ANTI-HYPERTENSIVE

DRUGS BY: JSN

 Introduction

Hypertension

> 140 mmHg > 90 mmHg

Systolic Blood Diastolic Blood

Pressure (SBP) Pressure (DBP)
 Types of
Hypertension

Essential Secondary

A disorder of unknown origin affecting the

Secondary to other disease processes
Blood Pressure regulating mechanisms

Environmental
Factors

Stress Na+ Intake Obesity Smoking

 Treatment Why?

Symptomatic treatment is Mandatory:

Damage to the vascular epithelium, paving the path for
atherosclerosis or nephropathy due to high intra-glomerular
pressure

Increased load on heart due to high BP can cause CHF

Hypertension, even asymptomatic needs treatment

 Normal Blood Pressure Regulation
Hydraulic equation:
Blood Pressure = Cardiac output (CO) X TPR
Physiologically CO and TPR is maintained minute to minute by
1. arterioles
2. postcapillary venules
3. Heart
4. Kidney is the fourth site volume of intravascular fluid

Baroreflex, humoral mechanism and renin-angiotensin- aldosterone system regulates

the above 4 sites
Local agents like Nitric oxide
In hypertensives Baroreflex and renal blood-volume control system set at higher
level
All antihypertensives act via interfering with normal mechanisms
CLASSIFICATION
DIURETICS
 Diuretics

1. Thiazides:
Hydrochlorothiazide, chlorthalidone, Indapamide

2. High ceiling:
Furosemide

3. K+ sparing:
Spironolactone, triamterene and amiloride
 Thiazide diuretics adverse effects
Hypokalaemia muscle pain and 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

All the above metabolic side effects higher doses (50 100 mg per day).
But, its observed that these adverse effects are minimal with low doses (12.5
to 25 mg)

-Average fall in BP is 10 mm of Hg
 Thiazide diuretics current status

Effects of low dose:

No significant hypokalaemia
Low incidence of arrhythmia
Lower incidence of hyperglycaemia, hyperlipidemia and hyperuricaemia
Reduction in MI incidence
Reduction in mortality and morbidity

JNC recommendation:
JNC recommends low dose of thiazide therapy (12.5 25 mg per day) in essential
hypertension
Preferably should be used with a potassium sparing diuretic as first choice in elderly
If therapy fails another antihypertensive but do not increase the thiazide dose
Loop diuretics are to be given when there is severe hypertension with retention of
body fluids
 High ceiling diuretic
Furosemide is a weaker anti-hypertensive than thiazides: fall in BP is entirely
dependent on reduction in plasma volume and c.o.

Moreover, the high ceiling diuretics are more liable to cause fluid and electrolyte
imbalance, weakness and other side effects.

They are indicated in hypertension only when it is Complicated by:

(a) Chronic renal failure: thiazides are ineffective, both as diuretics and
antihypertensives.

(b) Coexisting refractory CHF.

(c) Resistance to combination regimens containing a thiazide,

 Potassium Sparing Diuretic
Spironolactone (Aldosterone receptor antagonist)

Amiloride

Loss of sodium is not accompanied by loss of potassium.

Spironolactone or amiloride themselves lower BP slightly, but

they are used only in conjunction with a thiazide diuretic to
prevent K* loss and to augment the antihypertensive action.
ANGIOTENSIN CONVERTING ENZYME
( ACE) INHIBITORS
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
 RAS actions of Angiotensin-II.
Powerful vasoconstrictor particularly arteriolar

direct action and release of Adr/NA release

Promotes movement of fluid from vascular to extravascular

More potent vasopressor agent than NA promotes Na+ and water reabsorption

It increases myocardial force of contraction (CA++ influx promotion) and increases

heart rate by sympathetic activity

Aldosterone secretion stimulation retention of Na++ in body

Vasoconstriction of renal arterioles rise in IGP glomerular damage

Decreases NO release
Induces drinking behaviour and ADH release by acting in CNS increase thirst
 ANGIOTENSIN CONVERTING ENZYME
( ACE) INHIBITORS

Captopril
Enalapril
Lisinopril
Fosinopril
Ramipril
Imidapril
Benazepril
 Captopril Pharmacological actions
DOSE-25-50mg BD

1. In Normal:

Depends on Na+ status lowers BP marginally on single dose

When Na+ depletion marked lowering of BP

2. In hypertensive:
Lowers TPR and thereby mean, systolic and diastolic BP

RAS is overactive in 80% of hypertensive cases and contributes to the maintenance of

vascular tone inhibition causes lowering of BP

Captopril decreases t.p.r on long term

No effect on Cardiac output

Postural hypotension is not a problem

Renal blood flow is maintained greater dilatation of vessels

 Captopril Adverse effects
HHARD COUGH
Cough persistent brassy cough in 20% cases
Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta
blockers (routine check of K+ level)
Hypotension 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
Foetopathic: hypoplasia of organs, growth retardation etc
Neutripenia

Contraindications: Pregnancy, renal artery stenosis, hypersensitivity and hyperkalaemia

 ACE inhibitors - Enalapril

Its a prodrug converted to enalaprilate

Advantages over captopril:
Longer half life OD (5-20 mg OD)
Absorption not affected by food
Rash and loss of taste are less frequent
Longer onset of action
Less side effects
 Ramipril
Its a popular ACEI now
It is also a prodrug with long half life
Tissue specific Protective of heart and kidney
Uses: Diabetes with hypertension, CHF
Dose: Start with low dose; 2.5 to 10 mg daily
ANGIOTENSIN RECEPTOR BLOCKER
 Angiotensin Receptor Blockers (ARBs)

Losartan
Valsartan
Candesartan
Telmisartan
Irbesartan
 Angiotensin Receptor Blockers (ARBs)
Angiotensin Receptors:
Specific angiotensin receptors have been discovered, grouped and abbreviated as
AT1 and AT2
They are present on the surface of the target cells
Most of the physiological actions of angiotensin are mediated via AT1 receptor
Angiotensin-II bind to angiotensin receptor I (AT-I) and and mediates all classical
effects of angiotensin eg.vasocontriction, aldosterone release,sympathetic activation etc
which increases BP.
Angiotensin receptor blockers competitively bind to AT-I receptor and attenuates the
effect of angiotensin-II
Physiological role of AT-II receptor is unknown.
Because many tissue contain enzymic pathway which is capable of converting
Angiotensin-I to angiotensin-II independent of ACE.It is advantageous to target renin
angiotensin aldosterone system via, angiotensin recepor blockers
Losartan is the specific AT1 blocker
 Losartan
Theoretical superiority over ACEIs:

Cough is rare

Complete inhibition of AT1 alternative remains with ACEs

Result in indirect activation of AT2 vasodilatation (additional benefit)

However, losartan decreases BP in hypertensive which is for long period (24 Hrs)

heart rate remains unchanged and cvs reflxes are not interfered

no significant effect in plasma lipid profile, insulin sensitivity and carbohydrate

tolerance etc

Mild uricosuric effect

 Losartan
Pharmacokinetic:
Absorption not affected by food but unlike ACEIs its bioavailability is low
High first pass metabolism
Carboxylated to active metabolite
Highly bound to plasma protein
Do not enter brain

Adverse effects:
Foetopathic like ACEIs not to be administered in pregnancy
Rare 1st dose effect hypotension
Low dysgeusia and dry cough
Lower incidence of angioedema

Available as 25 and 50 mg tablets

CALCIUM CHANNEL BLOCKERS
Calcium Channel Blockers
 Calcium Channel Blockers
Three types Ca+ channels in smooth muscles Voltage sensitive, receptor
operated and leak channel

Voltage sensitive are again 3 types L-Type, T-Type and N-Type

Normally, L-Type of channels admit Ca+ and causes depolarization excitation-

contraction coupling through phosphorylation of myosin light chain contraction of
vascular smooth muscle elevation of BP

CCBs block L-Type channel:

Smooth Muscle relaxation
 Calcium Channel Blockers
Advantages:
Unlike diuretics no adverse metabolic effects but mild adverse effects
like dizziness, fatigue etc.
Do not compromise haemodynamics no impairment of work
capacity
No sedation or CNS effect
Can be given to asthma, angina and PVD patients
No renal and male sexual function impairment
No adverse fetal effects and can be given in pregnancy
Minimal effect on quality of life
 Calcium Channel Blockers current status
As per JNC 7 CCBs are not 1st line of antihypertensive unless indicated
ACEI/diuretics/beta blockers
However its been used as 1st line by many because of excellent
tolerability and high efficacy
Preferred in elderly and prevents stroke
CCBs are effective in low Renin hypertension
They are next to ACE inhibitors in inhibition of albuminuria and
prevention of diabetic nephropathy
Immediate acting Nifedipine is not encouraged anymore
 Calcium Channel Blockers

Contraindications:
Unstable angina
Heart failure
Interaction Hypotension
Verapamil should not be given with Severe aortic stenosis
blockers
It increases plasma digoxin level by
decreasing its excretion: toxicity can
develop.
It should not be used along with
other cardiac depressants like
quinidine and disopyramide.
BETA-ADRENERGIC BLOCKERS
 Beta-adrenergic blockers
Non selective: Propranolol (others: nadolol, timolol, pindolol, labetolol)

Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)

All beta-blockers similar antihypertensive effects irrespective of additional properties

Reduction in CO but no change in BP initially but slowly reduced CO antihypertensive

action

Other mechanisms decreased renin release from kidney (beta-1 mediated)

Reduced NA release and central sympathetic outflow reduction

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

 1 2 3

location Heart Bronchi, Adipose

JG cells in blood tissue
kidney vessels,
uterus, liver,
eye,etc
 Advantages:
No postural hypotension
No salt and water retention
Low incidence of side effects
Low cost
Once a day regime
Preferred in young non-obese patients, prevention of sudden cardiac death in post
infarction patients and progression of CHF

Drawbacks (side effects):

Fatigue, decreased work capacity
Loss of libido impotence
Cognitive defects forgetfulness
Difficult to stop suddenly
Therefore cardio-selective drugs are preferred now
 The nonselective blockers have an unfavourable effect on lipid profile
(raise triglyceride level and LDL/HDL ratio).

They have also fared less well on quality of life parameters like
decreased work capacity, fatigue, loss of libido and subtle cognitive
effects (forgetfulness, low drive), nightmares and increased incidence
of antidepressant use.

Many of these drawbacks are minimized in the 1 selective agents and

in those which penetrate brain poorly
 Advantages of cardio-selective over non-selective:
In asthma

In diabetes mellitus

In peripheral vascular disease

Current status:
JNC 7 recommends - 1st line of antihypertensive along with diuretics and
ACEIs

Preferred in young non-obese hypertensive

Angina pectoris and post angina patients

Post MI patients useful in preventing mortality

In old persons, carvedilol vasodilatory action can be given

ALPHA-ADRENERGIC BLOCKERS
 -Adrenergic blockers
Prazosin,
Terazosin,
Doxazosin,
Phentolamine,
Phenoxybenzamine

These drugs inhibit adrenergic responses mediated through

the adrenergic receptors without affecting those mediated
through receptors
 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
 PRAZOSIN

PRAZOSIN is the prototype of the alpha-blockers

Reduction in t.p.r and mean reduction in CO

Does not produce tachycardia as presynaptic auto (alpha-2)

receptors are not
 PRAZOSIN
Adverse effects:
Prazosin causes postural hypotension start 0.5 mg at bed time with increasing
dose and upto 10 mg daily
Fluid retention in monotherapy
Headache, dry mouth, weakness, blurred vision, rash, drowsiness and failure of
ejaculation in males
Current status:
Several advantages improvement of carbohydrate metabolism diabetics, lowers
LDL and increases HDL
But not used as first line agent, used in addition with other conventional drugs which
are failing diuretic or beta blocker
Doses: Available as 0.5 mg, 1 mg, 2.5 mg, 5 mg etc. dose:1-4 mg thrice daily
(Minipress/Prazopress)
VASODILATORS
 ARTERIOLAR
Hydralazine,
Minoxidil,
Diazoxide

ARTERIOLAR + VENOUS
Sodium Nitroprusside
 Hydralazine
Directly acting vasodilator

MOA: hydralazine molecules combine with receptors in the endothelium of arterioles NO

release relaxation of vascular smooth muscle fall in BP

Subsequently fall in BP stimulation of adrenergic system leading to

Cardiac stimulation producing palpitation and rise in CO

Tachycardia

Increased Renin secretion Na+ retention

These effects are countered by administration of beta blockers and diuretics

However many do not agree to this theory

Uses: 1) Moderate hypertension when 1st line fails with beta-blockers and diuretics

2) Hypertension in Pregnancy, Dose 25-50 mg OD

 Minoxidil
Powerful vasodilator, mainly 2 major uses antihypertensive and alopecia

Prodrug and converted to an active metabolite which acts by hyperpolarization of

smooth muscles and thereby relaxation of SM leading to hydralazine like effects

Rarely indicated in hypertension

More often in alopecia to promote hair growth

Orally not used any more

Topically as 2-5% lotion/gel and takes months to get effects

MOA of hair growth:

Enhanced microcirculation around hair follicles and also by direct stimulation of follicles
 Sodium Nitroprusside
Rapidly and consistently acting vasodilator

Relaxes both resistance and capacitance vessels and reduces t.p.r and CO (decrease
in venous return)

MOA: RBCs convert nitroprusside to NO relaxation also by non-enzymatically to NO

by glutathione
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

Adverse effects: All are due release of cyanides (thiocyanate) palpitation, pain
abdomen, disorientation, psychosis, weakness and lactic acidosis.
 Centrally acting Drugs
Clonidine: Imidazoline derivative, partial agonist of central alpha-2 receptor
Not frequently used now because of tolerance and withdrawal hypertension
 Methyl Dopa
This -methyl analogue of dopa, the precursor of dopamine (DA) and NA
is one of the first rationally designed antihypertensives.
The methyl-NA (a selective 2 agonist) formed in the brain from
methyldopa acts on central 2 receptors to decrease efferent
sympathetic activity.