ACE inhibitor, Sodium nitroprusside, etc

Safer drugs: Hydralazine, Methyldopa, Cardioselective -blockers & Prazosin

All -blockers similar antihypertensive effetcs irrespective of additional properties]

o Reduction in cardiac output (CO) but no change in blood pressure (BP) initaially but slowly

o Adaptation by residence vessels to chronically reduced CO antihypertensive action

o Other mechanisms - renin release from kidney (-1 mediated)

o Reduced NA release & central sympathetic outflow reduction

o Non-selective ones reduction in g.f.r. but not with selective one

o Drugs with intrinsic sympathomimetic activity may cause less reduction in heart rate (HR) & CO

Drawback (side effects)

o Fatigue, lethargy (low CO) - work capacity

o Loss of libido impotence

o Cognetive defects - forgetfulness

o Difficult to stop suddenly

Therefore cardio-selective drugs are preffered now

Aiman Tymer 2012

 & adrenergic blockers: Labetolol & Carbedilol

adrenergic blockers:

Prazosin, terazosin, doxazosin, phenoxybenzamine & phentolamine

MOA: Blocking of adrenergic receptors in smooth muscles vasodilatation

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

Specific -1 blockers like Prazosin, Terazosin & Doxazosine are used

Prazosin is the prototype of -blockers

Redcution in t.p.r. & mean BP also reduction in venomotor tone & pooling of blood reduction in CO

Does not produce tachycardia as presynaptic auto (-2) receptor are not inhibited autoregulation of NA release remains intact

Adverse effect

Prazosin causes postural hypotension start 0.5mg at bed time with dose & up to 10mg daily

Fluid retention in monotherapy

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

Aiman Tymer 2012