Antihypertensive

Agents
Presented by:
• Sameena Ramzan
M.Pharma 1st year
• Branch : Pharmaceutical chemistry

Department of pharmaceutical sciences university of Kashmir

outline of the
presentation
1. Introduction
2. Classification
3. Synthesis
4. Mechanism of Action
5. Structure activity
relationship
6. Uses
 Hypertension

 Hypertension is a very common disorder , particularly past middle age. It is not a disease itself, but
is an important risk factor for cardiovascular mortality and morbidity.

 For practical purposes “Hypertension “could be that level of BP at or above which long-term
antihypertensive treatment will reduce Cardiovascular mortality.

 Almost all HT management guidelines including ;

 NICE (2011), JNC8(2014), WHO-ISH(2003), EUROPEAN SOCIETY OF HYPERTENSION

(2007, 2013) define the cut-off level to be 140mmHg systolic & 90mmHg diastolic. However the
JNC8 have raised the defining level to 150/90 mmHg for individuals above 60years of age
 Classification of hypertension:

Hypertension may be classified into Primary and secondary hypertension.

1. Primary hypertension:
Itis known as the essential hypertension (Cause is not known)and is
characterized by;
Elevation of diastolic BP
Normal cardiac output
An increase in peripheral resistance
2. Secondary hypertension:
Itis known as the non essential hypertension. Factors causing secondary
hypertension are as;
Acute or chronic renal disease
Pheochromocytoma
Cushing's syndrome
Oral contraceptives, steroids, Sympathomimetics
Antihypertensive drug therapy
 Antihypertensive agents are the drugs used to decrease the elevated BP in hypertension. Antihypertensive drug
therapy has been remarkably improved in the last 60 years. Different classes of drugs have receive prominence
with passage of time in this period. Before 1950 hardly any effective and tolerated antihypertensive was
available. Veratrum & Sodium thiocyanate could lower BP, but were toxic and difficult to use.

 The ganglion blockers developed in the 1950s were effective, but produced a variety of side effects. Reserpine
was a breakthrough but produced mental depression. The therapeutic potential of Hydralazine couldn’t be tapped
fully because of marked side effects. The antihypertensives of the 1960-70s were methyldopa, 𝛽 blockers,
thiazide and high ceiling diuretics & clonidine. The status of beta blockers and diuretics were consolidated in the
1970s and selective alpha blockers Prazosin broke new grounds.

 The antihypertensives introduced in 1980-90s were angiotensin II converting enzyme (ACE) inhibitors &
calcium channel blockers.

 Angiotensin receptor blockers (ARBs) were added soon after, and the direct renin blocker Aliskiren is the latest
drug.
Pharmacological classification of Antihypertensive agents:
Synthesis of Diuretics used as antihypertensive agents:
 1.Thiazides :
 MECHANISM OF ACTION:
 Thiazides are medium efficacy diuretics with primary site of action in the cortical diluting
segment or the early DT (site III) . Here they inhibit Na+ —Cl– symport at the luminal
membrane.

 Initially, the diuresis reduces plasma and e.c.f. Volume by 5—15% and this decreases
cardiac output. Thiazides are mild antihypertensives, average fall in mean arterial pressure
is ~10mmHg.

 Hydrochlorothiazide is the diuretic of choice for uncomplicated hypertension.

 Synthesis of loop diuretics:

4-Chloro-N-furfuryl-5-Sulphamoylanthranilic acid

 Mechanism of Action:
 The major site of action is thick ascending limb of loop of Henle, therefore, called loop diuretics. Furosemide inhibits Na + -
K+ -2Cl– cotransport (site II) . The corticomedullary osmotic gradient is abolished and positive as well as negative free water
clearance is blocked. K+ excretion is increased mainly due to high Na + load reaching DT.

 FUROSEMIDE has weak Case inhibitory action, increases bicarbonate excretion as well ; urinary pH may rise but the
predominant urinary ion is Cl–.
 Synthesis :
 Adverse effects of Diuretics:
Most of the adverse effects of these drugs are related to fluid and electrolyte changes caused by
1.

them.
2.Hypokalaemia
3.Hyperuricaemia
4.Hyperglycaemia & dyslipidaemia
5.Magnesium depletion
6.Allergic Manifestations
7.Hearing loss

Daily Dose(mg) :
Hydrochlorothiazide: 12.5 – 100
Furosemide: usually 20-80 mg once daily in the morning
Trade names :
Hydrochlorothiazide: AQUAZIDE, HYDRIDE THIAZIDE, ESIDREX
Furosemide: LASIX, FRUSENEX
 Mechanism of Action:
 Captopril, a dipeptide analogue, is the first orally active ACE inhibitor. It is sulfhydryl
Containing dipeptide surrogate of proline which abolishes the presser action of Ang I but
not that of Ang II. It doesn’t block AT1 or AT2 receptors.

 Captopril prevents the generation of the active principle Ang II.

 Fall in BP is more marked when sodium ion has been depleted by diuretics, because renin
level is high .

 ACE inhibitors causes feedback increase in renin release resulting in overproduction of Ang
I. Since it’s conversion to Ang II is blocked, Ang I is diverted to produce more Ang (1-7)
which has vasodilator property and could contribute to the BP lowering action.

 Captopril is used in both essential and non-essential hypertension

Adverse effects of ACE Inhibitors:
1.Hypotension
2.Hyperkalaemia
3.Cough
4.Rashes
5.Dysgeusia
6.Foetopathic
7.Headache, dizziness, nausea, bowel upset
8.Granulocytopenia and proteinuria
Daily dose (mg ) :
Captopril : 25 mg BD, Increased gradually upto 50mg TDS according to
response. In patients on diuretics and in CHF it is wise to start with
6.25mg BD to avoid marked fall in BP initially.
Trade names: ANGIOPRIL, ACETEN
Synthesis and mechanism of calcium channel blockers :
Mechanism of Action:
 Calcium ions play a pivotal role in Vascular smooth muscle contraction. calcium
enters cells through specialized pores In the membrane wall called calcium channels ,
activated by membrane depolarization (Voltage-operated)

 Calcium channel blockers inhibit these channels (L-type) in cardiac and smooth
muscles. By decreasing calcium influx during action potential in a frequency and
voltage dependant manner , they reduce Systolic intracellular calcium concentration
and muscle contraction.

 They markedly relax arterioles but have mild effect on veins.

Adverse effects of CCBs:

1.Palpitation

2.Flushing
3.Ankle edema
4.Headache, drowsiness, nausea
5.Gastroesophageal reflux may be worsened
Daily Dose :
Nifedipine : 5-20mg BD oral
TRADE NAMES: CALCIGARD, DEPIN, NIFELAT
Synthesis and Mechanism of
beta-blockers:
Mechanism Of Action:
 These drugs block the beta – adrenergic receptors of the heart , slow the
heart , reduce the force of contraction and reduce the cardiac output.

 They also inhibit the secretion of renin by the juxtaglomerular apparatus

of the kidney and hence reduce the plasma of Ang II which is a potent
Vasoconstrictor.
Adverse effects of beta blockers:
1.Propanolol can accentuate myocardial insufficiency and can precipitate
CHF/Edema by blocking sympathetic support to the heart.
2.Bradycardia
3.Precipitates attack of bronchial asthma
4.Hypoglycaemia
5.Plasma lipid profile is altered to long term use
Daily Dose:
Propanolol : 40-480 mg
Atenolol : 25-100 mg
Trade names :
Propanolol : INDERAL, CIPLAR, BETABLOC
Atenolol : BETACARD, TENORMIN
Synthesis and Mechanism of central sympatholytics :
 Mechanism Of Action:
 The mechanism of action of these drugs is caused by stimulation of Alpha2-receptors in
the inhibitory structure of the brain.

 The interaction of the drugs with alpha 2 receptors is expressed in the suppression of
vasomotor centre neurons of the medulla and reduction of hypothalamus activity , which
leads to a decline in sympathetic impulses to the vessels and heart . Cardiac output and
heart rate are moderately reduced and consequently arterial pressure is reduced.
Adverse Effects:
1.Sedation
2.Impotence
3.Postural hypotension
4.Reduced mental capacity
5.Positive coomb’s test occurs with methyldopa in 1/6 patients, few develop haemolytic
anaemia
6.Rebound hypertension
Daily Dose :
Clonidine: 100 micro gram
Methyldopa: 0.25-0.5 g
Trade names:
Clonidine : CATAPRES, ARKAMIN
Methyldopa : EMDOPA, ALPHADOPA
Synthesis and Mechanism of action of Arteriolar dilator :
Mechanism Of Action:
 Hydralazine is a directly acting arteriolar vasodilator with little
action on venous capacitance vessels.

 Hydralazine reduces total peripheral resistance and causes greater

decrease In diastolic than in systolic BP.

 Minoxidil is a powerful vasodilator, the active metabolite of

minoxidil is an opener of ATP sensitive K+ channels; causes
vasodilatation by hyperpolarizing smooth muscles.
Adverse Effects:
1.Facial flushing

2.Angina and MI may be precipitated in patients with coronary artery disease

3.Postural hypotension

4.Tremor, muscle cramps, headache, dizziness, palpitation

5.Local irritation and burning sensation is common with minoxidil

6.Hirusitism was observed as a frequent side effect of minoxidil but now is used
in alopecia.
Daily Dose:
Hydralazine: 25-50mg
Trade name: NEPRESOL
Synthesis and Mechanism of Arteriolar + Venodilator:
 Sodium Nitroprusside:

Mechanism of Action:
 Sodium Nitroprusside is a rapidly (within seconds) and consistently acting vasodilator
with brief duration of action(2-5min)

 Nitroprusside relaxes both resistance and capacitance vessels, reduces t.p.r as well as
cardiac output. Myocardial work is reduced.

 Endothelial cells, RBCs split Nitroprusside to generate NO which relaxes vascular

smooth muscle. This occurs both Enzymatically and non Enzymatically.

 Nitroprusside is now a second line drug for certain hypertensive emergencies.

Adverse effects:

1.Thiocyanate toxicity

2.Psychosis and other CNS effects

3.Palpitation, nervousness, vomiting, perspiration, pain in abdomen, weakness,

disorientation

4.Lactic acidosis (caused by released cyanide)

Daily Dose:

Nitroprusside : 50mg in 5ml inj.

Trade names: SONIDE, PRUSIDE, NIPRESS

Structure activity relationship (SAR) Of ACE inhibitors:
SAR Of ARBs :
References:
1.Textbook of Medicinal Chemistry vol 1 by V.Alagarsamy

2.Medicinal Chemistry by Ashutosh Kar Fourth Edition

3.Medicinal Chemistry by D.Sriram ,P.Yogeeswari Second Edition

4.Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry 12 th

Edition

5.Foye’s Principles of Medicinal Chemistry

6.Goodman & Gilman’s The Pharmacological Basis of Therapeutics 13 th Edition

7.Essentials of Medical Pharmacology by KD Tripathi 8 th Edition