ANTIHYPERTENSIVE

DRUGS

DR CHAITALI PATTANAYAK
PROFESSOR, PHARMACOLOGY
KIMS, BHUBANESWAR
 LEARNING OBJECTIVES

At the end of the class, the learner will be able to :-

• Classify the Antihypertensive Drugs
• Write the pharmacological basis of the use of
Diuretics, ACE I’s, ARB’s, CCB’s in hypertension
 INTRODUCTION
• For practical purposes ‘HYPERTENSION’ – level of
blood pressure (BP) at or above which long-term
antihypertensive treatment will reduce
cardiovascular morbidity
• Common disorder, particularly past middle age
• Hypertension can be:-
- Primary (essential) in majority of cases (cause not
known)
- Secondary due to renal, endocrine/vascular
disorders
• Hypertension is elevation of systolic and/or diastolic BP
above 140/90 mmHg (most of the management guidelines)
• As per Joint National Committee (JNC) 8:
CATEGORY (adults ≥ 18 years) SBP (mmHg) DBP(mmHg)
Normal <120 and <80

Prehypertension (mild) 120-139 or 80-89

Hypertension Stage 1 140-159 or 90-99
(moderate)
Hypertension Stage 2 (severe) ≥160 or ≥100
• JNC 8 have raised defining level to 150/90 mm Hg for
individuals > 60 years of age
• Blood pressure (BP) is determined by cardiac
output(C.O) & total peripheral resistance (P.R)
• Prolonged hypertension damages the blood vessels
of the heart, brain & the kidneys  complications
like stroke, CAD, renal failure
• Hence, hypertension needs to be treated even if it
does not produce obvious troublesome symptoms
• Antihypertensives act by influencing the BP
regulatory systems i.e, by C.O or P.R or both
decreasing plasma volume &/or vasoconstriction
SITES OF ACTION OF ANTIHYPERTENSIVES
 CLASSIFICATION
1) DIURETICS:
• Thiazides: Hydrochlorthiazide, Indapamide
• Loop diuretics: Frusemide, Bumetanide, Torsemide
• K+ sparing diuretics: Amiloride, Triamterene, Eplerenone
2) DRUGS ACTING ON
RENIN ANGIOTENSIN
SYSTEM: Captopril, Enalapril, Lisinopril,
• ACE Inhibitors: Ramipril, Perindopril, Fosinopril
Quinapril, Benazepril
Losartan, Valsartan, Irbesartan,
• ARB’s: Olmesartan, Eprosartan
Telmisartan, Candesartan
• Renin inhibitor: Aliskiren
3) SYMPATHOLYTICS:
• Centrally acting drugs: Clonidine, Methyldopa
Guanabenz, Guanfacine
• Ganglion blockers: Trimethophan
• Adrenergic neuron blockers: Guanethidine, Reserpine
• Adrenergic receptr blockers
- α-blockers: Prazosin, Terazocin, Doxazocin
- β-blockers: Propanolol, Atenolol, Esmolol
- Mixed α & β-blockers: Labetalol, Carvedilol
4) CCB’S: Nifedipine, Amlodipine, others
5) VASODILATORS:
• Arteriolar dilators: Hydralazine, Minoxidil
• Arteriolar & venular dilators Sodium nitroprusside
 DIURETICS IN HYPERTENSION
Diuretics in hypertension

immediate effect Diuresis long-term use(6-8 wks)

Na+ & water excretion Body sodium

Plasma volume Intracellular Na+ in

vascular smooth muscle cell

CO Relaxation of vascular smooth muscles

PVR
BP
• Restriction of dietary salt intake will the dose of
the diuretic needed
• On long term treatment with diuretics, PVR is , but
CO & HR are not altered
• Thiazides are one of the 1st line antihypertensives
• Used for uncomplicated hypertension
• Hydrochlorothiazide (<24hrs) / Chlorthalidone
(~48hrs) initial dose of 12.5mg daily is given
• Average mean arterial pressure falls by ~ 10mmHg
• If response is not adequate, dose may be to a
maximum of 25mg daily.
• May be combined with K+ sparing diuretic (Amiloride,
Hydrochlorothiazide 1:10) to avoid hypokalemia
• Adverse effects dose dependent – Hydrochlorothiazide
at 25mg/day  best benefit risk ratio
• Thiazides combined with other antihypertensives for
synergistic effect if low dose fails to reduce BP
• Indapamide (Thiazide related) useful
- BP in subdiuretic doses
- may have additional vasodilator properties
- 2.5mg OD , long duration of action, mild electrolyte
disturbances
 Advantages of Thiazides:
• OD dosing, flat dose response curve
• No fluid retention/ tolerance
• incidence of postural hypotension, lesser S/E
• Effective in isolated systolic hypertension (ISH)
& in older patients
• Low cost
 Loop diuretics in hypertension:

• powerful diuretics, antihypertensive efficacy is low

(weaker than Thiazides)
• Furosemide is short acting, S/E are more profound
• Fall in BP due to plasma volume & C.O  brief
duration of action
• uniform reduction in vascular resistance cannot be
achieved
• So, used only in hypertension with CRF / CHF & in
hypertensive crisis to lower the BP
 Drawbacks of diuretics as antihypertensives:
- Hypokalemia,
- Carbohydrate intolerance,
- Dyslipidemia,
- Hyperuricaemia
- sudden cardiac death
ALDOSTERONE ANTAGONISTS:
• Spironolactone, Eplerenone – resurgence in the use
• hypertension related ventricular and vascular
hypertrophy and renal fibrosis
 INHIBITION OF RENIN-ANGIOTENSIN SYSTEM
Angiotensinogen
(RENIN) X RENIN INHIBITOR
Angiotensin I
(ACE) X ACE INHIBITORS

Angiotensin II
AT1R AT2R
- Vasoconstriction X
- Sympathetic activation ANGIOTENSIN RECEPTOR
- Aldosterone release BP BLOCKERS
- Renal Na+ reabsorption
- Heart remodelling
 ACE INHIBITORS IN HYPERTENSION

• ACE inhibitors are presently one of the 1st line drugs

• Useful in the treatment of hypertension of all
grades (essential / renovascular) due to all causes
• Addition of a diuretic their antihypertensive effect
• K+ sparing diuretic avoided
• ACE inhibitors are well tolerated
• Specially indicated as antihypertensives in:
- more effective in younger pts.(< 55 years) than
in elderly
- hypertensives with left ventricular hypertrophy
- pts. with CHF, co-existing IHD including post-MI
- pts. with diabetes mellitus, nephropathy
- in severe hypertension(combined with other
drugs)
 ARB’s IN HYPERTENSION
• Losartan, Candesartan, Irbesartan, Valsartan,
Telmisartan are some of the AT1 receptor
antagonists in clinical use, given orally
• Main advantage of ARB’s over ACE I’s -
no in bradykinin levels & it’s associated adverse
effects like dry cough & angio-oedema
• Well tolerated, C/I in pregnancy
• ARB’s preferred over ACE I’s, as antihypertensives
• Can be used as 1st line drugs in hypertension
• ARB’s can be combined with diuretics
 RENIN ANTAGONIST
ALISKIREN: recently introduced direct renin inhibitor
• Blocks the effects of renin  BP
• ACE I’s, ARB’s, diuretics tend to bring about a
compensatory in plasma renin levels
• Aliskiren blocks the effects of renin, so it’s action is
synergistic with ACE I’s/ARB’s – combined with them
• Can also be used as monotherapy -150-300mg OD
& is orally effective (2nd line drug when ACE
I’s/ARB’s cannot be used)
 CALCIUM CHANNEL BLOCKERS (CCB’s)
• Dilate the arterioles PVR
Nifedipine • Nifedipine produces reflex tachycardia,
not seen with Verapamil & Diltiazem
Nicardipine
• Fluid retention is negligible
Nimodipine
• Earlier used as 1st line drugs
Amlodipine
• Not preferred in pts with left ventricular
Felodipine
hypertrophy & previous MI
Verapamil
• Short acting Dihydropyridines produce
frequent changes in BP & sympathetic
activity  avoided in hypertension
 CCB’s IN HYPERTENSION
• Well tolerated & effective
• Effective in elderly patients, ISH, diabetics, PVD
• May be used as monotherapy / in moderate-severe
hypertension alongwith other antihypertensives
• Short acting CCB’s ( S/L DHPs) associated with
mortality & sudden death
• Sustained release preparations / long acting DHPs
may be used for smoother control of BP
• Parenteral short acting DHPs can be used in
hypertensive emergencies
• IV Clevidipine used for quick reduction of BP
 LEARNING OBJECTIVES

At the end of the class, the learner will be able to :-

• Write short notes on Clonidine, Methyldopa
• Write the pharmacological basis of the use of
central sympatholytics, α blockers, β blockers in
hypertension
 SYMPATHOLYTICS
α Methyl dopa

Clonidine
Reserpine
α Methyl NE
Guanethidine
False transmitter

α blockers β blockers
Trimethaphan
 CENTRALLY ACTING DRUGS
1)CLONIDINE: selective α2 agonist,
lipid soluble, attains peak effect in
3-5hrs at a dose of 100-300μg BD
orally. Also available as Clonidine
transdermal patch, acts for 7
days, applied over the arm Clonidine
• ADR: drowsiness, dryness of
mouth, nose & eyes, parotid Stimulates postsynaptic α rec.
2
gland swelling & pain, fluid in VMC & hypothalamus
retention, constipation,
sudden withdrawal leads to central sympathetic outflow,
rebound hypertension,
& NA release from nerve
headache, tremors, sweating terminals in the periphery
& tachycardia dose should (presynaptic action)
tapered
HR, CO, PVR, BP
 USES OF CLONIDINE
• Mild-moderate hypertension: not preferred due to
S/E, withdrawal hypertension, tolerance
• Opioid withdrawal: for sympathetic overactivity
seen in withdrawal phenomenon in opioid addicts
• Diabetic neuropathy: improves absorption of NaCl
& water in the gut by stimulation of α2 receptors in
the intestines  controls loose motions
• With anaesthetics: given preoperatively the dose
of the general anaesthetic needed due to it’s
analgesic effects
• vasomotor symptoms of menopausal syndrome
2 )GUANFACINE & GUANABENZ: α2 agonists similar to
Clonidine, can be used as antihypertensives
 3) α-METHYL DOPA :
- onset of action ~ 4-6hrs, α-methyl dopa (prodrug)
duration of action 12-24hrs
- left ventricular hypertrophy is α-methyl NE
reversed in about 12 weeks of tt.
- at higher doses, inhibits dopa Stimulates α2 receptors
decarboxylase NE & acts as ‘false in VMC
transmitter’ in periphery as well
ADR: sedation, dryness of mouth &
nose, night mares, depression, Central sympathetic outflow
vertigo, E/P signs, PRL, headache
USES: used in mild-moderate HR, CO, PVR
hypertension along with a diuretic
- safe in hypertension during BP
pregnancy (preferred)
Started at 250mg BD, dose is gradually
 GANGLION BLOCKERS
• These drugs block both sympathetic &
parasympathetic ganglia sympathetic tone & BP
• Produce several S/E due to ganglionic blockade

TRIMETHOPHAN:
• only ganglion blocker that is in use now,
• given IV to produce controlled hypotension during
certain surgical procedures due to it’s rapid & short
action (15 mins)
 ADRENERGIC NEURON BLOCKERS
• GUANETHIDINE: displaces NA from storage granules,
blocks it’s release & uptake at axonal membrane
ADR like postural hypotension, diarrhoea & sexual
dysfunction limit the use
• RESERPINE: an alkaloid obtained from Rauwolfia
serpentina. Binds to the vesicles that store
monoamines like NA, DA, 5-HT & inhibits the vesicular
uptake of monoamines  monoamines are destroyed
by MAO  depletes stores  BP
ADR- drowsiness, depression, nightmares, postural
hypotension, oedema, weight gain, gynaecomastia &
sexual dysfunction. Though it is inexpensive, long
acting, effective, well tolerated, it is not preferred
 ADRENERGIC RECEPTOR BLOCKERS
α-BLOCKERS:
• Nonselective α blockers : Phenoxybenzamine &
Phentolamine
• Failure in the management of essential
hypertension
• Fall in t.p.r  compensatory in H.R & C.O
• Unacceptable S/E: postural hypotension, nasal
blockage, impotence etc.
• Reserved for  treatment of hypertension due to
pheochromocytoma, clonidine withdrawal etc.
 Selective α1 blockers
• Prazosin, Terazosin, Doxazosin block α1 receptors in
arterioles & venules  dilate them  PVR  BP
with mild tachycardia
• Lesser reflex cardiac stimulation, no presynaptic α2
blockade
• Prazosin central sympathetic tone
• α1 blockers can be used in mild-moderate hypertension
• As monotherapy, 1st dose phenomenon seen
• Salt & water retention can occur  combined with
diuretics & β blockers
• α1 blockers particularly useful in hypertensive men with
BPH – benefit both conditions
 β BLOCKERS
• mild antihypertensives
• Block cardiac β1 receptors  HR, myocardial
contractility & cardiac output ( t.p.r initially due to
β2 receptors, so there is little change in BP.)
With continued tt., resistance vessels adapt
gradually to C.O, t.p.r also  SBP & DBP fall  BP
• NA release from sympathetic terminals due to
blockade of β receptor mediated facilitation of
release process
• renin release from kidney (β1 mediated)
• central sympathetic outflow
 β BLOCKERS:
• Effective & well tolerated, also used in pts with
arrhythmias
• Used in younger patients
• Can be used alone / with other drugs having
tachycardia as S/E
• Selective β1 blockers preferred over non selective
blockers
• Dose should be always tapered while withdrawing
• One of the 1st line drugs in mild-moderate
hypertension earlier, nowadays not preferred
• β blockers now found to be inferior to Thiazides or
ACE I/ARBs or combination in preventing MI, stroke,
left ventricular hypertrophy & in diabetic pts.
• They compromise with quality of life more than
other antihypertensives  work capacity, fatigue,
loss of libido, nightmares, depression
• Rebound hypertension occurs on sudden
discontinuation  risk of MI, angina
• Due to these drawbacks, β blockers no longer the
1st line drugs in hypertension for monotherapy
• Can be combined with ACE I/ARBs to prevent
sudden cardiac death in post infarction pts. & in
stable heart failure
• Atenolol: preferred β blocker due to OD dosing,
no CNS S/E, β1 selectivity
• Metoprolol: may be given as sustained release
preparation. Used in pts with concurrent
hypertension & heart failure
• Esmolol: short acting β1 blocker, t1/2 = 10mins, given
IV, suitable for intraoperative & postoperative
hypertension & in hypertensive emergencies
• α & β blockers: Labetalol & Carvedilol block α1& β
receptors. Used IV in the treatment of
hypertension in pheochromocytoma & in
hypertensive emergencies
- Labetalol - preferred for rise in BP in preeclampsia
 LEARNING OBJECTIVES

At the end of the class, the learner will be able to :-

• Write short notes on Hydralazine, Sodium
nitroprusside
• Write the pharmacological basis of the use of
Sodium nitroprusside in hypertension
• Write notes on the drug therapy in hypertensive
crises, hypertension in pregnancy, management of
hypertension
 VASODILATORS
Arteriolar dilators: Hydralazine, - ADR: headache, dizziness,
Minoxidil, Diazoxide flushing, palpitation, nausea,
anorexia, hypotension, salt &
HYDRALAZINE: directly acting water retention, SLE like
arteriolar dilator, BP, assoc hypersensitivity reactions
with tachycardia, renin - USES:
release & fluid retention. 1) used with a β-blocker &/or
Coronary, cerebral & renal a diuretic in moderate-severe
hypertension not controlled
blood flow by the 1st line drugs
- Well absorbed, high first 2) may be combined with
pass metabolism, nitrates in hypertensives with
metabolised by acetylation CCF.
in the liver(like INH), fast 3) Can be given in
hypertension during
acetylators have low BA  pregnancy (2nd & 3rd
antihypertensive effects trimester)
 MINOXIDIL
• Directly acting arteriolar dilator
used in severe hypertension,
not responding to other drugs.
Minoxidil is a prodrug -
converted to Minoxidil sulfate
 opens up the K+ channels in
the smooth muscles  efflux of
K+ ions  hyperpolarisation
smooth muscle relaxation
- Causes sodium & water
retention oedema,
- palpitations, anginal episodes,
headache, sweating
- combined with Diuretics & β1
blockers
USES:
• Hypertension - used
with a diuretic, as a
reserve drug in pts with
severe hypertension
who do not respond to
other drugs
• Baldness - directly
stimulates hair growth
on prolonged use, used
topically(2%solution) for
correction of alopecia.
Cessation of treatment
may lead to hair fall
 DIAZOXIDE
• Related to thiazide diuretic, potent arteriolar
vasodilator
• Mechanism same as Minoxidil
• Causes hyperglycaemia
• Salt & water retention, palpitations & myocardial
ischemia
• Used IV in hypertensive emergencies, where
monitoring of infusion is not possible
• Has long duration of action (24hrs), suitable in such
situations
 SODIUM NITROPRUSSIDE
• Rapidly acting vasodilator, relaxes Sodium nitroprusside
both arterioles & venules
• Both PR & CO are  myocardial O2 Nitric oxide (NO)
demand
• Given IV, acts within 30 secs, short Guanylyl cyclase
acting – acts for 3 mins  allows
rapid titration of dose
• Earlier DOC in hypertensive GTP cGMP
emergencies, given by IV infusion, BP
should be constantly monitored vasodilatation
• Useful in severe heart failure &
myocardial infarction (where short BP
term reduction of myocardial
workload is required)
 SODIUM NITROPRUSSIDE
ADVERSE REACTIONS:
• Palpitations, sweating, weakness,
nausea, vomiting & hypotension
• At higher doses, nitroprusside is
converted to cyanide &
thiocyanate  toxicity (nausea,
anorexia, disorientation, psychosis,
muscle spasm, convulsions, severe
hypotension, metabolic acidosis,
cardiac arrhythmias, death)
Treated with Sod.thiosulpate or
hydroxocobalamin
FENOLDOPAM: D1 receptor agonist
devoid of thiocyanate related S/E,
short t1/2= 10mins, IV infusion
PRECAUTIONS:
• Acts within secs  BP
should be constantly
monitored
• Dissolved in 2ml of 5%
dextrose, then diluted in
IV fluids, used preferably
with an infusion pump
• Light sensitive
• Used for short periods,
not more than 2-3 days
• If infusion is prolonged,
blood levels of cyanide &
thiocyanate should be
checked
 TREATMENT OF HYPERTENSION
• Hypertension per se does not produce troublesome
symptoms, but requires lifelong treatment in most pts 
to prevent target organ damage (TOD)
• Several antihypertensives cause undesirable S/E may
complicate treatment
• Choice of drugs need consideration of several factors like
patient age, severity of disease, risk factors
• Joint National Committee (JNC) 2014 recommendations for
treatment of hypertension
CATEGORY SBP (mmHg) DBP(mmHg)
Normal <120 and <80
Prehypertension (mild) 120-139 or 80-89
Hypertension Stage 1 (moderate) 140-159 or 90-99
Hypertension Stage 2 (severe) ≥160 or ≥100
• Risk of complications depend not only the BP levels,
but also on risk factors and existing TOD

CARDIOVASCULAR RISK FACTORS:

- Age >55yrs(men), >65yrs(women)
- Family H/O premature CVS disease
- Smoking
- Dyslipidemia
- Diabetes mellitus
- Hypertension
- Obesity (BMI ≥ 30)
- CKD
- Sedentary life style
• Non pharmacological measures & lifestyle modifications
should be tried first - low salt diet (< 2 - 4g/ day),
moderate exercises, weight reduction, meditation help in
reducing the BP.
• Prehypertension can be managed with diet, weight reduction,
adequate exercises & moderation of alcohol intake.
Antihypertensives started in presence of compelling
indications –
DIURETICS ACE Is /ARBs
- heart failure - heart failure, CAD risk
- CAD risk - H/O MI in past
- H/O stroke in past - diabetes, CKD
CCBs β -adrenergic blockers
- Diabetes - stable heart failure
- stroke prevention - post MI
- CAD risk
• STEP 1: Hypertension is treated with an ACE
inhibitor / ARB / β blocker/ CCB / Thiazide diuretic.
ABCD rule. A preferred in younger pts. (<55yrs),B
not preferred, used in women of child bearing age/
intolerance to ACE I/ARB, C , D preferred in older
pts.( > 55yrs)
If uncontrolled by adequate doses of one drug, a
second drug may be added
• STEP 2: Hypertension would require a combination
of 2 drugs - ARB / ACE I + CCB / Thiazide diuretic. β
blocker (not preferred). In pts with chronic renal
disease, treatment should be initiated with an ACE
I /ARB with/without other antihypertensives
• STEP 3: If BP not controlled with a 2 drug
combination dose of existing medication to be
titrated to the optimal / best tolerated 
3 drug combination – ACE I /ARB+ CCB+ Diuretic
• STEP 4: RESISTANT HYPERTENSION includes:-
- BP uncontrolled even on 3 drugs of different classes
one of which is a diuretic, a 4th drug- aldosterone
antagonist/ higher dose of Thiazide/ β blocker-
carvedilol, nebivolol/ selective α1 blocker can be
added
- BP controlled but requiring 4 or more drugs of
different classes
- When BP has been controlled for > 1year, stepwise
reduction in dose and/or withdrawal of one drugs
may be attempted.
 COMBINATION THERAPY
• When it is not possible to achieve control of BP with
a single drug, a combination may be used
• Combination therapy overcomes the S/E of one
another, allows use of lower doses of each drug:
- Sympatholytics & vasodilators cause fluid retention
 Diuretics should be added
- Nifedipine & Hydralazine evoke reflex tachycardia
 countered by β blockers
- ACE I’s & Diuretics are synergistic
 HYPERTENSIVE CRISES
Include hypertensive emergencies & urgencies
HYPERTENSIVE EMERGENCIES:
• Very high BP (210/120 mmHg) associated with target
organ damage, life threatening due to malignant
hypertension, hypertensive encephalopathy, AMI,
dissecting aneurysm of aorta, acute LVF with
pulmonary edema, eclampsia & hypertensive crisis in
pheochromocytoma
• These require treatment in ICU with constant
monitoring of BP & gradual lowering of BP
• In chronic hypertension, autoregulatory changes take
place in the blood vessels of vital organs  sudden fall
in BP may cause hypoxia of vital organs
 HYPERTENSIVE URGENCIES
• Highly elevated BP with no target organ damage
• Require gradual reduction of BP over about 24hrs –
DBP brought down to about 100mg Hg
• Parenteral drugs are preferred in the treatment of
hypertensive crises
• Nicardipine(CCB) IV infusion has replaced IV
Sodium nitroprusside as drug of choice
• IV Esmolol, Diazoxide, Fenoldopam, Nitroglycerin,
Labetalol, Hydralazine & S/L Nifedipine are
alternatives
• BP should be constantly monitored
 DRUGS IN HYPERTENSIVE EMERGENCIES
• Nicardipine – 5mg/hr IV infusion increased upto
15mg/hr acts for 3-4 hrs - DOC
• Sodium nitroprusside – 0.5-10μg/kg/min IV infusion
(acts for 1-2min) under close monitoring
ALTERNATIVE DRUGS:
• Nitroglycerin – 5-100 μg/min IV infusion (3-5mins)
• Fenoldopam – 0.1-1.6 μg/kg/min IV infusion (15-30
mins)
• Hydralazine – 10-20 mg IV bolus/10-50 mg IM (4-8hrs)
• Esmolol – 50-300 μg/kg/min IV infusion(10-15mins)
• Labetalol – 20-80 mg IV every 10 min (max 300mg) (3-6
hrs)
As soon as possible, switch to oral drugs
 HYPERTENSION IN PREGNANCY
A sustained BP > 140/90 mmHg during pregnancy is
risky, seen in pregnant woman with preexisting
hypertension or in toxaemia of pregnancy.
The antihypertensives found safe in pregnancy are:
• Labetalol orally effective, widely used now
• CCB’s like Nifedipine (sustained release) if used should
be withdrawn during labour - inhibit uterine
contractions
• Methyldopa orally - still used
• However, they should be used only after 1st trimester
• Other drugs like Prazosin, Clonidine, Atenolol,
Acebutolol may be used
• Pregnant women with diabetes, CKD, preexisting
hypertension, are at a higher risk of developing
pre-eclampsia  Aspirin (80-100mg/day) given from
12th wk of gestation till baby is born

• Non-selective β blockers should be avoided: ( blood

supply to the placenta  placental size & cause LBW)
• ACE I’s, ARB’s: risk of foetal damage, growth
retardation
• Diuretics: uteroplacental perfusion deficit, risk of
miscarriage, stillbirth
• Sod.nitroprusside: contraindicated