PHARMACOTHERAPY OF

HYERTENSION

Dr. Sanjay Kumar

Asst. Professor
Dept. Of Pharmacology
LCMC&H
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 Contents
✓Introduction
✓Epidemiology
✓Essence of controlling Blood pressure
✓Physiology of hypertension normal regulation
classification
✓Hypertension treatment Non pharmacological
Pharmacological(with recent advances)
✓JNC-8 guidelines
✓Analysis of JNC-8 guidelines
✓JNC-7 versus JNC-8
✓Hypertension in special cases
✓Resistant hypertension : Etiology, Evaluation, Therapy.
✓Secondary hypertension / hypertensive emergency & urgency
✓Recent treatments of hypertension
✓Summary & Conclusion 2
 Introduction
• Definition

• Hypertension may be clinically defined as that level

of blood pressure at which the institution of
therapy reduces blood pressure–related morbidity
and mortality.

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Epidemiology of hypertension (Global)

According to World health statistics(2012), among

the 57 million global deaths that occurred during
2008

• 36 million (63%) were due to non communicable

diseases (NCDs).
• Cardio vascular (48%) deaths were the major
proportion of NCDs.
• Hypertension is one of the attributable risk factor
for 13% of the global deaths.
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Hypertension is responsible for at least 45% of
deaths due to heart disease.

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Hypertension is also responsible for 51% of
deaths due to stroke.

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Epidemiology of hypertension ( INDIA )
• The prevalence of hypertension ranges from 20-40%
in urban adults and 12-17% among rural adults.

• The number of people with hypertension is projected

to increase from 118 million in 2000 to 214 million in
2025

• Recent ( 2012 ) studies show that for every known

person with hypertension there are 2 persons with
either undiagnosed hypertension or prehypertension

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Essence of controlling blood pressure

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 Small Decreases Make a Difference:
A Reduction of 2 mm Hg Lowers CVD Risk
by up to 10%
7% reduction
in risk of IHD
Decrease of mortality
2 mm Hg in ==========
mean SBP

10% reduction
in risk of stroke
mortality

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Regulation of blood pressure

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Regulation of Blood pressure

• AUTONOMIC NERVOUS SYSTEM

• RENIN-ANGIOTENSIN-ALDOSTERONE

• INTRAVASCULAR VOLUME

• VASCULAR MECHANISMS

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Postural
Baroreflex:
This is
responsible for
a rapid
movement to
movement
control of
blood pressure

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By controlling blood volume, kidney is responsible for
long term control of blood pressure. 14
Intravascular volume
• Vascular volume is primary determinant of arterial pressure
• Sodium is predominantly an extracellular ion and is a primary
determinant of the extracellular fluid volume

NaCl intake NaCl-dependent

exceeds hypertension Reduced renal functi
Abnormal hormones
Pressure
natriuresis

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 Regulation of blood pressure
Other mechanisms:
• Vasopressin ( ADH ) released from posterior pituitary
also plays a very important role by its ability to
regulate water reabsorption through kidney.

• Local vasoactive substances released from

endothelium is also involved in regulation of vascular
resistance.
Ex: Endothelin-1 constricts blood vessels
Nitric oxide dilates blood vessels

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Classification of hypertension

Based on the etiology, hypertension is classified into:

• Essential or primary hypertension: hypertension

without any identifiable medical cause (>95%).
• Environmental
• Genetic

• Secondary hypertension: hypertension due to a

specific medical pathology (<5%).

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Management of hypertension

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,.

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Treatment of hypertension

A ) life style modification

1. Weight reduction: maintain normal body weight (
BMI between 18.5 to 24.9 ) – (5-20mmHg/10 kg
weight loss)

2. DASH diet: diet rich in fruits, vegetables and low

fat diary products with reduced content of
saturated and total fat.
8-14mmHg

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 Treatment of hypertension
3) Dietary sodium reduction: reduce dietary sodium
intake to < 100 mmol/day ( 2.4g of sodium or 6g of
NaCl ) 2-8mmHg

4) Regular aerobic physical activity : at least 30 minutes

per day most days of week. 4-9 mmHg

5) Moderation of alcohol consumption

MEN: <2 drinks/day
WOMEN: <1 drink/day
( 1 drink = 15 ml of ethanol ) 2-4mmHg

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Classification of Antihypertensive

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ACE inhibitors, AT-1 antagonists, Direct Renin inhibitors

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ACE-inhibitors

• The differences among these drugs are mainly

pharmacokinetic. All are almost equally potent and
efficacious.

• All are prodrugs except Captopril and Lisinopril.

• All ACE inhibitors are eliminated by kidney except

Fosinopril which is eliminated by both the kidney and
liver.

• Contraindicated in pregnancy

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ACE-inhibitors

Adverse effects

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 ACE-inhibitors
Advantages
• Lack of postural hypotension
• No tachycardia
• Safe in diabetics.
• No deleterious effect on plasma lipid profile, no
hyperuricemia.
• Delays the development of diabetic glomerulopathy.
• Reverses LVH and increases wall-lumen ratio.
• No rebound hypertension on withdrawal.
• AIRE (1993), HOPE (2000), ALLHAT (2002) have confirmed
the antihypertensive and cardioprotective effects of ACE
inhibitors

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 ACE-inhibitors

Current status:
• First-line antihypertensive as per JNC-8 guidelines.

Recent drugs:
• MC-4232 ( combination of MC-1 & Lisinopril )
• Presently under trial
• To evaluate efficacy in hypertension co existing with
diabetes
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 ARBs ( Angiotensin receptor blockers )
Features :
• They are similar to ACE inhibitors but with better
tolerability profile ( decreased cough & angioneurotic
edema )
• Complete inhibition of all angiotensin-2 actions.
• However ARBs did not exhibit distinct advantages over
ACE inhibitors in reducing morbidity and mortality
from CHF.
• JLIGHT have attested to the favourable effects of ARBs
on morbidity and mortality in hypertensive patients

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ARBs ( Angiotensin receptor blockers )

Adverse effects
• Unlike ACE inhibitors, no Cough & Angioneurotic
edema.
• Like ACE inhibitors, hyperkalemia and fetal toxicity.

Current status
• First-line antihyertensive as per JNC-8 guidelines

• Like ACEIs efficacy is increased with diurects

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ARBs ( Angiotensin receptor blockers )

New drugs :
• Azilsartan approved by US-FDA in Feb 2011 for mild
to moderate hypertension.

• LCZ-696: it is Valsartan+ Nephrilysin inhibitor

(sacubitril) under phase-2 trial intended for use in
hypertension with heart failure.

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 Direct Renin inhibitors

First generation:
• They were disappointing due to poor bioavailability.
• Long trem effect on cvs not known

Second generation ( Aliskiren ):

• Approved by FDA in Dec 2011
• Claimed to have better efficacy than other drug as it
directly inhibits Renin.

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Direct Renin inhibitors

Adverse effects of Aliskiren:

• The drug was recently found to increase non-fatal

stroke.
• Kidney impairment
• Hyperkalemia
• Cough and angioedema

• Used as add on therapy – ARB, ACEI, CCB

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Diuretics

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Diuretics

Features :
• Hypokalemia ( excluding potassium sparing diuretic )
• Hyperuricemia, hypercalcemia, hyperlipidemia,
hyperglycemia can occur.
• Thiazide conserves calcium, whereas loop diuretic
looses calcium.
• Thiazides are avoided in diabetes mellitus, gout,
hyperlidemia ( however indapamide can be used in
diabetic hypertensives )
• Among loop diuretics indacrinone can be used for
hypertensives with gout.
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Diuretics

Current status
• First line anti-hypertensives as per JNC-8 guidelines
• Dose 12.5-25mg found a dose-dependent increase in the
occurrence of sudden death at doses of hydrochlorothiazide
>25 mg daily.
• This finding supports the hypothesis proposed by the
Multiple Risk Factor Intervention Trial Research Group
(1982), suggesting that increased cardiovascular mortality is
associated with higher diuretic doses.

Recent advances
• FK-453 is an investigational potassium sparing diuretic which
causes brisk diuresis with least potassium loss. It is selective
adenosine receptor antagonist
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• Drug interaction with diuretics

• Potentiates arrhythmia arising from digitalis

toxicity- K & Mg depleting effect

• Corticosteroids amplify hypokalemia produce by

diuretics

• Decrease clearance of lithium

• B-blockers & ACEI potentiates K sparing effect

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β- blockers

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β- blockers
Adverse effects and toxicity:
(1) Withdrawal syndrome (nervousness, tachycardia,
angina, BP increase).
(2) Reduced myocardial reserve and peripheral vascular
insufficiency exacerbates asthma, diabetes.
(3) Increased plasma triglycerides and decreased HDL
cholesterol (propranolol).
(4) CNS effects: lassitude, mental depression, insomnia,
nightmares.
(5) GI effects: diarrhea, constipation, nausea, vomiting.

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 Alpha blockers

Mechanism:

• By blocking α1 receptors reduce arterial pressure by

dilating both the resistance vessels & capacitance vessels.
These drugs cause only minimal changes in cardiac
output, renal blood flow, and glomerular filtration rate.
Therefore, long-term tachycardia does not occur
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 Alpha blockers
Adverse effects:

• First dose syncope

• Reflex tachycardia
• Postural hypotension
• Salt & water retention
These drugs are more effective when used in
combination with a β blocker and a diuretic than used
alone.
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Central Sympatholytics

These agents reduce sympathetic outflow from vasopressor

centre without affecting its sensitivity to baroreceptor
control.
Example: Clonidine,α-methyl dopa

The principal difference between both drugs is that clonidine

acts directly on receptors where as α-methyl dopa must be
converted to α-methyl noradrenaline for its action.
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 Central Sympatholytics
Adverse effects
• Clonidine: Rebound hypertension, dry mouth, sedation,
nasal stuffiness, constipation, impotence.

• α-methyl dopa: sedation, dry mouth, gynaecomastia,

galactorrhea, hepatic dysfunction, hemolytic
anaemia(rarely).

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 Central Sympatholytics
Newer drugs:

Moxonidene & Rilmenidine: they are the new

congeners of clonidine that have a longer plasma
half life and are said to be selective for α -1
receptors rather than α-2 receptors.

Therefore rebound hypertension is much less

frequent with these drugs.

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Calcium channel blockers
Mechanism

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Calcium channel blockers

• The binding of the CCBs to their receptor stabilises

the calcium channel in its inactivation state.

• The binding of the CCB reduces the frequency of

opening of voltage-gated L-type calcium channel in
response to depolarisation, because these channels
are now taking longer time to revert to resting state
for being available for activation

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Calcium channel blockers

• The net result is a marked decrease in the trans-

membrane calcium current which in smooth muscle
is associated with relaxation in cardiac muscle with
a decrease in pace maker activity and in AV-node
with a decrease in conduction velocity.

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Calcium channel blockers

• Their relaxant effect on large arteries is more

beneficial in elderly patients.
• They improve arterial compliance and retard
atherogenesis.
• They can be safely used in patients with asthma,
angina & PVD.
• They do not have significant effects on release of
renin and have no adverse effects on lipid profile.

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Calcium channel blockers

• Postural hypotension, first dose effect, rebound

phenomena are not observed.

• They neither impair cerebral or renal perfusion.

• These neither impair sexual activity nor the physical

working capacity.

• They are not fetotoxic.

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 Calcium channel blockers
Adverse effects:
• Peripheral oedema

• Reflex tachycardia

• Reversible gingival hyperplasia

Contra indications:
Unstable angina

LV failure

Aortic stenosis

Obstructive cardiomyopathy
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Calcium channel blockers

• Clevidipine :
Clevidipine is a dihydropyridine L-type calcium channel blocker, highly
selective for vascular, as opposed to myocardial, smooth muscle and,
therefore, has little or no effect on myocardial contractility or cardiac
conduction for IV use.

• Cilnidipine :
• Cilnidipine is the novel calcium antagonist accompanied with L-type

and N-type calcium channel blocking function.

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Vasodilators
The vasodilators decrease the total peripheral resistance & thus lower blood
pressure irrespective of the aetiology of hypertension.

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Vasodilator

Adverse effects:
Hydralazine: headache, nausea, nasalcongestion
tachycardia.
Minoxidil: Hirsuitism
Diazoxide: Sodium water retention
Fenoldopam: tachycardia, headache, flushing,
Sodium nitroprusside: headache, tachycardia,
flushing, toxicity due to
thiocyanate accumulation.
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Vasopeptidase inhibitors
• New class of drug having dual inhibitor effect on two key enzymes
involved in metabolism of vasoactive peptide

• ACE & Prevent breakdown of natriuretic peptides by neutral

endopeptidase

• Drugs include

• Sampatrilat

• Fasidotril

• Gemopatrilat

• omapatrilat 58
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JNC 8 guidelines

Blood pressure treatment guidelines:

• On December 18 2013, the controversial JNC 8

guidelines was released by the JNC ( joint national
committee ) in association with ACC ( American
college of cardiology ) and AHA (American heart
association).

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 JNC-8
• JNC-8 proposes 9 recommendations ; out of which
• 1st to 5th is concerned with thresholds and goals for
B.P treatment

• 6th, 7th & 8th is concerned with selection of

antihypertensive drugs

• Recommendation 9 is concerned with summary of

strategies based on expert opinion for starting and
adding antihypertensive drugs.

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Recommendation 1 63
Recommendation 6-8 64
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Recommendation 9 66
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 Combination therapy

diuretics, vasodilators, β blockers, clonidine, Plasma renin activity

CCBs, ACEIs methyldopa
All sympathetic inhibitors diuretics Fluid retention
(exp b blocker)&
vasodilators ( expt CCB)
Hydralazine and DHPs β blockers Tachycardia

β blockers vasodilator. Initial increase in t.r.p

Combinations to be avoided

α or β adrenergic blocker clonidine antagonism of clonidine at

Hydralazine
Verapamil or diltiazem
presynaptic receptor
DHP or prazosin similar pattern of
haemodynamic action
β blocker Marked bradycardia, A-V
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block
Hypertension in pregnancy
• Drugs to be used
• First line - Methyldopa
• Second line – nefidipine , hydralazine
• Third line –α & β blockers, doxazocin , atenolol

• Drugs to be avoided
• ACE inhibitors, ARBs: Risk of foetal damage, growth retardation.

• Diuretics: Tend to reduce blood volume— accentuate uteroplacental perfusion

deficit (of toxaemia)—increase risk of foetal wastage, placental infarcts,
miscarriage, stillbirth.

• Nonselective β blockers: Propranolol has been implicated to cause low birth

weight, decreased placental size, neonatal bradycardia and hypoglycaemia.

• Sod. nitroprusside: Contraindicated in eclampsia 70

Hypertension in Asthma
• B blockers – are contraindicated

B1 selective & B2 agonist – celiprolol

nevibilol B1 selective & NO

Diuertics - inihibit pulmonary vascular remodelling

hypokalaemia add on effect with steroid

Indapemide
• ACEI - attenuates cough
• ARB – ACEIs induced cough is tolerated by ARB
losartan

• α 2 blockers – increase parasympathetic tone – CI

• CCB – safe – reduce perfusion ventilation ratio 71

Resistant hypertension

Resistant hypertension (RH) is defined as blood

pressure above a goal despite adherence to at least
3 optimally dosed antihypertensive medications of
different classes, one of which is a diuretic.

This definition does not apply to patients who have

been recently diagnosed with HT

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Resistant hypertension

• Resistant HT is not synonymous with uncontrolled

HT

• Uncontrolled HT includes all hypertensive patients

who lack BP control under treatment, namely,
• those receiving an inadequate treatment regimen, those with poor
adherence, and those with undetected secondary HT, as well as those
with true treatment resistance

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Factors Contributing to Resistant Hypertension
• Drug-induced
• Nonsteroidal anti-inflammatory drugs
• Sympathomimetics (decongestants, anorectics)
• Oral contraceptive hormones
• Adrenal steroid hormones
• Erythropoietin
• Cyclosporine and tacrolimus
• Licorice (included in some chewing tobacco)

• Excess alcohol intake

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Resistant hypertension primary
Volume overload

Volume retention from Inadequate

Excess sodium intake diuretic therapy
kidney disease

Secondary Causes of Resistant Hypertension

Common Uncommon
• Obstructive sleep apnea • Pheochromocytoma
• Renal parenchymal • Cushing’s disease
disease • Hyperparathyroidism
• Primary aldosteronism • Aortic coarctation
• Renal artery stenosis • Intracranial tumor
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Pseudo-resistance
Lack of BP control with appropriate treatment in a
patient who does not have resistant hypertension.

Factors include
-Suboptimal BP
measurement technique
- The white-coat effect and
- Poor adherence to
prescribed therapy.

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Step by step evaluation of resistant
hypertension

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Step by step evaluation of resistant
hypertension

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• Pharmacotherapy (intensifying therapy)

- Increase dose of diuretic (or change Hydrochlorthizide to

chlorthalidone) or change to a loop diuretic for those with GFR
30 mL/min.

- If no contraindications, add spironolactone as first-choice

(starting at 12.5 mg daily); eplerenone (starting at 25 mg daily),
or amiloride (starting at 2.5 mg daily) are alternatives.

- Use a vasodilating β -blocker (eg, carvedilol).

- Add a calcium channel blocker from the alternate class (eg, add
a nondihydropyridine if already on a dihydropyridine).

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Resistant hypertension
newer approaches

• Endothelial receptor antagonist: Darusentan

• Catheter-based renal sympathetic denervation

• Baroreceptor activation

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• Darusentan

• It is an endothelin receptor antagonist under trials for

resistant hypertension which has shown promising
results during studies

• However, oedema fluid accumulation & cardiac

related adverse events & deaths have been observed.

• Darusentan provides additional reduction in blood pressure in patients

who have not attained their treatment goals with three or more
antihypertensive drugs.

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 Hypertensive emergency/ urgency
• ‘Hypertensive Urgency’.
• Systolic BP > 220 or diastolic BP > 120 mm Hg
• without overt signs of end organ damage
• Blood pressure should be reduced within few hours

• ‘Hypertensive Emergency’,
• with evidence of active end organ damage is labelled
• Reduction of blood pressure within 1 hour to avoid the risk of
serious morbidity or death.
• Include
• Hypertensive encephalopathy
• hypertensive nephropathy intracranial hemorrhage, aortic
dissection, preeclampsia-eclampsia, pulmonary
• unstable angina myocardial infarction. 83
• initial goal – reduce no more than 25% (within minutes to 1 or
2 hours)

• level of 160/100 mm Hg within 2–6 hours.

• Excessive reductions – harmful - avoid sublingual or oral fast-

acting nifedipine
• In acute ischemic stroke antihypertensives should only be used
if BP > 180–200 mm Hg, BP reduced by 10-15%
• In hemorrhagic stroke minimize MAP <130mmhg
• Sodium nitroprusside is no longer recommanded treatment of
choice; in most situations, appropriate control of blood
pressure is best achieved using combinations of nicardipine or
clevidipine plus labetalol or esmolol.
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Newer non pharmacological therapies

A)Catheter based renal sympathetic denervation:

Renal sympathetic activity contributes to

hypertension in part through simulation of renin
release, increased sodium reabsorption, and
neurogenic mechanisms. Selective denervation of
the renal nerves responsible for these effects has
been shown to reduce BP.

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Newer non pharmacological therapies

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Baroreceptor activation

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Baroreceptor activation:

• Baroreflex activation therapy (BAT) is a device-based

approach to treating hypertension that has been
intensively investigated.

• The BAT device consists of an implantable pulse

generator that activates the carotid sinus via an
electrical signal, delivered by bilateral leads.

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Baroreceptor activation:

• The leads are implanted during open surgery and the

electrodes are positioned at the areas of greatest
response in the carotid sinus.

• Stimulation of the sinus by the BAT device supplies

the blood pressure control centres with false
information of increased blood pressure, leading to
reflexive blood pressure lowering

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 References
• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13 th ed.
• Essentials of Medical Pharmacology, K D. Tripathi, 8th ed
• Drug Discovery And Evaluation, HG Vogel, 3 rded
• Harrison’s Principles of Internal Medicine. 17th ed .New Delhi. Mcgraw Hill
Publications;162-170
• http://jama.jamanetwork.com/ on 02/03/2016 ;2014 Guideline for
Management of High Blood Pressure in Adults Report From the Panel
Members Appointed to the Eighth Joint National Committee (JNC 8)
• Current Medical Diagnosis & Treatment 2023.

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Thank You !

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