Topics of antihypertensive drug: 1. Definition 2. Classification 3. Sympatholytic agent (SAR of beta blockers, mechanism, examples, synthesis of propanolol) 4 .ACE inhibitor (SAR, mechanism, examples, synthesis of one drug) 5. Antiarrhythmic agent (definition, classification, mechanism, 6. Antianginal drug (definition, classification, mechanism)

1. ANTIHYPERTENSIVE
. DRUGS
A S S I G N M E N T O N

2. CONTENTS
• Antihypertensive drug:
1. Definition
2. Classification
3. Sympatholytic agent (SAR of beta blockers, mechanism, examples,
synthesis of propranolol)
4. ACE inhibitor (SAR, mechanism, examples,synthesis of one drug)
5. Antiarrhythmic agent (definition,classification,mechanism,
6. Antianginal drug (definition,classification,mechanism).

3. ANTIHYPERTENSIVE DRUGS
• Hypertension is defined as either a sustained systolic blood
pressure (SBP) of greater than 140 mm Hg or a sustained diastolic
blood pressure (DBP) of greater than 90 mm of Hg.
• Antihypertensives are a class of drugs that are used to
treat hypertension (high blood pressure).
• Evidence suggests that reduction of the blood pressure by 5 mmHg
can decrease the risk of stroke by 34%, of ischemic heart
disease by 21%, and reduce the likelihood of dementia, heart
failure, and mortality from cardiovascular disease.

4. CLASSIFICATION OF
ANTIHYPERTENSIVE DRUGS
1. Diuretics :
➢ Thiazides : Hydrochlorothiazide, chlorthalidone, indapamide.
➢ High celling/Loop diuretics: Furosemide.
➢ K+ sparing: Spironolactone, triamterene, amiloride.
2. Angiotensin-converting Enzyme (ACE) inhibitors:
➢ Captopril, lisinopril, enalapril, ramipril, perindopril.
3. Angiotensin (AT1 receptor) blockers/antagonists:
➢ Losartan, irbesartan, candesartan.
4. Direct renin inhibitor:
➢ Aliskiren .

5. 5. Calcium channel blockers (CCB):
➢ Verapamil, diltiazem, nifedipine, amlodipine.
6. β-adrenergic blockers:
➢ Non selective: Propranolol.
➢ Cardioselective: Metoprolol, atenolol.
7. β and α – adrenergic blockers:
➢ Labetolol, carvedilol.
8. α – adrenergic blockers:
➢ Prazosin, terazosin, doxazosin, phenoxybenzamine, phentolamine.
9. Centrally acting:
➢ Clonidine, methyldopa.

6. 10.Vasodilators:
➢ Arteriolar : Hydralazine, minoxidi, diazoxide.
➢ Arteriolar +Venous: Sodium nitroprusside

7. SYMPATHOLYTIC AGENT
• Sympatholytic agents are antihypertensive drugs (most
notably β-blockers) which depress heart rate and contractility (this
decreases stroke volume) by blocking the influence of
sympathetic nerves on the heart.
• e.g. Alprenolol, bucindolol, carteolol.
SAR OF BETA-BLOCKERS
• β-blockers are classified according to structure into two classes:
1) Arylethanolamines ;
Basic drug:- Isoproterenol.
2) Aryloxypropanolamines ;
Basic drug:- Propranolol.

8. SAR OF ARYLETHANOLAMINES
• Basic drug in this category is Isoproterenol.
• Various modification :
1. Phenolic –OH groups are important for agonist activity.
2. Replacement of 3rd and/or 4th position –OH group by other groups leads to
removal of agonist activity and will make the compound antagonist.
e.g. A) Replacement of –OH groups by chlorine gives Dichloroisoproterenol
(DCI). First useful β-Blocker.

9. B) Replacement of electron rich hydroxyl (-OH) group with electron rich phenyl
at 3rd and 4th position gives pronethalol ( Better β-Blocker than DCI).
3. The two carbon side chain is required for the activity.
It cannot be decreased or increased i.e. two carbon chain must be there it
should not be less than and more than two.

10. 4. Small substituents on N produces alpha-activity, for beta-activity larger
groups must be substituted on 'N’.
Various substitution on 'N' are as follows:
a. N, N- di-substituted compounds are inactive.
b. Phenylethyl, hydroxy phenylethyl groups when added to 'N' maintains the
beta-blocker activity.
c. Cyclic alkyl substitution provides better pharmacological activity than open
chain substituents at 'N' atom of amine.
d. Alpha-carbon: methyl substitution decreases the activity.

11. 5. p-OH group on the phenyl ring can be replaced by methyl-sulphonamide to increase
the activity. E.g. Sotalol
P-OH group on phenyl ring can also be replaced by nitro group to produce good
activity.

12. SAR OF ARYLOXY PROPANOLAMINES
• Prototype drug in this category is propranolol which is potent beta-antagonist.
1. -OCH2 group is placed between the aromatic ring and the ethanolamino side
chain, which is essential for the activity.

13. • 2. Most of the derivatives have substituted phenyl rings in place of naphthyl
ring.These aryl rings are of different types like phenylether ring in oxprenolol,
Naphthalene (Propranolol), Indoles in (Pindolol).

14. 3. Alkenyl groups when present in the ortho position on phenyl ring gives good
beta- antagonist activity e.g. Oxprenolol and Alprenolol

15. 4. Substitution of -CH3, -OCH3, -NO2 groups on the phenyl ring generally done
at 2nd and 3rd positions and if occurs at 4th position it is least favored. e.g.
Metipranolol

16. 5. Isopropyl and t-butyl groups present on the amino group provides
nucleophilicity to the amino group. E.g.Atenolol

17. MECHANISM OF ΒETA-BLOCKERS
A. MECHANISM OF B-BLOCKER BENEFITS IN
ISCHEMIC HEART DISEASE :
• Increases threshold to ventricular fibrillation.
• Reduction in infarct size and reduction in the risk
of cardiac rupture.
• Reduction in the rate of reinfarction.
• Regression of the atheromatous
• Reduction in myocardial oxygen
requirements via a decrease in heart rate,
blood pressure and ventricular contractility.
• Slowing of the heart rate prolongs coronary
diastolic filling period.
• Redistribution of coronary flow.

18. MECHANISM OF ΒETA-BLOCKERS
B. MECHANISM OF BETA BLOCKERS IN HEART FAILURE :
• Upregulation of B receptors and improved B adrenergic signaling.
• Reducing the hyperphosphorylation of calcium release channels of
sarcoplasmic reticulum and normalizing their function
• Bradycardia (increase coronary blood flow and decreased myocardial oxygen
demand).
• Protection from catecholamine myocyte toxicity.
• Suppression of ventricular arrhythmias.
• Anti-apoptosis. B2 receptors, which are relatively increased, are coupled to
inhibitory G protein & block apoptosis.
• Inhibition of RAAS.When added to prior ACE-I or ARB, metoprolol augments
RAAS inhibitors

19. BETA BLOCKERS: EXAMPLES
• Atenolol (tenormin)
• Carvedilol (coreg)
• Esmolol (brevibloc)
• Labetalol (normodyne)
• Metoprolol (lopressor)
• Propranolol (inderal)
• Sotalol (betapace)

20. SYNTHESIS OF PROPRANOLOL
Propranolol

21. ANGIOTENSIN-CONVERTING ENZYME
(ACE) INHIBITORS
• A.C.E. (Angiotensin converting enzyme) inhibitor is an agent which block
the angiotensin converting enzyme which ultimately inhibit the conversion of
Angiotensin-II from Angiotensin-1.
• Angiotensin-converting enzyme (ACE) inhibitors are heart medications that
widen, or dilate blood vessels.That increases the amount of blood heart pumps and
lowers blood pressure.They also raise blood flow, which helps to lower hearts
workload.
• ACE inhibitors available - Benazepril, Captopril,
Enalapril, Fosinopril,
Lisinopril, Moexipril,
Perindopril, Quinapril,
Ramipril and Trandolapril

22. SAR OF ACE INHIBITORS
• The N ring must contain a carboxylic acid to mimic the C-terminal
carboxylate of ACE substrate.
• The N-ring should be large hydrophobic rings because it increase the potency
by altering pharmacokinetic parameters.

23. • The A, B, C groups can serve as Zn2+ binding sites
• The thiol group shows superior binding to Zn2+ among the
carboxylate and phosphate.
• Esterification of carboxylate (B) and phosphate (C) produces
orally active products
• The X should be -CH3
• In carboxylate derivatives X should be n- butylamine
• The n usually 2 for activity

24. MECHANISM OF ACE INHIBITORS
• ACE Inhibitors work in the lungs to inhibit
Angiotensin Converting Enzyme from
turning Angiotensin I into Angiotensin II.
• These medications cause an increase of
bradykinin, which inhibits kinase II, another
name for Angiotensin Converting Enzyme.
(Lehne, 2007, pg. 464)
• Blood Pressure is decreased due to a
decrease in blood volume, peripheral
resistance, and cardiac load.
• ACE Inhibitors, inhibit vasoconstriction and
release of aldosterone which inhibits the
retention of sodium and water.

25. ACE INHIBITORS
• Examples :-
-Benazepril (Lotensin)
- Captopril (Capoten)
- Enalapril (Vasotec)
- Fosinopril sodium (Monopril)
- Lisinopril (Prinivil, Zestril)
- Moexipril hydrochloride (Univasc)
- Quinapril (Accupril)
- Ramipril (Altace)

26. CHEMICAL SYNTHESIS OF ACE
INHIBITOR (CAPTOPRIL)
• A chemical synthesis of captopril
by treatment of L-proline with
(2S) -3-acetylthio-2-
methylpropanoyl chloride under
basic conditions (NaOH),
followed by aminolysis c the
protective acetyl group to
unmask the drug's free thiol,
L-proline
(2S) -3-acetylthio
-2-methylpropanoyl
chloride
captopril

27. ANTIARRHYTHMIC AGENTS
• Antiarrhythmic agents, also known as Cardiac dysrhythmia medications, are
a group of pharmaceuticals that are used to suppress abnormal rhythms of the
heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular
tachycardia, and ventricular fibrillation.
• Examples : - Quinidine
- Procainamide
- Disopyramide
- Lidocaine
- Tocainide
- Mexiletine

28. CLASSIFICATION OF ANTIARRHYTHMIC DRUGS
1. Membrane stabilizing agents (No + channel blockers)
1 (A) Moderately decrease dv / dt of 0 phase: e.g. Quinidine, Procainamide,
Disopyramide
1 (B) Little decrease in dv / dt of 0 phase: e.g. Lidocaine, Mexiletine
1 (C) Marked decrease in dv / dt of 0 phase: e.g. Propafenone, Flecainide
2. Antiadrenergic agents (B blockers): e.g. Propranolol, Esmolol, Sotalol (also class III)
3. Agents widening AP : e.g.Amiodarone, Dronedarone, Dofetilide, Ibutilide
4. Calcium channel blockers : e.g.Verapamil, Diltiazem
5. Miscellaneous
- For PSVT ; Adenosine, Digoxin
-For A-V block ; Sympathomimetics-Isoprenaline, etc. ;Anticholinergics-Atropine
Digitalis is used in AF,AFI and PSVT to control ventricular rate .

29. MECHANISM OF ANTIARRHYTHMIC
AGENTS
• Drugs affecting the cardiac action
potential The sharp rise in voltage
("0") corresponds to the influx of
sodium ions, whereas the two decays
("1" and "3", respectively) correspond
to the sodium-channel inactivation
and the repolarizing efflux of
potassium ions.The characteristic
plateau ("2") results from the opening
of voltage-sensitive calcium channels.

30. ANTIANGINAL DRUGS
• The drugs which act by increasing coronary blood flow and oxygen supply, or
by preventing vasospasm and clot formation, and associated decreases in blood
flow is known as Antianginal agents.
• Examples of antianginal agents include:
-Nitrates (eg, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin)
-Calcium antagonists (eg, diltiazem, nifedipine, nimodipine, verapamil)
-Beta blockers (eg, atenolol, pindolol, propranolol, metoprolol)
-Ranolazine.

31. CLASSIFICATION OF ANTIANGINAL
AGENTS
1. Nitrates:
a) Short acting (10 minutes): Glyceryl trinitrate (GTN and Nitroglycerine) –
EMERGENCY
b) Long acting (1 Hour): Isosorbide dinitrate, Isosorbide mononitrate, Erythrityl
tetranitrate, Pentaerythritol tetranitrate
2. Calcium Blockers:
a) Phenyl alkylamine:Verapamil
b) Benzothiazepin: Diltiazem
c) Dihydropyridines: Nifedipine, Felodipine,Amlodipine, Nitrendipine and Nimodipine
3. Beta-adrenergic Blockers: Propranolol, Metoprolol,Atenolol and others
4. Potassium Channel openers: Nicorandil
5. Others: Dipyridamole,Trimetazidine, Ranolazine and oxyphedrine

32. MECHANISM OF ANTIANGINAL DRUGS

33. MECHANISM OF ANTIANGINAL DRUGS

34. • Thank you…..