2.AHT

NO ATTENDANCE AFTER 5 MINUTES OF START OF CLASS

OBJECTIVES OF THIS LECTURE:

• Classify antihypertensive drugs.

• Outline the mechanism of action of

antihypertensive drugs.

• Describe the adverse effects of the

antihypertensive drugs.

BP= CO X PVDCO- Cardiac out put,PVD- Peripheral Vascular Resistance

* Two mechanisms which control CO & PVD are Baroreflexes (for

moment to moment regulation) & Renin Angiotensin System

DIFFERENT CLASSES OF ANTI HYPERTENSIVE AGENTS

Diuretics

Thiazide diuretics First-line drug in mild

hypertension

Loop diureticsSevere hypertension & patient with poor renal function

Potassium-sparing Agents Especially in patient with heart failure

SYMPATHOLYTIC (SYMPATHOPLEGIC) AGENTS

CENTRAL SYMPATHOLYTICS • Central Alpha2-selective agonists (clonidine, methyldopa)

• Effects: reduces sympathetic out flow.

• Uses

• HT complicated by renal disease (no reduction in renal perfusion)

• Methyldopa – Drug of choice HT during pregnancy

• Side effects

• Rebound HT on abrupt withdrawal (Gradual tapering recommended)

• Methyldopa produces sedation and drowsiness

CLONIDINE

• Imidazoline derivative

• Partial agonist at α2A subtype receptors of brain stem

• Stimulation of α2A subtype receptors decreases sympathetic outflow

• Produces fall in BP and bradycardia

• Moderately potent antihypertensive

• Adverse effects:

• Sedation, mental depression, dryness of mouth, impotence

• Withdrawal hypertension

METHYL DOPA

• α- methyl analogue of dopa- precursor of dopamine and nor-adrenaline

• Acts on central α 2 receptors to decrease efferent sympathetic activity

• Decreases total peripheral resistance more effectively

• In large doses it inhibits dopa-decarboxylase enzyme and reduces the formation of Nor-adrenaline and forms a false neurotransmitter in peripheral

• It is a moderate efficacy antihypertensive

• Widely used as antihypertensive especially along with diuretic agent

• Preferred for he management of hypertension during pregnancy

β-ADRENOCEPTOR–BLOCKING AGENTS

Β-ADRENOCEPTOR–BLOCKING AGENTS

• The hypotensive response to β blockers develop over 1-3 weeks and well sustained

• Most β blockers maintains antihypertensive effect over 24 hours

• The β blockers are classified in to

• Non-selective β blockers (propranolol)

• Selective β blockers (Atenolol, nebivolol)

• The non-selective β blockers carries risk for alteration in lipid profile of the patient- rise LDL/HDL ratio

• The contraindication for the use of β blockers are

• Cardiac disorders such as sick sinus syndrome, congestive cardiac failure

• Pulmonary disorders (especially for non-selective β blockers)

• Peripheral vascular diseases (especially for non-selective β blockers)

BETA -ADRENOCEPTOR–BLOCKING AGENTS (PROPRANOLOL, ATENOLOL, NEBIVOLOL)

Uses

• Mild to moderate Hypertension – used alone for stage I hypertension

• HT associated with cardiac disease.

Adverse effects

Common: bradycardia, exercise intolerance and alteration in serum lipid profile

Rebound hypertension on Abrupt withdrawal

ΑLPHA-ADRENOCEPTOR–BLOCKING AGENTSAlpha1-selective agents eg, prazosin

•Pharmacological effect

• reduce vascular resistance and venous return.

•Uses:

• mild to moderate hypertension

• relax smooth muscle in the prostate, which is useful in benign prostatic hyperplasia.

•Side effects:

• orthostatic hypotension, especially with the first few doses.

• Ejaculation failure and impotency

PRAZOSIN• Selective α1 inhibitor

• Dilates both resistance and capacitance vessels

• Haemodynamic effects

• Reduces t.p.r (total peripheral resistance)

• Reduces mean BP

• Minor reduction in venous return and cardiac output

• Maintains renal perfusion and g.f.r

• Prazosin does not impair CHO (carbohydrate) metabolism- suitable for diabetes (but not if neuropathy is present)

• It has favourable effect on lipid profile

• Symptomatic improvement of co-existing benign prostatic hypertrophy

VASODILATORS

Hydralazine•Mechanism of action

• Direct vasodilation of arteries and arterioles - reduces PVR

•Uses

• Moderately severe hypertension

•Adverse effects:

• compensatory responses (tachycardia, salt and water retention)

• Reversible lupus erythematosus

Minoxidil

•Mechanism of action

• Direct dilatation of arterioles.

•Uses

• Severe hypertension (refractory to other antihypertensives)

•Adverse effects

• Reflex tachycardia and fluid retention may be severe

CALCIUM CHANNEL BLOCKERSMechanism of action

They block L-type Ca channels in various tissues

Verapamil: More selective on cardiac muscle

Deltiazem: Acts equally on both cardiac & smooth muscles

Nifedipine: More selective on blood vessels

(-) SA Node → ↓Heart rate

(-) AV Node → ↓ Conductivity

(-) Cardiac contractility

Vasodilatation → ↓ peripheral resistance

↓cardiac

output ↓Blood

Pressure

useshypertensive patients who also have asthma,

diabetes, angina, and/or peripheral vascular disease

Adverse effects

verapamilConstipation

should be avoided in patients with congestive

heart failure or with atrioventricular block due to its negative

inotropic and dromotropic

NifedipineDizziness, headache, fatigue

gingival enlargement, dependent edema

All are contraindicated during pregnancy

Angiotensin converting enzyme inhibitors (ACE (Inhibitors (e.g.captopril)

Mechanism of action

Uses of ACE inhibitors

slow the progression of diabetic

nephropathy and decrease albuminuria.

patients with chronic heart failure.

Adverse effects

1.Dry cough, angioedema (due to increased bradykinin)

2.Rash

3.Fever

4.Altered taste

ANGIOTENSIN RECEPTOR BLOCKERS (ARBS)

Losartan•Mechanism of action

• Competitive inhibition angiotensin II at its AT1 receptor site

• uses

• as ACE inhibitors

• do not affect bradykinin metabolism

RENIN INHIBITOR

Aliskiren

Directly inhibits renin

lowers blood pressure about as effectively as ARBs, A

CE inhibitors, and thiazides.

can also cause cough and angioedema

ALGORITHM FOR ANTIHYPERTENSIVE THERAPY

ANTIHYPERTENSIVE DRUG CHOICE

IN SPECIAL CONDITIONS

Diabetes

ACE inhibitors or ARBs are the first-line treatment, since

they reduce proteinuria and slow down renal deterioration.

Coronary arterial disease

β-blockers are the first-line choice

ANTIHYPERTENSIVE DRUG CHOICEIN SPECIAL CONDITIONS

Heart failure

• ACE inhibitors and diuretics are the first-line treatment for

hypertension

Pregnancy

• α- methyl dopa is the drug of first choice.

• Other drugs that could be used include: labetalol, hydralazine and

nifedipine

DRUGS FOR HYPERTENSIVE EMERGENCY

Nitroprusside•Parenteral vasodilator & short-acting agent

• should be prepared freshly -light-sensitive

mechanism of action

•release of nitric oxide (from the drug molecule itself), which mediates

vascular smooth muscle relaxation

Adverse effects

1.excessive hypotension

2.reflex tachycardia

3.if infusion is continued over several days, accumulation of cyanide in the

blood can be treated with an infusion of sodium thiosulfate.

LabetalolBlocks both an α- and a β-blocker

Does not cause reflex tachycardia

The major limitation is a longer half life

Nicardipine

A calcium-channel blocker, for intravenous infusion.

Long half-life (approximately 8 hours)

Fenoldopam

Peripheral dopamine-1 receptor agonist that is given as an

intravenous infusion.

Relaxes mainly the renal (renal artery, afferent and efferent

arterioles) and mesenteric arterial vessels

Diuretic action caused by the increase in renal blood flow.

Beneficial in patients with renal insufficiency.