Antihypertensive

 Hypertension is not a disease in itself, but

is an important risk factor for
cardiovascular morality & morbidity
 Hypertension in adult is defined by WHO-
ISH as a systolic blood pressure equal to
or greater than 140 mm Hg and/or a
diastolic blood pressure (fifth Korotkoff
phase) equal to or greater than 90mm
Hg.
 For practical purposes ‘hypertension’
could be that level of B.P. at or above
which long term antihypertensive
treatment will reduce cardiovascular
mortality
• A hypertensive state may defined as an
abnormal elevation of either systolic or
diastolic pressure. In past years, the
diastolic value was emphasized in
determining whether or not a person was
hypertensive. However, elevations in
systolic pressure ("systolic hypertension")
are also associated with increased incidence
of coronary and cerebrovascular disease
(e.g., stroke). Therefore, we now recognize
that both systolic and diastolic pressure
values are important to note.
• Epidemiological studies have confirmed that
higher the pressure (systolic or diastolic or
both) greater is the risk of cardiovascular
• 3 grades of hypertension –
 Mild HTN includes BP level of 140-
159/90-99mm Hg.
 Moderate HTN includes BP level of 160-
179/100-109 mm Hg.
 Severe HTN includes BP level
above180/110mmHg.
• Mild HTN thiazide, β blocker, α
methyldopa, reserpine
• Moderate HTN thiazide+ β blocker,
thiazide + ACEI, sympatholytic drugs
• Mild to moderate HTN thiazide, ACEI, Ca++
channel blocker, K+ channel activator, α
methyl dopa, β blocker
• Severe HTN thiazide + β blocker + ACEI
+ Ca++ channel blocker to prevent reflex
tachycardia produced by vasodilator
• HTN emergency:
– Oral  Labetalol (drug of choice),
Alternative  Nifedipine, hydralazine,
methyldopa, trimethaphan (I/V),
diazoxide (I/V)
– If encephalopathy:
• 1st choice  I/V sodium nitropruside.
Alternative I/V diazoxide, labetalol,
fenoldopam, nitroglycerine, Ca++
channel blocker , hydralazine
• According to the latest U.S. national
guidelines (JNC 7 Report), the following
categories of hypertension have been
defined:
Classification Systolic Diastolic
(mmHg) (mmHg)
Normal* <120 <80
Prehypertensio 120-139 80-89
n
Stage 1 140-159 90-99
Stage 2 >160 >100
• * Arterial pressures less than 90/60
mmHg are considered hypotension, and
therefore not normal.
 Can be caused by:
– an underlying disease process (secondary
hypertension)
• Renal artery stenosis leading to high
plasma renin
• Hyperaldosteronism
• pheochromocytoma
• Can be cured if rectify underlying cause
– idiopathic process (primary or essential
hypertension)
• Cause(s) unknown
• Disease of lifestyle: obesity, sedentary,
diet high in salt and saturated fats.
• Can only be controlled
• 20% in USA affected
 Treatment Rationale
Therapeutic goals in hypertension
 Short-term goal of antihypertensive
therapy:
To lower the high blood pressure
• Primary (essential) hypertension
• Secondary hypertension
 Long-term goal of antihypertensive
therapy:
Reduce mortality due to
hypertension-induced disease -
– Stroke, Congestive heart failure,
Coronary artery disease,
Nephropathy, Peripheral artery
disease, Retinopathy
For most of the HTN patients: life-long
 Major Risk Factors Increasing Mortality
• Smoking
• Dyslipidemias
• Diabetes Mellitus
• Age >60
• Gender: men, postmenopausal women
• Family history
 Major risk factor for:
• cerebrovascular disease –
Thromboembolic, Intra cranial bleed
• Cardiovascular disease - Myocardial
infarction, Heart failure, Coronary artery
disease
• peripheral vascular disease
• renal failure
• The 4th most common cause of death world-
wide
• Directly and indirectly responsible for >20%
of all deaths
 Ways of Lowering Blood
Pressure
 Prime contributors to blood pressure are:
– Cardiac output
• Stroke volume
• Heart rate
– Peripheral vascular resistance
 Each of these factors can be manipulated
by drug therapy
 Reduce cardiac output (ß-blockers, Ca2+
channel blockers)
 Reduce plasma volume (diuretics)
 Reduce peripheral vascular resistance
(vasodilators)
 Tissue target for antihypertensive
drug
 Sympathetic nerve (release
vasoconstrictor NA)
 Kidney (regulate blood volume through
renin)
 Heart (output can be altered)
 Arterioles (determine peripheral
resistance)
 Endothelial cell (regulate circulating
level of Angiotensin II)
 PRINCIPLES OF TREATMENT
• Non-drug treatment – diet, risk
factor modification, exercise and
relaxation.
• Begin with one drug
(monotherapy)
 BHS Guidelines
Young Elderly(low renin)
A B C D

A ACE Inhibitor
B Beta Blocker
C Calcium Channel Blocker
D Diuretic
 Common treatment regimes
If there are no contraindications start treatment
according to age and other pathology
IF ELDERLY
• Start Bendroflumethiazide
– No or incomplete effect
• Add Calcium channel blocker Amlodipine
– Incomplete effect
• Add ACE inhibitor
– Still incomplete effect
• Add Beta-blocker
– Still incomplete effect
• Add one of the less commonly used agents
IF YOUNG
• Start ACEI/ Beta-blocker
• No or incomplete effect
• Add Bendroflumethiazide
– Incomplete effect
• Add Calcium channel blocker
– Still incomplete effect
• Add Beta-blocker
– Still incomplete effect
• Add one of the less commonly used agents
If a single agent doesn’t control BP
– Then use the two together
• A single agent will control BP in 40-50% of
patients
 Classification of
antihypertensives
 Diuretics: to reduce blood volume. e.g. Frusemide,
Thiazide.
 Inhibition of renin-angiotensin system:
– 1. Sympathetic blockers ( blockers, adrenergic
neurone blockers, central sympatholytics)—
decrease renin release.
– 2. Direct renin inhibitors (DRIs): block renin action
—interfere with generation of Ang I from
angiotensinogen (rate limiting step).
– 3. Angiotensin converting enzyme (ACE) inhibitors
—prevent generation of the active principle Ang II.
– 4. Angiotensin receptor blockers (ARBs)—
antagonise the action of Ang II on target cells.
– 5. Aldosterone antagonists—block
mineralocorticoid receptors.
 Drugs that reduce peripheral resistance/C.O.:
 Directly acting vasodilatos:
• Ca++ channel blocker, e.g. Nifedipine.
• K+ channel activator, e.g. Minoxidil,
Diazoxide.
• Elevation of cGMP, e.g. Nitropruside.
• Others, e.g. Hydralazine.
 Sympathoplegic drugs or sympathetic nervous
system depressant drugs –
• Centrally acting, e.g. α methyl dopa.
• Ganglion blocking drug, e.g. trimethophan.
• Adrenergic neurone blocking drug, e.g.
guanithidine.
• Adrenoceptor antagonist:
–
 ACE Inhibitors: Classification
• Chemical • Pharmacokinetic
classification classification
– Sulfhydryl-group – Class I : Captopril -
• Captopril like
– Carboxyl-group • Captopril
• benazepril, – Class II : Pro-Drug
enalapril,
• benazepril,
lisinopril,
quinapril, enalapril, fosinopril,
ramipril, quinapril, ramipril,
spirapril spirapril
– Phosphoryl - – Class III: Not
group Metabolized
• fosinopril
 1st generation – Captopril, Enalapril
(prodrug), Lisinopril (long
acting)
 Newer generation – Ramipril, Perindropril,
Trandolapril
 M/A same, only pharmacokinetic
difference.
 Antihypertensive effects of ACEI –
 They are competitive inhibitor of ACE.
Angiotensin I is biologically inactive.
Captopril (ACEI)  Inhibit ACE 
Decrease Angiotensin II  decrease
vasoconstriction  decrease peripheral
 Bradykinin inactivation also done by ACE.
So, ACEI  inhibit inactivation of
bradykinin which is a potent endogenous
vasodilator  increase vasodilatation 
decrease peripheral resistance (decrease
afterload) decrease blood pressure.
 Decrease aldosterone  decrease Na+ and
H2O reabsorption  increase Na+ and H2O
excreted through kidney  decrease fluid
volume  decrease plasma volume
(decreased preload)  decrease blood
pressure.
 No direct effect on heart myocardium. No
decrease cardiac output.
 Pharmacokinetics
• Rapidly absorbed from GIT with a
bioavailability 70% in fasting stage, 30-
40% with food.
• Well distributed in the body except in
CNS.
• Metabolized chiefly to disulfide
conjugates.
• Less than half of oral dose is excreted in
urine directly in unchanged form.
• t ½  3 hours.
• Dose  25 mg 2-3 times daily 1-2 hours
 Enalapril –
 M/A – same. Not an active drug. It must
be metabolised by de esterification and
acts as enalaprilat.
 Dose – 10-20 mg once or twice daily.
 Lisinopril –
 Lysin derivative of enalaprilat.
 Dose – 10-80 mg once daily. Clinically 5
mg used.
 Converting enzyme – It is a dipeptidyl
carboxypeptidase. Usually in endothelial
cell, conversion occurs when blood passes
through lung. Converting enzyme inhibits
 Indication of ACEI –
 Effective in all grades of HTN.
 In congestive cardiac failure (1st line drug).
 Diabetic nephropathy (long term treatment
with ACEIs prevent the progression of renal
disease & retards the worsening of renal
function. They reduce albuminuria,
intraglomerular pressure & check
hyperfiltration)
 Following MI (especially when there is
ventricular dysfunction): started within 24
hours & given for several weeks prevent the
development of CCF & reduce mortality. In
post MI patients, ACEI are used to reduce the
long term mortality & prevent ventricular
  Patients at high risk of IHD: in patients
who are at risk of ischemic
cardiovascular conditions like MI &
stroke, ACEIs are protective & afford
significant benefit by reducing the risk of
MI, stroke, heart failure, diabetes &
sudden death. They are useful to prevent
reinfarction in post MI
 Progressive renal insufficiency.
 Contraindication of ACEI –
 Pregnancy
 Hyperkalamia
 Bilateral renal artery stenosis
 Adverse effects of ACEI
 1st dose hypotension – marked fall in blood
pressure after 1st dosing specially in patient
already taking diuretics (in whom renin
secretion is enhanced). Hence, treatment
should be started with small doses & if patients
are already on diuretics – temporarily diuretics
should be stopped
 A persistent dry cough – possibly the result of
accumulation of bradykinin in the bronchial
mucosa. More common in woman.
 Patient with bilateral renal artery stenosis
predictably develop renal failure if treated with
ACEI – because glomerular filtration in the face
of low afferent arteriolar pressure is maintained
by Angiotensin II mediated constriction of
 Hyperkalamia: particularly in patients on
k+ sparing diuretics, NSAIDs, β blockers or
on k+ supplements
 Rash, Blood discrasia (neutropenia)
 Angioedema: rarely (0.1%incidence) 
swelling in the lips, nose, larynx & airway
obstruction. It may be due to increased
bradykinin levels & can be fatal.
Treatment: drug should be immediately
withdrawn at the first sign of
angioedema. Severe cases may need
adrenaline & glucocorticoids
 Heavy proteinuria, Enlarged liver,
 Teratogenicity:
– 1st trimester:
• Increase fetal mortality
• Increased teratogenic risk
– Given during 2nd & 3rd trimester of
pregnancy
• Fetal hypotension, anuria & renal failure
• ACEI can cause various foetal
malformations including fetal growth
retardation, malformed lungs & even
death. ACEIs are therefore
contraindicated in pregnancy
 Dysgiusia: an altered taste sensation is more
 Clinical pharmacology of
ACEIs
• ACEIs are preferred drugs in diabetes
with HTN
• ACEIs have better efficacy than ARB
• Dry cough (20% incidence) is the
commonest side effect of ACEIs
• To avoid ‘first dose effect’ all ACEIs are
started with low dose at night
• They postpone the onset of diabetes
mellitus
 Angiotensin receptor blocker
 Saralasin –
 A peptide analogue of angiotensin II.
 Inhibit the function of angiotensin II by
blocking angiotensin II receptors.
 It blocks both vasoconstrictor effect
and aldosterone mediated effects.
 It best act in high renin state.
 In low renin state with hypertensive
patient it causes partial agonistic
effect and must be administered
parenterally so it is not used clinically.
This mechanism is not known.
• Losartan, valsartan were the first
marketed blockers (non peptide) of the
angiotensin II type 1 receptor.
• More recently, candesartan, eprosartan,
irbesartan and telmisartan have been
released.
• They have no effect on bradykinin
metabolism and therefore more selective
blockers of angiotensin effect than ACEI.
• Indication – hypertension with heart
failure.
• Advantage in relation to ACEI – does not
cause persistent dry cough as it does not
 Calcium Channel Blockers
 Benzothiazepines (both cardioselective &
vaso-selective)
 Diltiazem
 Phenylalkamines (cardioselective)
 Verapamil
 Dihydropyridines (vaso-selective)
 Amlodipine,
 Bepridil,
 Nicardipine,
 Nifedipine,
 Nimodipine.
 Role of calcium channel in
maintenance of BP
 Cardiac muscle cells are normally
depolarized by fast inward flow of Na+
which is followed by a slow inward flow of
Ca++ and thus subsequently increases the
intracellular concentration of Ca++ which
stimulates the contractile mechanism.
 Pace maker cells of S.A. or A.V. node rely
heavily on the slow Ca++ movements for
their automaticity.
 The vascular smooth muscle cells
contraction requires an influx of Ca++
across the membrane through slow Ca++
channel.
 Calcium channel blockers (CCBs)–
 Inhibit the passage of Ca++ through these
calcium channel and thus causes the
smooth muscle to relax (antihypertensive
effect).
 Cardiac muscle to depress contractility
(antianginal effect).
 Pace maker cells to suppress automaticity
(antiarrhythmic effect).
 Because the skeletal muscle uses
intracellular Ca++ for contraction & does
not depend on Ca++ influx during
depolarization, there is no skeletal muscle
relaxation with CCBs
 CCBs are another class of first line
antihypertensive drugs. They lower BP by
decreasing peripheral resistance without
 Pharmacological action –
 Vasodilatation
 Negative inotropic effect i.e. decrease force
of contraction.
 Decrease chronotropic effect i.e. decrease
heart rate due to suppression of automaticity.
 Other effects:
 Verapamil in high doses inhibits insulin
release
 CCBs may interfere with platelet
aggregation & prevent atheroma formation
in animals but these effects have not been
proved in human
 Verapamil blocks the p-glycoprotein which
is involved in the efflux of drugs out of
cancer cells. Thus it may reverse the
resistance of cancer cells to chemotherapy.
Its clinical significance is yet to be
Indications
 Angina pectoris.
 Hypertension – nifedipine, amlodipine,
verapamil. Except diltiazem.
 Dysrhythmias – supraventricular
tachycardia – verapamil.
 Raynaud’s disease – nifedipine.
 Dilated cardiomyopathy – diltiazem.
 Prevention of ischemic neurological
damage following subarachnoid
hemorrhage due to cerebral vasospasm
- nimodipine.
 Other uses:
 Nifedipine is an alternative drug for
premature labour
 Verapamil supresses nocturnal leg
cramp
 Migraine prophylaxis (verapamil)

• Advantage of CCBs as antihypertensive:
– The onset of antihypertensive action is
quick. With the availability of long acting
preparation, most agents can be
administered once a day. Monotherapy
with CCBs is effective in 50%
hypertensives. Their action is independent
of patient’s renin status, & they may
improve arterial compliance
• Other advantages of CCBs:
– Do not compromise haemodynamics: no
impairement of physical work
– No sedation or other CNS effects; cerebral
perfusion is maintained
– Not contraindicated in asthma, angina
(especially variant) & peripheral
vascular disease (PVD) patients; may
benefit these conditions
– Do not impair renal perfusion
– Do not affect male sexual function
– No deleterious effect on plasma lipid
profile, uric acid level & eletrolyte
balance
– Shown to have no/minimal effect on
quality of life
– No adverse fetal effects, can be used
during pregnancy (but can weaken
• Other concerns in the use of CCBs as
antihypertensive:
– The negative inotropic/dromotropic
action of verapamil/diltiazem may
worsen chronic heart failure & cardiac
conduction defects (Dihydropyridines
are less likely to do so)
– By their smooth muscle relaxation
action, the dihydropyridine can worsen
gastroesophageal reflux
– CCBs (especially dihydropyridines) may
attenuate bladder voiding difficulty in
elderly males
 Contraindications
 Heart failure
 Bradycardia
 A.V. block
 Sick Sinus Syndrome
 Wolf Parkinson White Syndrome.
 Status –
 Good systolic HTN control. Amlodipine is
commonly used
 Can be given in elderly patient where β-
blocker can not be given.
 Can be given in asthmatic, diabetic patient.
 Cheap.
 Pedal edema is the commonest side effect of
all CCBs
 All CCBs are generally well tolerated
 Diltiazem & Verapamil are the commonly used
CCBs in arrhythmia
 Side Effects
 Cardiovascular
• Hypotension, palpitations, dizziness,
bradycardia (verapamil) in high dose,
heart block, heart failure, reflex
tachycardia (only for nifedipine)

 Gastrointestinal
• Constipation, nausea, vomiting.

 Other
• Rash, facial flushing, headache,
peripheral edema (Ankle edema),
 K+ channel activator
 Minoxidil –
 Mechanism of action – It opens the K+
channel of the smooth muscle cell
membrane by its active metabolytes
minoxidil sulfate. Thus it stabilizes the
smooth muscle membrane at resting
potential or relaxes the arterioles but
not venules i.e. it decrease the
peripheral resistance not venous return.
 Pharmacokinetics –
 Well absorbed. Metabolized by liver. t ½
4 hours but its antihypertensive effect
remains for 24 hours.
 Indication –Mild to moderate HTN.
 Side effect –
• Reflex sympathetic stimulation,
• Palpitation
• Tachycardia.
• Angina (if myocardial abnormality present, due to
reflex tachycardia and coronary lesion by its
metabolite)
• Edema due to Na+ & fluid retention
• Headache, sweating.
• Hirsuitism: the hair growth is generalised &
although a cosmetic problem in woman, it has
been exploited as a solution for the treatment of
baldness in men. Thus minoxidil illustrates how
one person’s toxicity may become another
person’s therapy
 Diazoxide –
 M/A, Pharmacological effect – same as
minoxidil.
 Pharmacokinetics – intravenously used.
Lowers blood pressure within 3 – 5 minutes. It
is bound with plasma protein.
 Indication – It is used intravenously for the
treatment of hypertensive emergencies like
• Malignant HTN (BP 350/140) +
papilloedema + proteinuria.
• Hypertensive encephalopathy.
 Side effect –
• It causes harm in patient of myocardial
abnormality (MI, Stroke, Angina).
• Na+ and H2O retention – edema.
• Stop labour in eclampsia.
 Hydralazine
• A hydrazine derivative, dilates arterioles (not
veins).
• Tachyphylaxis to its antihypertensive effects
developed rapidly.
• The benefit of combination therapy is now
recognized, and may be used more effectively,
particularly in severe HTN.
• P/K –
• Well absorbed and rapidly metabolized by the
liver during 1st pass (bioavailability low – 25%
and variable among individuals).
• Metabolized in part by acetylation (bimodally
distributed in the population). Rapid acetylators
have greater 1st pass metabolism, lower
bioavailability, and less antihypertensive
benefit from a given dose than do slow
• t½ 1.5 to 3 hours, but vascular effects persist
longer than do blood concentrations, possibly
due to avid binding to vascular tissue.
• Toxicity –
• Most common – headache, nausea, anorexia,
palpitations, sweating, and flushing.
• In patient with IHD, reflex tachycardia and
sympathetic stimulation may provoke angina or
ischemic arrhythmias.
• With dosages of 400 mg/day or more, 10 to 20%
case in persons who slowly acetylate the drug – a
syndrome characterized by arthralgia, myalgia,
skin rashes, and fever (resembles lupus
erythematosus). This syndrome is not associated
with renal damage and is reversed by
discontinuation of hydralazine.
• Peripheral neuropathy and drug fever – other
 Nitropruside
 M/A – It stimulates guanylyl cyclase which
causes elevation of cGMP by nitric oxide or
directly causes arteriolar relaxation.
 Pharmacological effect – If patient have no
myocardial insufficiency or heart failure the
drug reduce BP by decreasing peripheral
vascular resistance. It increase some C.O. in
patient with heart failure.
 P/K – rapidly metabolised to cyanide and then
nitric oxide by smooth muscle. Cyanide is
further metabolized by liver rhodanase to
thiocyanate, which is eliminated almost
entirely in the urine. Used intravenously. Half
life is short (30 – 40 seconds). Usually within 1
– 10 minutes the function of this drug is
 Sodium nitropruside in aqueous solution is
light sensitive. Must be prepared fresh before
each time of administration and it should be
covered with opaque foil.
 Toxicity –
 Hypotension (most common) – there may
be nausea, vomiting, headache, sweating,
restlessness, chest pain, confusion, and
palpitation.
 Thiocyanate toxicity develops if the drug is
infused for more than 24 – 48 hours,
especially in patient of renal impairment.
Manifestations – weakness, disorientation,
psychosis.
 Metabolic acidosis
 Arrhythmia
 Hypothyroidism.
 Sympathoplegic drugs
• Centrally acting drugs – α Methyl dopa –
• M/A – It reduces the sympathetic discharge
from vasomotor centers present in the brain
stem without interfere in sensitivity to
baroreceptor reflexes. This methyl dopa is
converted ultimately to α methyl dopamine
and α methyl norepinephrine. This pathway
directly parallels the synthesis of
norepinephrine from DOPA. This α methyl
norepinephrine is collected within the
adrenergic nerve granule by replacing
norepinephrine and on stimulation this α
methyl norepinephrine is released and it acts
as false neurotransmitter on the receptor.
Thus it decreases the norepinephrine release
 α-methyl dopa competes with dopa for
dopa decarboxylase.
Tyrosine
Tyrosine hydroxylase
DOPA
dopa decarboxylase
Dopamine
DβH
NA
α-methyl dopa
DOPA decarboxylase
α-methyl dopamine
DβH
α-methyl NA (false NT)
• NA is metabolized by MAO and COMT
enzyme. But the false neurotransmitter α-
methyl NA is not metabolized by MAO. So, it
blocks the synthesis of NA and occupy the
synaptic vesicle by the same process as NA
and also occupy the cytoplasm. This false
neurotransmitter expel NA from vesicle.
This NA is metabolized by MAO in the
cytoplasm and form VMA which is excreted
through urine.
• Centrally - α-methyl NA binds with α2
receptor  decrease sympathetic discharge
 inhibit sympahtetic ganglia  decreased
NA in the target organ  decreased
peripheral resistance and heart rate 
decreased blood pressure.
 α-methyl DOPA
Crosses BBB
Go to brain
Converted to
α-methyl NA

Comes to circulation.
• In the periphery –
 α-methyl NA + α2 – it is more potent than NA
– effect is more prominent – more decrease in
release of NA – decrease peripheral
resistance and cardiac output – decrease
blood pressure.
 α-methyl NA + α1 – increase peripheral
resistance but less potent than NA.
• Uses – treatment of mild to moderate type of
HTN.
• P/K – Has extensive first pass metabolism. So
it has bioavailability of 25% and ¾ of the drug
excreted through urine. It can cross BBB
easily.
• t½ life 2 hours.
• An oral dose of methyl dopa produces its
maximum antihypertensive effect within 4 – 6
hours but persist for 24 hours (due to storage
in the nerve granule from where it release
very slowly).
• Dose: 1 – 2 gm.day in divided doses (usually 2
divided doses)
 Adverse effects -
 Central effects – NA, dopamine, 5-HT all are
synthesized in the nerve ending. α-methyl dopa
blocks all of them or causes decreased release of
them leading to – Sedation, Mental lassitude,
Impaired mental concentration, Nightmare,
Mental depression, Vertigo, Extra pyramidal signs
(due to decreased dopamine level), Lactation.
These effects are seen after long term use of high
dose.
 Peripheral side effects – Due to over activity of
parasympathetic nerve as sympathetic nerve is
inhibited – Postural hypotension, Failure of
ejaculation, Nasal congestion, Abdominal cramp,
Aggravation or development of peptic ulcer,
Bradycardia, Urinary hesitancy.
 Other side effects – Positive coomb’s test,
 Clonidine
• Clonidine is a partial agonist with high
affinity & high intrinsic activity at α2
receptors, especially α2A subtype in
brainstem. The major haemodynamic effect
results from stimulation of α2A receptors
present mainly postjunctionally in medulla
(VMC)  this decrease sympathetic outflow 
fall in BP & bradycardia (due to enhanced
vagal tone). Plasma noradrenaline declines.
Though clonidine is capable of reducing
noradrenaline release from peripheral
adrenergic nerve endings (release inhibitory
prejunctional α2 action), this is not manifest
at clinically used doses. Clonidine is a
• Indications of clonidine:
– Popular antihypertensive (but frequent side
effect, risk of withdrawal hypertension &
development of tolerance have relegated it to
a 3rd or 4th choice drug)
– Opioid withdrawal: opioid & α2 adrenergic
systems converge on the same effectors in
many systems; both activate the Gi proteins.
Clonidine suppresses sympathetic
overactivity of opioid withdrawal syndrome &
reduces craving to some extent. Clonidine
has also facilitated alcohol withdrawal &
smoking cessation
– Clonidine has analgesic activity. It has been
used to substitute morphine for
 – Clonidine attenuates vasomotor symptoms of
menopausal syndrome
– Clonidine has been used to control loose
motion due to diabetic neuropathy. It may
be acting by α2 receptor mediated
enhancement of salt absorption in gut
mucosa
• Toxicity:
– Dryness of mouth , nose, eyes
– Sedation
– Mental depression
– Impotence
– Salt & water retention
– Bradycardia
 Ganglion blocking drug:
Trimethaphan
• M/A – Competitively blocks the nicotinic
cholinoceptors on the postsynaptic neuron in
both sympathetic and parasympathetic
ganglia. It is an antagonist, so can not open
the channel and there is no depolarization
(competitive non depolarizing ganglion
blocker). Also it directly block the nicotinic
Ach channel.
• Use – Hypertensive crisis (parenteral route)
• Controlled hypotension during neurosurgery.
• Side effect –
• Due to sympathoplegia – postural
hypotension, sexual dysfunction.
• Due to parasympathoplegia – constipation,
retention of urine, precipitation of glaucoma.
 Storage blocker - Reserpine
 It is an alkaloid extracted from roots of an
Indian plant named Rauwolfia serpentia.
 This was used by the Indian’s for the treatment
of maniac patients. Later it was found that it
has antihypertensive effect.
 Mechanism of action –
 Reserpine inhibit the transport of reuptaken NA
from the cytoplasm into the synaptic vesicle.
So, NA cannot be stored. Then it is metabolized
by MAO in the cytoplasm. Ultimately it causes
depletion of all amines (NE, E, 5HT) both in
central and peripheral neurons.
 Reserpine enters the vesicle and causes
intraneuronal release of NA and this NA is again
metabolized by MAO. It also causes depletion of
catecholamines in the adrenal medulla.
 Pharmacological action –
 Ultimately tissue content of NA is decreased.
• Peripheral – antihypertensive effect – mainly in the
blood vessesl and in the heart.
• Central – antipsychotic effect. In psychosis – NA,
dopamine, 5-HT increased concentration of all
these neurotransmitter. Reserpin decreased
dopamine concentration – antipsychotic effect.
 Dose: < 1 mg/day – usually 0.2 mg/day – single
dose.
 Toxicity – Postural hypotension, Failure of
ejaculation, Sedation, Lassitude, Night mere,
Mental depression, Suicidal tendency (prolong use
of increased dose), Extrapyramidal syndrome (due
to decreased dopamine), GIT (increased motility) -
abdominal cramp, mild diarrhoea, peptic ulcer
disease.
 C/I - Patients who suffer from mental depression
 Release blocker - Guanithidine
 They are quarternary NH4 compound – they
are highly polar (charged) – they are not
absorbed orally and can not cross BBB – no
action on brain – no CNS side effect.
 These drugs are used as antihypertensive.
 Pharmacological action – Guanithidine has

 Bretylium like action

 Cocain like action These 3 mechanism
have
 Reserpin like action antihypertensive
effect
 Tyramine like action
 Bretylium like action – Bretylium has local
anesthetic like action. So, it blocks the
conduction of electrical impulse over nerve –
no poening of Ca++ channel – no entry of Ca++
- no exocytosis of NA.
 Cocain like action – Guanithidine inhibit the
uptake – 1 mechanism of NA – no storage of
NA.
 Reserpin like action – Guanithidine expel
out NA from vesicle – metabolized – no store
of NA in the vesicle.
 Tyramine like action – Guanithidine enters
the nerve ending – enters the vesicle by ATP
and Mg++ dependant mechanism – expels out
NA – NA acts on the α1 and β1 – rise of blood
pressure (initially). But when store is depleted
– decreased NA – decreased sympathetic
 Guanithidine has biphasic action –
 When given I/V

 When given orally

 P/K – bioavailability 30 – 50%. 50% excreted

by kidney. t½ 5 days.
 Dose – Though the variation of dose is greater
for individual to individual, so it starts from 10
mg/day then gradually it can be increased for
the expected effect.
 Toxicity – In high doses
 Postural hypotension
 Excrecise induced hypotension
 Failure of ejaculation (delayed and
retrograde ejaculation)
 Parasympathetic overactivity – GIT
disturbance, Nasal stuffiness,
Urinary hesitancy.
 Drug interaction of Guanithidine -
 TCA + Guanithidine – hypertensive
crisis.
 If  TCA +  Guanithidine – hypotensive
crisis.
 Selective α blocker
• α1 block

• Decreased peripheral resistance

• Vasodilatation

• Decreased blood pressure

• Reflex sympathetic stimulation

• Increased heart rate and force of contraction

• Tachycardia.
• But as α2 is not blocked – no release of NA – so,
no activation of β1 in the heart – so, less
tachycardia is produced due to selectively α1
 Prazosin
• Contain piperazinyl quinazoline nucleus
• Short acting
• Highly selective for postsynaptic α1receptors
• Terazosin and doxazosin are longer acting,
allowing once daily dose.
• Tamsulosin - α1A receptor antagonist
(selectivity for bladder)
• Pharmacokinetics of prazosin –
• Well absorbed after oral administration
• Substantial amount undergoes 1st pass
metabolism
• Bioavailability: 50 – 70%
• Tightly bound to plasma protein α1 acid
glycoprotein (about 95%), only 5% remain free
form
• Extensively metabolized in liver and excreted in
bile and feces 90%, urine 10%
• Pharmacological properties of prazosin –
• Blockade of α1 receptor in arteriole and vein –
decrease peripheral resistance and venous
return to the heart – decrease diastolic blood
pressure.
• May cause rapid reduction in blood pressure
after first dose (1st dose phenomena), so
should start with lowest possible dose usually at
bed time and then gradually increasing dose.
• Heart rate – does not increase heart rate (since
little or no α2 blocking effect).
• Prazosin in patients with CCF – reduces left
ventricular end diastolic volume – decrease
• Cardiac output and renal blood flow are not
changed.
• Causes relaxation of smooth muscle of bladder
neck and prostatic capsule. Useful in urinary
retention with benign prostatic hypertrophy.
• There is retention of Na+ and H2o –  plasma
volume.
• Prazosin appears to depress baroreflex function
in hypertensive patients.
• Serum lipid in human –  LDL and TG while  HDL
concentration (Clinical significance – not known)
• May have effect on cell growth unrelated to
antagonism of α1 receptor.
• Clinical uses of prazosin
• Congestive Cardiac Failure (CCF)
• Mild to moderate hypertension – preferred drugs
are longer acting doxazosin, terazosin used
• Benign Prostatic Hypertrophy - preferred drug
is Tamsulosin. Prazosin, doxazosin terazosin
may be used.
• Raynaud’s disease
• Prinzmetal angina due to coronary vasospasm.
• Pheochromocytoma: in combination with
propranolol.
• Adverse effects of selective α blocker -
• Postural hypotension, dizziness, vertigo,
headache, fatigue, palpitation (less marked)
• Sexual dysfunction (impotence)
• Abdominal discomfort, nausea, vomiting – less
frequent
• Retention of Na+ and H2o – increased plasma
volume
 Postural hypotension (First dose
phenomena)
 Hypotension produced by sudden change of the
posture.
 Mechanism: Person stands up – excessive
vasodilatation – central venous pressure
decrease – decrease venous return – decrease
cardiac output – decrease blood pressure.
 Drugs causing postural hypotension –
• Ganglion blocker – Hexasmethonium.
• α adrenoceptor blocker – phenoxybenzamine,
prazosin.
• Adrenergic neurone blocker –α methyldopa,
guanethidine.
• Antihypertensive – ACEI, Ca++ channel blocker,
diazoxide, Na+ nitropruside. Antidepressant –
 β Adrenoceptor Antagonist
 Most of the clinically important β
adrenoceptor antagonists have an
oxymethylene bridge (O-CH2) between
the aromatic nucleus and the
ethanolamine side chain. This
oxymethylene bridge attached to the
benzene ring converts the drug into an
antagonist.
 When OH group is replaced by 2 Cl- then
they become β blocker. e.g. Dicloro
isoprenaline. But isoprenaline has low
potency and it has got sometimes partial
agonistic effect. Subsequently propranolol
discovered, still now this is the best β
blocker. It is a pure antagonist.
 Classification of β blockers
 According to relative affinity for β1, β2
receptor –
 Non specific or non selective or cardio non
selective β blockers
- Propranolol, Oxprenolol, Alprenolol,
Pindolol,
Nadolol, Sotalol, Timolol, Carteolol,
Penbutolol.
 Specific or cardioselective – They only act on
β1 receptor of heart (if used in therapeutic
dose. But when used in higher dose they loss
their specificity)
- Metoprolol, Atenolol, Acebutalol,
 According to solubility –
 Lipid soluble – High : Propranolol, Penbutalol.
Moderate: Metoprolol, Pindolol,
Timolol, Labetalol.
 Water soluble – Atenolol, Sotalol, Acebutalol,
Betaxolol, Esmolol, Nadolol.
 β blocker with partial agonist activity/Intrinsic
sympathomimetic activity -
Oxprenolol, Alprenolol, Pindolol, Acebutalol,
Penbutolol, Carteolol, Celiprolol.
 β blocker with membrane stabilizing property –
- Propranolol, Acebutalol, Labetalol,
Metoprolol, Pindolol.
 β blocker with α blocking effect –
- Labetalol, Carvedelol.
 β blocker with direct vasodilating property –
- Labetalol, Carvedelol, Carteolol,
Nebivolol.
 Propranolol (model of β blocker)
 Pharmacological actions –
 On CVS:
• On heart –
 Negative inotropic
 Negative chronotropic
 Negative bathmotropic (excitability)

Antiarrhythmic
effect
 Negative dromotropic (automaticity)
Due to negative inotropic and negative chronotropic
effect – decrease heart rate and force of contraction
– decrease blood pressure. Blood pressure decreased
in patient with hypertension not in normotensive.
• On circulation of heart i.e. on O2 supply to heart
– As it is nonselective – so, β2 receptor of
coronary artery is also blocked – coronary
vasoconstriction – decreased coronary supply. β
blockers also indirectly decreases cardiac
workload – decrease O2 demand.
• On other blood vessels – Decrease the size of
lumen of blood vessel – decreased perfusion to
organ. Normal individuals are not affected, but
in patients having Raynaud’s disease, Burger’s
disease, Intermittent claudication - β blockers
aggravate these disease.
 Respiratory system: In bronchial smooth muscle
β2 receptor – bronchodilatation.
β blockers - bronchospasm in those who are
susceptible for asthma.
 Eye:
Decreased aqueous humor production – decrease
intra ocular pressure in case of glaucoma.
 Antirenin activity:
Decrease angiotensin II and aldosterone –
vasodilatation – decrease peripheral resistance –
decrease blood pressure.
 On metabolism:
In the liver – β2 receptor causes glycogenolysis and
neoglucogenesis after stimulated by adrenaline.
β blockers – reduce glycogenolysis – hypoglycemia.
Normal persons are not affected. But patients of
IDDM on insulin it is of clinical signifcance.
Insulin – introduces glucose within muscle and
β blockers – causes decreased glycogenolysis –
patient may go hypoglycemic shock.
• Diabetic patients who are taking insulin plus β
blockers, the effects are –
• During onset of hypoglycemia the action of insulin
is not hampered. It hampers the recovery by
inhibiting β2 receptor from hypoglycemic state.
• Exercise induced hypoglycemia will be more.
• Hypoglycemic manifestations are –
Tachycardia, palpitation, tremor, sweating –
these effects are due to stimulation of
sympathetic activity due to hypoglycemia.
Indicating – hypoglycemia.
But β blockers – block these manifestations. So,
patient dies in unnoticed condition due to
cerebral nutritional insufficiency.
• Inhibit peripheral conversion of T4 to T3, this
decrease the elevated circulatory levels of more
metabolically active thyroid hormone.
• Lipid metabolism:
Adipose tissue β1 – lipolysis – free fatty acid.
β blockers – decrease lipolysis.
LDL, TG are responsible for IHD.
β blockers – increase LDL : TG, decrease
lipolysis, decrease HDL – patients are prone to
IHD.
 On CNS: Excitation occurs –
Insomnia,restlessness,tremor,nightmare.
 Pharmacological actions unrelated to β blocking
effects
 Local anesthetic like action – blockade of Na+
channel – in neurons, heart, skeletal muscle.
 Antiarrhythmic effect - Blockade of Na+ channel
– membrane stabilizing property – slowing of AV
conduction – so used in atrial arrhythmia, not
 Uses of β blocker
 In hypertension: Drug of first choice in mild to
moderate hypertension. They don’t produce
postural hypotension. Mechanism of
antihypertensive effect –
 Heart – decrease heart rate and force of
contraction – decreased cardiac output –
decreased blood pressure.
 Kidney – Renin released from β receptor in the
juxtraglomerular apparatus. β receptor is
inhibited by β blockers – no renin –
antihypertensive effect.
 Nerve ending – β2 receptor – NA release. β
blocker –decrease NA release –
antihypertensive effect.
 CNS – decrease NA release – decrease blood
 Arrhythmia:
 Normal rhythm is maintained through β1
receptor of S.A. node.
 β blockers are effective in the treatment of both
supraventricular and ventricular arrhythmia.
 By increasing the atrioventricular nodal
refractory period, β antagonists slow ventricular
response rates in atrial flutter and fibrillation.
 These drugs can also reduce ventricular ectopic
beats.
 Sotalol has additional antiarrhythmic effects
involving ion channel blockade in addition to its
β blocking action.
 Antianginal effect:
 β1 block –  force of contraction –  work load of
heart –  O2 demand – prevent MI (antianginal).
 MI:
 It reduces the infarction size.
 Following MI gives protection against
dysrrhythmia and repeated infarction.
 Heart failure:
 Cautious long term use with gradual dose
increments in patients who tolerate them may
prolong life.
 Obstructive cardiomyopathy:
 Slowing of ventricular ejection and decreased
outflow resistance –increase stroke volume.
 Dissecting aortic aneurysm:
 To decrease the rate of development of systolic
pressure.
 In glaucoma:
 Increased intraocular pressure due to increase
aqueous humor secretion and decrease drainage of
aqueous humor through canal of schlemn.
 Timolol and related β antagonists are suitable for
local use in the eye because they lack local
anesthetic properties.
 Mechanism – reduce production of aqueous humor
by the ciliary body, which is physiologically
activated by cAMP.
 M3 agonist like pilocarpine, physostigmine –
constriction of pupil and contraction of ciliary
muscle – increased convexity of lens (far vision
disturbed) and opening of canal of schlemn.
 But timolol is not related to visual disturbance. It
directly reduces the secretion of aqueous humor.
 Other drugs approved for the treatment of
glaucoma – Betaxolol, carteolol, levobunolol,
 Hyperthyroidism:
 Associated with sympathetic activity – increase NA
release – increase heart rate and force of
contraction – increase blood pressure.
 Mechanism of antithyroid effect –
• Blockade of β adrenoceptors – decrease
sympathetic effect.
• Inhibition of peripheral conversion of thyroxine to
triiodothyronine.
 In prophylaxis of migraine: Mechanism is not
clear.
 Anxiety with somatic symptoms:
 Increased sympathetic activity – tachycardia,
palpitation, tremor, diarrhoea, increase frequency
of micturation.
 Low dose of propranolol (10 to 20 mg) lowers the
manifestation of sympathetic activity during
 Pheochromocytoma:
 Labetalol is the drug of choice. Prazosin and
propranolol is given combined if labatalol is not
found.
 Benign essential tremor:
 A familial disorder.
 Sympathetic activity may enhance skeletal
muscle tremor.
 β blocker reduce certain tremor.
 Portal hypertension:
 Diminish portal venous pressure in patient with
cirrhosis.
 Both propranolol and nadolol decrease the
incidence of the first episode of bleeding from
oesophageal varices in patients with cirrhosis.
 Side effects of β blocker
 Due to consequence of β blocking action –
 Respiratory system - Bronchoconstriction
specially who are susceptible to asthma.
 CVS – Bradycardia, Heart failure, Even heart
block (partial or complete).
 Diabetic patients and taking insulin –
hypoglycemic shock.
  CO - inadequate muscle perfusion - muscle
fatigue.
 Skeletal muscle blood vessel constrict due to
nonselective β blocker - Cold extremities and
lethargic.
 Sudden withdrawal of β blocker – IHD.
 Effect on lipid metabolism -  VLDL,  HDL, no
change in LDL. HDL : LDL ratio changed. So there
 Unrelated to β blocking side effects –
 CNS – Bad dreams, Sleep disturbance,
night mare, hallucination.
 Oculo muco cutaneous syndrome –
mainly by practolol.
• In eye – it damages lacrimal gland – no
tear fluid – corneal dryness – corneal
ulceration.
• In mucous membrane – Sclerosing
peritonitis – malabsorption syndrome.
• In skin – skin rash.
• All these syndromes are related to
immune system.
 Contraindications of β
blocker
 Nonselective β blocker –
 Bronchial asthma or respiratory insufficiency.
 Peripheral vascular disease.
 Heart block.
 Hypertension with diabetes mellitus.
 Bradycardia.
 Selective β blocker –
 Bradycardia.
 Heart block.
 Heart failure.
 Peripheral vascular disease.
 Pregnancy hypertension
• Methyldopa is still the drug of choice for
many obstetricians. Ca++ channel
blockers (especially nifedipine) are
common second-line drugs; parenteral
hydralazine is reserved for emergency
reduction of blood pressure in late
pregnancy, preferably in combination
with a β blocker to avoid unpleasant
tachycardia. β blockers (labetalol &
atenolol) are often effective & are
probably the drug of choice in the third
trimester; there is evidence to suggest
growth retardation with β blocker used in
first & second trimester.
• Diuretics reduce the chance of
developing pre-eclampsia, but are
avoided in pre-eclampsia itself
because these patients already have
a contracted circulatory volume.
• ACEI (& ARB) are absolutely
contraindicated during pregnancy,
where they cause fetal death,
typically mid-trimester.
• Magnesium sulphate halves the
risk of progress to ecplampsia.
 Malignant hypertension
• BP >240/>140.
• Usually prompt oral treatment with the
objective of reducing the BP over at least 12
hours will suffice, e.g. Labetalol. Alternatives
are nifedipine, hydralazine or methyldopa.
• Abrupt drop in BP are dangerous. The goal of
treatment in the 1st few hours or days is not
complete normalization of BP because chronic
HTN is associated with autoregulatory change
in cerebral blood flow. Thus, rapid
normalization of BP may lead to cerebral
hypoperfusion and brain injury (cerebral
ischemia – stroke, blindness). The BP should
not be acutely reduced below 160/100 mmHg
and this level should be attained over hours.
• A drop of 25% in pressure is about the maximum
that can be tolerated over minutes, maintaining
the diastolic BP at no less than 100 – 110 mmHg.
BP should be lowered over 24 hours in the elderly.
• Subsequently, BP can be reduced to normal levels
using oral medications over several weeks.
• When there is encephalopathy (an emergency)
parenteral therapy is essential, not only for speed
but for certainty that the drug is in the
blood.Sodium nitropruside I.V. is a drug of 1 st choice
but its action is so fast that it needs extrremely
careful (1 minute) monitoring.
• Alternative parenteral use are diazoxide, labetalol,
fenoldopam, nitroglycerin, Ca++ channel blocker
and hydralazine.
• Diuretics (frusemide) are administered to prevent
the volume expansion that typically occurs during
administration of powerful vasodilators.
MONOTHERAPY VS POLYPHARMACY IN
HTN
• Monotherapy of HTN (treatment with a
single drug) is desirable because –
– Better compliance
– Lower cost
– Fewer adverse effect
• However, most patients with HTN require
two or more drugs, each acting by a
different mechanism (polypharmacy).
• The rationale for polypharmacy – each of
the drugs acts on one of a set of
interacting, mutually compensatory
regulatory mechanisms for maintaining BP.
• An adequate dose of hydralazine causes
significant decrease in PVR, there will be a
drop in mean arterial BP, evoking a strong
response in the form of compensatory
tachycardia and salt and water retention. This
results in increase in cardiac output that is
capable of almost completely reversing the
effect of hydralazine. The addition of a β
blocker prevents the tachycardia; addition of a
diuretic prevents the salt and water retention.
In effect, all three drugs increase the
sensitivity of the cardiovascular system to
each other’s actions.
• A normal compensatory response accounts for
the toxicity of an antihypertensive agent, and
the toxic effect can be prevented by
administering a second type of drug.