Anti anginal drugs

DRUGS USNIG IN CARDIO VASCULAR
SYSTEM
PREPARED BY
K.SATTANATHAN., M.PHARM.,
ASST.PROFESSOR
Dept. of ph. chemistry

INTRODUCTION
ANTI ANGINAL AGENTS
4/9/2021
K. SATTANATHAN M.PHARM. ASST.
PROFESSOR DEPT. OF PH. CHEMISTRY
2

INTRODUCTION
• Angina pectoris was first brought to the attention of the
medical profession by william Heberden in 1772.
• Angina pectoris is the chronic disease affect in the coronary
arteries, which supply oxygenated blood from the left
ventricle to all heart tissues, including the ventricles.
• Angina represents the clinical symptom of myocardial
ischaemia which in turn occurs when the myocytes do not
have enough oxygen for the mitochondrial oxidation as a
result of an imbalance between myocardial oxygen demand
delivery.
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INTRODUCTION
• The major determination of oxygen delivery include
coronary blood flow which in turn depends on the
pressure gradient across the coronary circuit and the
integrity of the coronary arteries, as well as from the
oxygen carrying capacity of the blood and the
hemoglobin level.
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INTRODUCTION
WHAT IS ANTI ANGINAL AGENTS?
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INTRODUCTION
• An antianginal drugs may relieve attacks of acute
myocardial ischemia by increasing myocardial oxygen
supply or by decreasing myocardial oxygen demand
or both.
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INTRODUCTION
• TYPES OF ANGINA
1. CHRONIC STABLE ANGINA
2. UNSTABLE ANGINA
3. VASOSPATIC ANGINA
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CLASSIFICATION
• 1. NITRITES AND NITRATES
• 2. CALCIUM CHANNEL BLOCKER
• 3. BETA BLOKCER
• 4. CARDIO VASCULAR AGENTS
• 5. POTASSIUM CHANNEL BLOCKER
• 6. MISCELLANOUS
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CLASSIFICATION
NITRITE AND NITRATE
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STRUCTURE OF ANTI ANGINAL AGENTS
• IUPAC NAME: 1,3-
bis(nitrooxy)propan-2-yl
nitrate
• MELTING POINT: 13. 5
• LOG P :1.62
• PKA -5.6
• USES : ANGINA PECTORIS
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• IUPAC NAME:
(3R,3aS,6S,6aS)-6-(nitrooxy)-
hexahydrofuro[3,2-b]furan-3-yl
nitrate
• MELTING POINT: 70
• LOG P : 1.31
• PKA : -4.2
• USES : TREATMENT OF HEART
FAILURE, ESOPHAGEAL SPASMS
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• IUPAC NAME :
3-(nitrooxy)-2,2-
bis[(nitrooxy)methyl]prop
yl nitrate
• LOG P : 1.622
• PKA : -5.5
• USES :VASO DILATOR
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• IUPAC NAME:
(2S,3R)-1,3,4-
tris(nitrooxy)butan-2-yl
nitrate
• LOG P: 1.68
• PKA : -5.5
• USES : VASO DILATORS
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• IUPAC NAME: PENTYL
NITRITE
• LOG P : 1.98
• PKA : -1.98
• USES : ANTI ANGINAL
AGENTS,ANTI DOTE FOR
CYANIDE POISOINING,
CLEANING AGENT
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• LOG P : 0.071
• PKA -3.3
• NAME : NITROPRUSSIDE
SODIUM
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CLASSIFICATION
BETA BLOCKER AGENTS
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• NAME: PROPANOLOL
• IUPAC NAME:
1-[(1-methylethyl)amino]-3-(1-
naphthalenyloxy)-, hydrochloride
• MELTING POINT : 163- 165 in
Celsius
• SOLUBILITY: Soluble in water
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• NAME: ATENOLOL
• IUPAC NAME : 2-[4-[2-
hydroxy-3-(propan-
2ylamino)propoxy]phenyl
]acetamide
• MELTING POINT:158-160
• SOLUBILITY: FREELY
SOLUBLE IN METHANOL
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• NAME: METOPROLOL
• IUPAC NAME: 1-[4-(2-
methoxy)phenoxy]-3-
(propan-2-
ylamino)propan-2-ol
• MELTING POINT: 120 c
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• NAME : ESMOLOL
• IUPAC NAME : methyl 3-
[4-[2-hydroxy-3-
(propan-2yl
amino)propoxy]phenyl
propanoate
• Log P :1.7
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CALCIUM CHANNEL BLOCKER
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• IUPAC NAME:
2-(3,4-dimethoxyphenyl)-5-{[2-
(3,4-
dimethoxyphenyl)ethyl](methyl)am
ino}-2-(propan-2-yl)pentanenitrile
• LOG P : 5.23
• PKA : 9.68
• USES : ANTI HYPERTENSIVE
AGENTS, ANGINA,
SUPRAVENTRICULAR ,MIGRAINE
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• IUPAC:
(2S,3S)-5-[2-
(dimethylamino)ethyl]-2-(4-
methoxyphenyl)-4-oxo-2,3,4,5-
tetrahydro-1,5-benzothiazepin-3-yl
acetate
• MELTING POINT : 187
• LOG P: 2.8
• PKA : 12.86
• USES : CALCIUM CHANNEL
BLOCKER, HYPERTHYRODISM,
ANGINA, ARRYTHMIAS
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• IUPAC NAME:
3,5-dimethyl 2,6-dimethyl-4-(2-
nitrophenyl)-1,4-dihydropyridine-3,5-
dicarboxylate
• LOG P : 2.2
• PKA 5.3
• USES : ANTI HYPERTENSIVE AGENT,
TOCOLYTIC AGENTS, HIGH ALTITUDE
AS PULMONARY EDEMA
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• IUPAC NAME :
3-(2-methoxyethyl) 5-propan-2-yl 2,6-
dimethyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate
• STEREOCHEMISTRY : Nimodipine
contains a stereocenter and can exist as
either of two enantiomers. The
pharmaceutical drug is a racemate, an
equal mixture of the (R)- and (S)- forms
• LOG P : 3.41
• PKA : 5. 41
• USES: CEREBRAL VASOSPASM,
HYPERTENSIVE AGENT
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• IUPAC :
3-{2-[benzyl(methyl)amino]ethyl}
5-methyl 2,6-dimethyl-4-(3-
nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate
• MELTING POINT : 136 – 138
• LOG P : 3.82
• PKA : 8. 2
• USES : ANTI HYPERTENSIVE
AGENTS
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• IUPAC NAME :
3-ethyl 5-methyl 2,6-dimethyl-4-(3-
nitrophenyl)-1,4-dihydropyridine-3,5-
dicarboxylate
• STEREOCHEMISTRY:Nitrendipine contains a
stereocenter and can exist as either of
two enantiomers. The pharmaceutical
drug is a racemate, an equal mixture of
(R)- and the (S)-forms.
• MELTING POINT : 156- 160
• LOG P : 2.88
• PKA : 5. 43
• USES : ANTI HYPER TENSIVE AGENTS
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• IUPAC NAME :
3-ethyl 5-methyl 2-[(2-
aminoethoxy)methyl]-4-(2-
chlorophenyl)-6-methyl-1,4-
dihydropyridine-3,5-
dicarboxylate
• MELTING POINT : 199-200
• LOG P : 3.00
• PKA : 19.12
• USES : ANGINAL PAIN, CAD,
HYPERTENSIVE AGENTS
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• IUPAC
3-ethyl 5-methyl 4-(2,3-
dichlorophenyl)-2,6-
dimethyl-1,4-
dihydropyridine-3,5-
dicarboxylate
• LOG P 3.86
• Pka : 19.46
• Uses: ANTI HYPERTENSIVE
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• IUPAC NAME :
N-benzyl-N-[3-(2-
methylpropoxy)-2-(pyrrolidin-1-
yl)propyl]aniline
• pKa: 9.6
• Log p : 5.3
• USES: ATRIAL FIBRILLATION
,ANTI HYPERTENISION
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• IUPAC NAME :
2-({6-[bis(2-
hydroxyethyl)amino]-4,8-
bis(piperidin-1-yl)-
[1,3]diazino[5,4-d]pyrimidin-2-
yl}(2-
hydroxyethyl)amino)ethan-1-ol
• HALF LIFE : 40 MINS
• USES : CAD, PULMONARY
HYPERTENSION, TISSUE
PLASMINOGEN ACTIVATOR
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• NAME : BOSENTEN
• IUPAC NAME: 4-tert-butyl-
N-[6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy)-2-
pyrimidin-2-yl pyrimidin-4-
yl)benzene sulfonamide
• USE: Treatment of
pulmonayatrial
hypertension
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• NAME: TEZOSENTAN
• IUPAC NAME: N-[6-(2-
hydroxyethoxy)-5-(2-
methoxyphenoxy)-2-[2-(2H-
tetrazol-5-yl)pyridine-4-
yl]pyrimidin-4-yl]-5-propan-
2-ylpyridine-2-sulfonamide
• USE: Drugs used to cause
dilation of the blood vessels
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DRUGS ACT ON CONGESTIVE HEART FAILURE
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CHEMISTRY OF CARDIAC GLYCOSIDES
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• Cardiac glycosides are an important class of naturally
occurring drugs the action of which include both
beneficial and toxic effect on the heart.
• Cardiac glycosides are known as positive ionotropic
drugs.
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• Cardiac glycosides and other similar glycosides and
other similar glycosides are composed of two portion
1. Non sugar moiety aglycone
2. Sugar moiety
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1. Non sugar moiety
The aglycone portion of the cardiac glycosides is
a steroid nucleus with a unique set of fused rings
Ring AB and CD are cis fused, and where as ring
BC is trans
The steroid nucleus also carries in most cases two
angular methyl group are located at C10
& C13
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• In C3 position hydroxyl group are attached in C 3
position the hydrogen replace from hydroxyl group an
addition of sugar moiety
• C14 hydroxyl group is unsubstituted however
additional hydroxyl group present in C12 & C16
• The presence or absence of hydroxyl groups are
important difference in genius
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• The lactone ring at C17 is another major role of
cardiac glycosides in aglycones
• The size of unsaturation of the lactone ring differ in
the source of glycoside
• In most cases, the cardiac glycosides of plant origin
called cardenolides, it is a five membered , α,β-
unsaturated lactone ring
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• The cardiac glycosides of animal origin called bufa
dienolides it is a six membered two conjugated
double bond of lactone ring
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2. The sugar moiety
The hydroxyl group at C3 of the aglycone moiety is
conjugated mono saccharide or poly saccharide with β-1,4-
glycosidic linkage
the most commonly found sugars in the cardiac
glycosides are D- Glucose, D- digitoxose, L- rhamnose and
D-cyarmone
the presence of and O- acetyl group on a sugar greatly
affects the lipophilic character
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• NAME: DIGIOXIN
• MELTING POINT:249
• SOLUBILITY : very
soluble in ethanol
• Log P: 1.26
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• DIOSGENIN
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• DIGITOXIGENIN
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SYNTHESIS OF ANTI ANGINAL DRUGS
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Synthesis of nitro-glycerin
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SYNTHESIS OF DIPYRIDAMOLE
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Mechanism of nitrate and nitrite anti anginal
agents
• These act by the formation free radical nitric oxide which
interact with and activate guanylate cyclase.
• Nitric oxide forms a reductive nitro-thiol intermediate
activate a soluble cytosolic form of the enzyme guanylate
cyclase and cGMP formation is thereby increased.
• The guanylate cyclase increase the synthesis of
guanosine 3’, 5’ monophosphate, which activates a
protein kinase which mediates dephosphorylation of
myosin responsible for the maintenance of the
contractile state in smooth muscle.
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agents
NITRATES
CORONARY ARTERY DILATION
DECREASE CORONARY BED RESISTANCE
INCREASE CORONARY BLOOD FLOW
INCREASE OXYGEN SUPPLY
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agents
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Mechanism of Beta blocker
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Mechanism of Calcium channel blocker
Coronary artery dilation
Decrease coronary bed resistance
Increase coronary blood flow
Increase oxygen supply
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Reduction on peripheral resistance
Decrease blood pressure
Decrease after load
Decrease workload
Decrease oxygen consumption
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Mechanism of calcium channel blockers
• These drugs act by selectively inhibit calcium ion
influx into hear muscle and inhibit calcium ion influx
into vascular smooth muscle. It dilates the main
coronary artery and by inhibiting coronary artery
spasm, they increase myocardial oxygen delivery in
patients with Prinz metal angina.
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Mechanism of Cardiac glycosides
• cardiac glycoside inhibits the sodium potassium
adenosine triphosphatase (ATPase) pump, thereby
increasing intracellular calcium and enhancing
cardiac contractility. This agent also acts directly on
the atrioventricular node to suppress conduction,
thereby slowing conduction velocity. Apparently due
to its effects on intracellular calcium concentrations,
digoxin induces apoptosis of tumor cells via a
pathway involving mitochondrial cytochrome c and
caspases 8 and 3
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SAR OF CALCIUM CHANNEL BLOCKER
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ANTI ARRYTHMIC AGENTS
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INTRODUCTION
• ANTI ARRYTHIMC DRUGS ARE USED TO PREVENT OR
TREAT IRREGULARITIES OF CARDIAC RHYTHM
• ARRHYTHMIAS ARE THE MOST IMPORTANT CAUSE OF
SUDDEN CARDIAC DEATH
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CLASSIFICATION OF ANTI ARRYTHMIC DRUGS
• CLASSIFICATION OFANTI ARRHYTHMIC DRUGS
• Class I – Sodium channel blocker
 Class I- A – Moderate potent sodium channel blocker
E.g.: Quinidine, Disopyramide, Procainamide
 Class I- B – Low potent as sodium channel blocker
e.g.: Lidocaine, Mexiletine, Phenytoin, Tocainide
 Class I – C – Most potent of sodium channel blocker
E.g ; Flecainide, Propafenone, Moricizine
• Class II – beta adrenergic blocker
e.g.: Propranolol, Sotalol, Esmolol, Timolol
• Class III- Inhibition of both sodium and potassium channels
E.g: Amiodarone, Dofetilide, Ibutilide, Bretylium tosylate
• Class IV- Calcium channel blocker
e.g: Verapamil, Diltiazem,
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MECHANISM OF ANTI ARRYTHMIC AGENTS
Class (1) agents :These act by blocking Na+ channels . These are
known as membrane-stabilizing agents .These agents decreases
the flow of Na+ into the cells and helps in the release of K+
from the myocardial cells and ultimately decreases re-
polarization time .It slows down propagation of excitation .
Based on their effect on action potential ,class 1 agents are
classified as:
Class 1a : Prolongs the action potential and has little effect
on O phase of de-polarization .
Class 1b : Decreases the action potential and has on
initiation of de-polarization .
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MECHANISM OF ANTI ARRYTHMIC AGENTS
• Class 1c :Has no effect on action potential and strongly effect initiation of de –polarization .
For ex :Encainide ,Flecainide ,propafenone
• Class 2 agents : These are beta- adrenergic blockers. They act by initiating the effect of catecholamines
at beta –receptors ,reduces cAMP levels and Ca+ influx .
For ex, atenolol ,propanolol
• Class 3 agents : These agents blocks the K+ channels and prolongs the re-polarization .These drugs have
no effect on Na+ channels. These agents prolongs the QT segment of the ECG .
For ex,Amiodarone, sotalol , and bretylium
• Class 4 agents :These agents are calcium channels blockers and blocks influx of Ca+2 ions .For Varapamil
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CLASS I- SODIUM CHANNEL BLOCKER
DRUGS
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STRUCTRUE OF ANTIARRYTHMIC
DRUGS
• NAME: QUINIDINE
• IUPAC NAME: (S)-[(2R,4S,5R)-5-ethenyl-
1-azabicyclo[2.2.2]octan-2yl]-(6-
methoxyquinolin-4-yl)methanol
• MELTING POINT: 174 c
• SOLUBILITY: Very soluble in methanol
• Log P: 3.44
• Pka: 8.56
• USES: Adrenergic alpha
blocker,Antiarrhythmic, Anti malarials
,Muscarinic blocker
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STRUCTRUE OF ANTIARRYTHMIC DRUGS
• NAME: PROCAINAMIDE
• IUPAC NAME: 4- amino –N-[2-
(diethylamino)ethyl]benzamide
• MELTING POINT: 165-169
• LOG P: 0.88
• Pka: 9.32
• Solubility : Freely soluble in
water
• USES: used as Paroxysmal
ventricular tachycardia
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DRUGS
• NAME: DISOPYAMIDE
• IUPAC NAME: 4-[di(propan-
2-yl)amino]-2-phenyl-2-
pyridin-2-ylbutanamide
• MELTING POINT: 94.5-95
°C
• LOg P : 2.58
• uses: Ventricular
arrhythmias, Ventricular
tachycardia and Cardiac
dysrhythmias
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DRUGS
• NAME: MEXILETINE
• IUPAC NAME : 1-(2,6-
dimethylphenoxy)propan-2-
amine
°C
• pKa: 9.2
• USES : ventricular
tachycardia and
symptomatic premature
ventricular beats, and
prevention of ventricular
fibrillation
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DRUGS
• NAME: LIDOCAINE
• IUPAC NAME: 2-
(diethylamino)-N-(2,6-
dimethylphenyl)acetamide
• MELTING POINT: 68.5 °C
• SOLUBILITY : VERY
SOLUBLE IN ALCOHOL
• LOG P : 2.44
• pKa: 7.86
• USES: USED AS
VENTRICULAR
ARRHYTHMIAS
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DRUGS
• NAME: TOCAINIDE
• IUPAC NAME: 2-amino-N-(2,6-
dimethylphenyl)propenamide
°C
• LOG P : 0.76
• USES :Ventricular
arrhythmias, such as
sustained ventricular
tachycardia
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DRUGS
• NAME: PROPAFENONE
• IUPAC NAME : 1-[2-[2-
hydroxy-3-
(propylamino)propoxy]phe
nyl]-3-phenylpropan-1-
one
• LOG P : 3.2
• PKA: 8.91
• USES: Paroxysmal atrial
fibrillation/flutter
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DRUGS
• NAME: MORICIZINE
• IUPAC NAME : ethyl N-[10-(3-
morpholin-4-
ylpropanoyl)phenothiazin-2-
yl]carbamate
• MELTING POINT : 156-157
°C
• USES:Used to treat irregular
heartbeats (arrhythmias) and
maintain a normal heart rate
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CLASS II- BETA BLOCKERS
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DRUGS
• NAME: SOTALOL
• N-[4-[1-hydroxy-2-(propan-2-
ylamino)ethyl]phenyl]methanesu
lfonamide
• MELTING POINT : 206.75 °C
• LOG P:0.24
• USES:Sotalol is indicated to
treat life threatening ventricular
arrhytmias and maintain normal
sinus rhythm in patients with
atrial fibrillation or flutter
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CLASS III- SODIUM AND POTASSIUM
CHANNEL BLOCKERS
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DRUGS
• NAM:PHENYTOIN
• IUPAC NAME : 5,5-
diphenylimidazolidine-2,4-
dione
• MELTING POINT: 295 °C
• LOG P: 2.47
• PkA : 8.33
• USES: Phenytoin is
indicated to treat grand
mal seizures
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DRUGS
• NAME: AMIODARONE
• (2-butyl-1-benzofuran-
3-yl)-[4-[2-
(diethylamino)ethoxy]-
3,5-
diiodophenyl]methanon
e
• LOG P : 7.2
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DRUGS
• NMAE: BRETYLIUM
TOSYLATE
• IUPAC NAME: (2-
bromophenyl)methyl-
ethyl-
dimethylazanium;4-
methylbenzenesulfona
te
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DRUGS
• NAME: VERAPAMIL
• IUPAC NAME:2-(3,4-
dimethoxyphenyl)-5-[2-(3,4-
dimethoxyphenyl)ethyl-
methylamino]-2-propan-2-
ylpentanenitrile
• SOLUBILITY : Insoluble in water
• LOG p: 3.79
• PKA: 8.92
• USES Verapamil is indicated in the
treatment of vasopastic (i.e.
Prinzmetal's) angina, unstable
angina, and chronic stable angina.
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DRUGS
• NAME: DILTIAZEM
• IUPAC NAME: [(2S,3S)-5-[2-
(dimethylamino)ethyl]-2-(4-
methoxyphenyl)-4-oxo-2,3-dihydro-
1,5-benzothiazepin-3-yl] acetate
• SOLUBILITY : Soluble in methanol
• LOG P: 2.8
• USES: Used as anti hypertensive
agent, chronic stable angina, rapid
conversion nof paroxysmal supra
ventricular tachycardias
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MECHANISM OF ACTION OF SODIUM CHANNEL
BLOCKERS
• Bind to and block sodium channels
• Act on initial rapid depolarisation
• Local anaesthetic : block nerve conduction
• Do not alter restign membrane potential
• At times, post repolarization refractoriness
• Bind preferentially to the open channel state
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Anti anginal drugs

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