Antihypertensives - drdhriti

ANTIHYPERTENSIVE DRUGS
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

INTRODUCTION
Hypertension
Systolic Blood
Pressure (SBP)
Diastolic Blood
Pressure (DBP)
> 140 mmHg > 90 mmHg
****************************************************

CONT…
Types of
Hypertension
Essential Secondary
A disorder of unknown origin affecting the
Blood Pressure regulating mechanisms
Secondary to other disease processes
Environmental
Factors
Stress Na+ Intake Obesity Smoking
****************************************************

TREATMENT – WHY?
 Symptomatic treatment is Mandatory:
1. Damage to the vascular epithelium, paving the path
for atherosclerosis (IHD, CVA)
2. Increased load on heart due to high BP can cause
CHF
3. Nephropathy due to high intra-glomerular pressure
4. Hypertension, even asymptomatic needs treatment
Available groups of major drugs – Diuretics,
ACEIs/ARBs, Beta-blockers, CCBs and others

DIURETICS - MOA
 Drugs causing net loss of Na+ and water in urine
 Mechanism of antihypertensive action:
 Initially: diuresis – depletion of Na+ and body fluid volume
– decrease in cardiac output
 Subsequently , prolong treatment (after 4 - 6 weeks) - Na+
balance and CO is regained by 95%, but BP remains low!
 Due to reduction in total peripheral resistance (TPR) due to
deficit of little amount of Na+ and water (Na+ causes vascular
stiffness)
 Decreased responsiveness to Adr and A-II
 Similar effect is seen with sodium restriction (low sodium diet)
 No postural hypotension – no effect on capacitance
vessels and sympathetic reflexes are not interefered
 Added advantage – potentiate all other
antihypertensives (not DHPs)

THIAZIDE DIURETICS – ADVERSE EFFECTS
 Drawbacks:
 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 and lowering of HDL
– risk of stroke
 Hyperurecaemia: inhibition of urate excretion
 Erectile dysfunction
 Sudden cardiac death – tosades de pointes
(hypokalaemia)
 All the above metabolic side effects – higher doses
(50 – 100 mg per day)
 But, these adverse effects are minimal with low
doses (12.5 to 25 mg) - Average fall in BP is 10 mm
of Hg
 JNC recommendation:
 Preferably, with a potassium sparing diuretic as first choice
in elderly – if fails – another antihypertensive but do not
increase the thiazide dose

DIURETICS – CONTD.
 K+ sparing diuretics:
 Thiazide and K sparing diuretics are combined
therapeutically – DITIDE (triamterene + benzthiazide)
is popular one
 Modified thiazide: indapamide
 Indole derivative and long duration of action (18 Hrs)
– orally 2.5 mg dose
 Reduces the risk of further stroke in stroke patients
 It is a lipid neutral i.e. does not alter blood lipid
concentration, but other adverse effects may remain
 Why Loop diuretics not useful for chronic control?
 Na+ deficient state is temporary, not maintained
round –the-clock and t.p.r not reduced
 Used only in complicated cases – CRF, CHF marked
fluid retention cases

ACE INHIBITORS AND HYPERTENSION
 1st choice of drug in all grades of hypertension
except in bilateral renal stenosis
 Advantages:
 No electrolyte imbalance (no fatigue or weakness) or
postural hypotension
 No hyperuraecemia or deleterious effect on plasma lipid
profile
 Safe in diabetics and asthmatics
 Prevention of secondary hyperaldosteronism and K+
loss
 Reverse the ventricular hypertrophy and increase in
lumen size of vessel
 No rebound hypertension
 Minimal worsening of quality of life – general wellbeing,
sleep and work performance etc.

ACEIS
 Particular advantages:
 Renal blood flow improvement
 Retard diabetic nephropathy
 Regression of LV and vascular hypertrophy -
cardioprotective
 Uses: effective in younger patients (below 55 yrs)
 Patient with diabetes
 Nephropathy
 CHF, angina and MI
 Enalapril/lisinopril – 2.5 mg to 10 mg per day

ANGIOTENSIN RECEPTOR BLOCKERS
 Losartan, candesartan, Valsartan and telmisartan
 Theoretical superiority over ACEIs: free from side effects
 Cough is rare – no interference with bradykinin and other
ACE substrates
 No angioedema, urticaria and taste disturbance
 No effect on heart rate and cardiac reflexes
 Metabolic and prognostic advantages
 Clinical benefit of ARBs over ACEIs (?)
 But, combination therapy: Total suppression of RAS
 A-II generated by non ACE mechanisms – ARBs block
 ACEIs produce bradykinin related vasodilatation – ARBs do
not
 ARBs cause compensatory increase of A-II – ACEIs block
 ARBs indirect activation of AT2 – ACEIs block
 Proved useful in CHF and non-diabetic renal disease –
haemodynamic and symptomatic benefit in CHF

BETA-ADRENERGIC BLOCKERS
 Non selective: Propranolol (others: nadolol, timolol, pindolol and
labetolol) and Cardioselective: Metoprolol (others: atenolol,
acebutalol, esmolol, betaxolol)
 All beta-blockers similar antihypertensive effects:
 Reduction in CO but no change in BP initially but slowly - adaptation
 Other mechanisms – decreased renin release from kidney (beta-1
mediated), decreased central NA ouflow, reduction in g.f.r (non-selective
ones) and reduction in reart rate and CO (ISAs)
 Several contraindications:
 Partial and complete heart block
 COAD and asthma
 Peripheral vascular disease
 Drawbacks: Rebound hypertension
 Raised LDL and lowered HDL and impaired carbohydrate tolerance in
diabetics
 Fatigue, lethargy (low CO?) – decreased work capacity
 Loss of libido – impotence
 Cognitive defects – forgetfulness and nightmares etc.
 Difficult to stop suddenly
 Therefore cardio-selective drugs are preferred now

BETA-ADRENERGIC BLOCKERS –
CONTD.
 Advantages of cardio-selective over non-selective:
 In asthma
 In diabetes mellitus
 In peripheral vascular disease
 Lower incidence of changes in lipid profile
 Overall: beta-blockers as first line of drug
 No postural hypotension
 No salt and water retention
 Low incidence of side effects
 Low cost
 Once a day regime
 Cardioprotective potential
 Preferred:
 In young non-obese patients
 Prevention of sudden cardiac death in post infarction patients and
progression of CHF
 Angina pectoris and post angina patients
 Post MI patients – useful in preventing mortality
 In old persons, carvedilol – vasodilatory action can be given

CALCIUM CHANNEL BLOCKERS
 Verapamil, diltiazem, nifedepine and amlodipine etc.
 Advantages:
 No haemodynamic effect – physical work capacity
 No effect on lipid profile, uric acid level and electrolyte imbalance
 No renal and male sexual function impairment
 Can be given to asthma, angina and PVD patients
 Unlike diuretics no adverse metabolic effects but mild adverse effects like
– dizziness, fatigue etc.
 No sedation or CNS effect
 No adverse fetal effects and can be given in pregnancy
 Minimal effect on quality of life
 Current status:
 Not first line of drug but …?
 However, 1st line - excellent tolerability and high efficacy
 Preferred in elderly and prevents stroke
 CCBs are effective in low Renin hypertension, PVD, asthma and COAD
and pregnancy
 They are next to ACE inhibitors in inhibition of albuminuria and prevention
of diabetic nephropathy

ΑLPHA-ADRENERGIC BLOCKERS
 Non selective alpha-1 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 is the prototype of the alpha- 1 blockers
 Reduction in t.p.r and mean BP – also reduction in
venomotor tone and pooling of blood – reduction in
CO
 Does not produce tachycardia as presynaptic auto
(alpha-2) receptors are not inhibited –
autoregulation of NA release remains intact

ΑLPHA-ADRENERGIC BLOCKERS –
CONTD.
 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, dry mouth, blurred
vision, rash, drowsiness and failure of ejaculation in males
 Current status:
 Several advantages – improvement of carbohydrate
metabolism – diabetics, lowers LDL and increases HDL,
symptomatic improvement in BHP
 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)

CENTRALLY ACTING DRUGS
 Clonidine: Imidazoline derivative, partial agonist of
central alpha-2A receptor in CNS – once popular
(moderately potent)
 Frequent side effects– sedation, depression, impotence, salt
and water retention, supersensitivity and rebound
hypertension
 Not frequently used now because of tolerance and withdrawal
hypertension
 Used rarely as 3rd or 4th choice drug – with diuretics
 Methyldopa: a prodrug
 Precursor of Dopamine and NA
 MOA: Converted to alpha methyl noradrenaline which acts on
alpha-2 receptors in brain and causes inhibition of adrenergic
discharge in medulla – fall in t.p.r and fall in BP
 Also inhibits dopadecarboxylase – no NA synthesis
 Various adverse effects – cognitive impairement, postural
hypotension, positive coomb`s test etc. – Not used
therapeutically now except in Hypertension during pregnancy

VASODILATORS - 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
 Subsequenly 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
 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

SODIUM NITROPRUSSIDE
 Rapidly and consistently acting vasodilator
 Relaxes both resistance and capacitance vessels and
reduces t.p.r 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
 MOA: 1) RBCs convert nitroprusside to NO – relaxation 2)
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 (wrap with black paper)
 Adverse effects: All are due release of cyanides
(thiocyanate) – palpitation, pain abdomen, disorientation,
psychosis, weakness and lactic acidosis.

VASODILATORS - MINOXIDIL (ROGAINE,
REGAINE, MINTOP)
 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 especially in life threatening
ones
 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
 Alteration of androgen effect of hair follicles

TREATMENT OF HYPERTENSION
Aim: To prevent mortality and morbidity associated
with persistently raised BP by lowering it to an
acceptable level, with minimum inconvenience to the
patient

TREATMENT OF HYPERTENSION: JNC
7 CLASSIFICATION
BP Systolic Diastolic
Normal >120 <80
Prehypertension 120-139 80-89
Stage1 149-159 90-99
Stage2 >160 >100
1. Age above 55 and 65
in Men and Woman
respectively
2. Family History
3. Smoking
4. DM and Dyslipidemia
5. Hypertension
6. Obesity
7. Microalbuminuria
Categories Risk factors

TREATMENT OF HYPERTENSION – CONTD.
 JNC 7 compelling Indications:
 Heart failure
 Coronary artery disease
 H/o MI
 H/o stroke
 Diabetes
 Chronic Renal failure

TREATMENT OF HYPERTENSION –
CONTD.

GENERAL PRINCIPLES
 Stage I:
 Start with a single most appropriate drug with a low
dose. Preferably start with Thiazides. Others like
beta-blockers, CCBs, ARBs and ACE inhibitors may
also be considered. CCB – in case of elderly and
stroke prevention. If required increase the dose
moderately
 Partial response or 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 the dose or substitute
with other group

COMBINATION THERAPY
 Stage 2: Start with 2 drug combination – one should
be diuretic
 In clinical practice a large number of patients
require combination therapy – the combination
should be rational and from different patterns of
haemodynamic effects
 Diuretics, CCBs, ACE inhibitors and vasodilators +
beta blockers (blocks renin release)
 Hydralazine /CCBs + beta-blockers (tachycardia
countered)
 ACEIs/ARBs + diuretics in CHF
 Others - ACEIs/ARBs + CCBs or ACEIs/ARBs + beta-
blockers or beta blocker + prazosin
 3 (three) Drug combinations:
CCB+ACE/ARB+diuretic; CCB+Beta blocker+
diuretic; ACEI/ARB+ beta blocker+diuretic

CONTD.
 Never combine:
 Alpha or beta blocker with clonidine - antagonism
 Nifedepine and diuretics synergism (?)
 Hydralazine with DHPs or prazosin – same type of
action
 Diltiazem and verapamil with beta blocker –
bradycardia
 Methyldopa and clonidine
 Hypertension and pregnancy:
 No drug is safe in pregnancy
 Avoid diuretics, propranolol, ACE inhibitors, Sodium
nitroprusside etc
 Safer drugs: Hydralazine, Methyldopa,
cardioselective beta blockers and prazosin

HYPERTENSIVE EMERGENCIES
 Cerebrovascular accident or head injury with high BP
 Left ventricular failure with pulmonary edema due to hypertension
 Hypertensive encephalopathy
 Angina or MI with raised BP
 Acute renal failure with high BP
 Eclampsia
 Pheochromocytoma, cheese reaction and clonidine withdrawal
 Drugs:
 Sodium Nitroprusside (20-300 mcg/min) – dose titration and
monitoring
 GTN (5-20 mcg/min) – cardiac surgery, LVF, MI and angina
 Esmolol (0.5 mg/kg bolus) and 50-200mcg/kg/min - useful in
reducing cardiac work
 Phentolamine – pheochromocytoma, cheese reaction nd clonidine
withdrawal (5-10 mg IV)

ANTIHYPERTENSIVE DRUGS
 Diuretics:
 Thiazides: Hydrochlorothiazide, chlorthalidone
 High ceiling: Furosemide
 K+ sparing: Spironolactone, triamterene and amiloride
MOA: Acts on Kidneys to increase excretion of Na and
H2O – decrease in blood volume – decreased BP
 Angiotensin-converting Enzyme (ACE) inhibitors:
 Captopril, lisinopril., enalapril, ramipril and fosinopril
MOA: Inhibit synthesis of Angiotensin II – decrease in
peripheral resistance and blood volume
 Angiotensin (AT1) blockers:
 Losartan, candesartan, valsartan and telmisartan
MOA: Blocks binding of Angiotensin II to its receptors

ANTIHYPERTENSIVE DRUGS – CONTD.
 Centrally acting: Clonidine, methyldopa
MOA: Act on central α - 2A receptors to decrease sympathetic
outflow – fall in BP
 ß-adrenergic blockers:
 Non selective: Propranolol (others: nadolol, timolol,
pindolol, labetolol)
 Cardioselective: Metoprolol (others: atenolol, esmolol,
betaxolol)
MOA: Bind to beta-adrenergic receptors and blocks the activity
 ß and α – adrenergic blockers:
 Labetolol and carvedilol
 α – adrenergic blockers:
 Prazosin, terazosin, doxazosin, phenoxybenzamine and
phentolamine
MOA: Blocking of alpha adrenergic receptors in smooth muscles
- vasodilatation

ANTIHYPERTENSIVE DRUGS – CONTD.
 Calcium Channel Blockers (CCB):
 Verapamil, diltiazem, nifedipine, felodipine,
amlodipine, nimodipine etc.
MOA: Blocks influx of Ca++ in smooth muscle cells –
relaxation of SMCs – decrease BP
 K+ Channel activators:
 Diazoxide, minoxidil, pinacidil and nicorandil
MOA: Leaking of K+ due to opening – hyper
polarization of SMCs – relaxation of SMCs
 Vasodilators:
 Arteriolar – Hydralazine, minoxidil (also CCBs and K+
channel activators)
 Arterio-venular: Sodium Nitroprusside

WHAT TO KNOW / LEARN ?
 Classification of Antihypertensives
 Antihypertensive mechanisms: Diuretics, ACE
inhibitors, ARBs, Beta-blockers, alpha-blockers,
CCBs
 Common Adverse effects of above groups of Drugs
 Pharmacotherapy of Hypertension
 Pharmacotherapy of hypertensive emergencies
 Central sympatholytics

Antihypertensives - drdhriti

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