e-content of anti hypertensive agents for M.pharm students.

1. Anti Hypertensive Agents
Presenting by:
Mr. Purushotham K N
Assistant Professor
Dept of Pharmaceutical Chemistry
SAC College of Pharmacy, B.G.Nagara
2021-2022
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2. Contents
• Introduction
• Classification
• SAR
• Mechanism of action
• Synthesis of Anti-Hypertensive drugs
• References
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3. HYPERTENTION
• Hypertension (high blood pressure) is when the pressure in your
blood vessels is too high (140/90 mmHg or higher).
• It is common but can be serious if not treated.
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4. Things that increase the risk of having
high blood pressure include:
• Older age
• Genetics
• Being overweight or obese
• Not being physically active
• High salt diet
• Drinking too much alcohol
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5. Anti Hypertensive drugs
• A type of drug used to treat high blood pressure. There are
many different types of antihypertensive agents, and they work
in different ways to lower blood pressure.
• Some remove extra fluid and salt from the body, Others relax
and widen the blood vessels or slow the heartbeat.
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6. Clasification
1.Diuretics
A. Thiazides
Chlorothiazide, Hydrochlorothiazide, Cyclopenthiazide, Bendroflumethiazide
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7. B. Loop Diuretics
Frusemide or furosemide, Ethacrynic acid, Bumetanide
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8. C. Potassium-sparing diuretics
Triamterene, Spironolactone
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9. 2.Drugs acting on sympathetic system
A. Centrally acting drugs
Clonidine, α-Methyl dopa, Gaunabenz
B. Catecholamine deplators
Reserpine
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10. C. Adrenergic blockers
ß-adrenergic blockers
Propranolol, Atenolol, Metoprolol, Oxprenolol, Acebutolol, Timolol, Nadolol, Pindolol
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11. α -Adrenergic blockers
Phentolamine, Phenoxy benzamine hydrochloride, Tolazoline, Prazosin, Terazosin, Doxazosin
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12. • Mixed α and ß blockers
Labetalol, Carvedilol
• Imidazole receptor agonist
Moxonidine, Rilmenidine
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13. D. Adrenergic neuron blockers
Guanethidine, Guanoxan, Debrisoquine, Betanidine
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14. E. Ganglion blockers
a. Quaternary ammonium compounds
Hexamethonium bromide, Pentolinium tartrate
b. Secondary amines
Mecamylamine HCl
c. Tertiary amines
Pempidine, Trimethophan
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15. 3. Calcium channel blockers
Verapamil, Nifedipine, Diltiazem, Felodipine, Amlodipine, Nicardipine, Nitrendipine
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17. 4. Drugs that inhibit angiotensin II receptors
Losartan, Irbesartan, Candesartan, Telmisartan, Valsartan
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18. a. Drugs that inhibit Aldosterone-Spironolactone
b. ACE inhibitors
i. Sulfhydryl containing ACE inhibitors –Captopril
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19. ii. Dicarboxylate containing ACE inhibitors
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20. 5. Vasodilators
Hydralazine, Diazoxide, Minoxidil, Sodium nitroprusside
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21. ACE INHIBITORS
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22. ACE INHIBITORS
Mechanism of action
• Renin is a proteolytic enzyme created by kidney and converts
angiotensinogen to decapeptide angiotensin-I (biologically inactive).
• Angiotensin-I is converted into angiotensin II by angiotensin converting
enzyme (ACE) which causes Na+ retention leads to vasoconstriction which
increases blood pressure.
• ACE inhibitors competitively binds with ACE and inhibits it’s activity and
blocks conversation of Angiotensin–I to Angiotensin–II.
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23. SAR OF ACE INHIBITORS
• The zinc binding group may be sulfhydryl (CH2SH) like in
Captopril, dicarboxylate group like in Enalapril, Lisinopril
Quinapril etc or phosphonate group like Fosinopril.
• Sulfhydryl group shows superior binding to Zn+2 ion with the side
effects like skin rash, taste disturbance etc so it can replaced by
dicarboxylate Or phosphonate groups.
• Esterification of the carboxylate Or phosphonate produces an
orally bioactive Prodrug. Dept of Pharmaceutical Chemistry 23

24. • Large heterocyclic hydrophobic rings generally N- containing
increases potency and alter pharmacokinetic parameters.
• The N-ring must contain a –COOH group to mimic the C-terminal
carboxylate of ACE substrate.
• Generally pyrrolidine ring is present (e.g.: captopril, enalapril) or
3,4 Dihydro 1-H isoquinoline in Quinapril Or 3,4-Dihydro-1H-
benzazepine in Benazepril.
Benazepril Captopril
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25. • R1 is usually methyl to mimic the side chain of Alanine may be n-
butylamine (e.g. Lisinopril) and this type of compound does not
require prodrug for oral activity
• Phenyl side chain is generally 2 carbon long and do not found in
captopril.
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26. CENTRALLY ACTING ANTIHYPERTENSIVE DRUGS
Mechanism of action
These agents stimulates the α-adreno receptors in CNS
Reduces the sympathetic outflow to cardiovascular system
Reduces cardiac output and Heart rate
Produces hypotensive effect
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27. SAR OF Centrally acting Antihypertensive agents
Clonidine and Guanabenz
• Both have 2,6 disubstituted ring with e- withdrawing –Cl
• -CH3 or –C2H5 decreases activity
• Unsubstituted ring decrease activity
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28. • Inductive effect of dichlorophenol basicity of drug decreases and
un ionisation increases
• Guanidine moiety is present in most of drugs
• Guanidine is basic pka (13.6) and ionised at physiological pH
• Due to substitution at nitrogen the basicity decreased and drug can
pass blood brain barrier
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29. Methyl dopa
• -NH2 Should not substituted it is required to mimic NH2 of nor adrenaline
• H is substituted with -CH2CH3 to form methyldopate.
• Substitution of H increases the solubility ,stability of drug in solution. So,
methyldopate may be used for IV.
• -CH3 also essential to mimic the noradrenaline
• Catechol is essential for activity
• Also susceptible to oxidation and it makes methyldopa unstable in presence
of oxidizing agents, alkaline pH and light.
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30. MECHANISM OF ACTION
• Methyldopate/methyldopa:
• They converted into α -methyl noradrenaline ,which is a potent α -
adrenergic agonist
• Which causes suppression of vasomotor centre neurones of medulla
and reduction of hypothalamus activity
• Thus there is decline in sympathetic impulses to the vessels, Heart
reduced cardiac output ,heart rate and finally reduced arterial
pressure
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31. CALCIUM CHANNEL BLOCKERS
Mechanism of action
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32. SAR OF Diphenyl alkyl amine
• R1 Substituted with Mono, di, tri substitution with –OCH3 or left unsubstituted
Verapamil (mono), gallopamil (tri) and Fendiline (No).
• R2 substituted with alkyl group (3-12 carbon long), aryl group may be like in
Fendiline.
• R3 generally replaced by -CN (Gallopamil, verapamil) or –H (Fendiline).
• R4 generally replaced by -CH3 (Verapamil, gallopamil) or –H (Fendiline).
• R5 is mono or di substituted with -OCH3 group and unsubstituted in Fendiline.
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Synthesis of Captopril

34. Dept of Pharmaceutical Chemistry 34
Synthesis of Clonidine
2,6-dichloro-aniline Ammonium thiocyanate 2,6-dichloro-phenyl-thiourea

35. Reference :
• Textbook of Medicinal chemistry volume 1 by V. Alagarsamy
• https://www.cancer.gov/publications/dictionaries/cancer-
terms/def/antihypertensive-agent
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