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Cardiovascular System (CVS)

Cardiovascular Drugs
Drugs used for the treatment of cardiovascular diseases. C.V. diseases, are responsible
for about 15 % of all deaths in the U.S.A.
C.V. Diseases include heart diseases, diseases of blood vessels and lymphatics.
Drugs used for heart diseases include cardiotonics, antiarrhythmics,
antihypertensives and other types of drugs.
Drugs used for treatment of blood vessels & lymphatic diseases include The
vasodilators, antihypertensive agents & drugs for atherosclerosis in addition to
anticoagulants and other agents.
I. Drugs used for heart diseases
1. Cadiotonics
Are used in treatment of heart failure, atrial fibrillation and paroxysmal atrial
tachycardia to make action of cardiac excitability, automaticity, and conduction,
velocity & refractory periods.
In the treatment of tachyarrhythmia or acute ventricular failure, when prompt action
is necessary, the drugs of choice are Ouabain and Deslanoside, because they have a
rapid onset of action and can be administered i.v.
For less acute, chronic or stabilized cardiac failure the drugs usually prescribed are
digitalis leaf or digitoxin, which are given orally and exert longer duration. Digoxin,
by oral or i.v. route shows an intermediate action between these two groups.
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Classification of Cardiotonics
Cadiotonic Glycosides
Cardiotonic glycosides isolated from Digitalis Purprea and Digitalis Lanata
consisting of steroidal aglycone or genin attached to a sugar moiety.
Essential features for cardiotonic activity
a. An ,-unsaturated lactone at the 17 position
b. 14-OH
c. cis configuration between ring A and B and between C ad D.
d. The sugar moiety, although not essential but plays a key role in modulating the
activity of the glycoside.
Cardiotonic steroids chemically are divided into two main categories, butenolides
(cardenolides) and pentadienolides (bufadienolides)
Butenolides cardenolides
They contain ,-unsaturated lactone derived from 4-hydroxybutenoic
acid (a butenolide) linked to the 17 carbon of a 14 OH steroid.
Digitoxin (Crystodigin)
Uses
Treatment of congestive heart failure and
most supraventricular tachyarrhythmias. 3

Assay
Spectrophotometric
Digoxin (Lanoxin)
Most widely used digitalis glycoside in treatment
of congestive heart failure. Digoxin is considered
one active metabolite of digitoxine
Assay
Spectrophotometric.

Pentadienolides (Bufadienolides)
Contain diunsaturated lactone derived from 5-hydroxy
pentadienoic acid linked to 17 -carbon of a 14 -OH
steroids. e.g. acrihellin


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Mode of action
It is known that cardiac glycosides inhibit sodium and potassiumdependent ATPase,
also named transport ATPase. Inhibtion of this enzyme leads to unequal distribution
of Na+, and K+ across cell membranes and hence positive inotropic effects as a
consequence of increased in the level of activator Ca+.
Interaction is initiated by long-range
attraction between the lactone and site A.
This leads to a two-point attachment of the
lactone to the receptor. The steroid undergoes
a short-range interaction of the Van der
Waal and/or hydrophobic type with the
site B. This is reinforced by the
interaction above the molecule resulting
from a rearrangement of the receptor
cleft . The interaction of the sugar
residue with site C greatly increases
the stability of the complex, giving
it the property of pseudo-irreversibility.
SAR data indicate the presence of nucleophilic groups in sites A and C.
Rearrangement of the receptor cleft produces an allosteric effect that mediates
biological activity. 5

Miscellaneous synthetic cardiotonics


They include certain inhibitors of phosphodiesterase: amrinone lactate (Inocor),
sulmazole and theophylline (Quibron-T); some -adrenergic receptor stimulants:
alifedrine, heptaminol, methoxamine HCl and phenylephrine; as will as some
compounds with unknown mechanism like imazodan, quazinone.
Amrinone
Was introduced in 1978. It is used in treatment of severe
chronic congestive heart failure and in refractory acute
heart failure caused by myocardial infarction. It exerts
both positive inotropic effect and concentration
dependent vasodilator actions. In 2000, the name
of amrinone was changed to inamrinone
Sulmazole
Exerts both positive inotropic effect and vasodilator actions.
It is a candidate to replace older drugs
in treatment of congestive heart failure.


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Mode of action
The positive inotropic effect of amrinone and sulmazole is believed due to their
ability to inhibit the fraction III cardiac phosphodiesterase.
On the basis of the results obtained in a computer assited pharmacophore concluded
that: The basic structural features for positive inotropic action are hydrophobic area
and an electronegative region. Produced by pyridyl nitrogen or an amide system
capable of existing in a tautomeric form to stimulate an electronegative region, at a
distance of about 5 from the aromatic center and at a highest of 0.5 to 0.9 form its
plane.

Antiarrhythmics

What is arrhythmia

Causes of arryhthmia

Fail in function of the pace maker

cells located in the A-V and S-N

nodes.

Diseases like atherosclerosis,

hyperthyrodism, or lung diseases.

Ectopic arrhythmia


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Antiarrhythmic drugs
Antiarrhythmic drugs are drugs used to modify, or restore to normal, the abnormal
cardiac rhythm

Classification
Structurally specific drugs, which act by complexation with a receptor; example:
-blockers
Structurally non-specific drugs, which act by accumulation in certain regions

Membrane-stabilizing drugs
-adrenergic blocking agents
Drugs that prolong the action potential
Selective calcium antagonists
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Class Drug Primary pharmacologic Effect


IA Quinidine, Procainamide Decreases maximal rate of depolarization;
Disopramide increases duration of action potential

IB Lidocaine, Phenytoin Decreases maximal rate of depolarization;


Tocainide decreases duration of action potential

IC Flecainide, Encainide Decreases maximal rate of depolarization;


Propafenone, Moricizine no change duration of action potential

II Propranolol Inhibition of sympathetic activity

III Sotalol, Bretylium Prolongation of duration of action


Amiodarone potential

IV Verapamil, Diltiazem Inhibition of inward slow calcium current


Bepridil
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Class I antiarrhythmic drugs


Are generally local anesthetics acting on nerve and myocardial membranes to slow
conduction by inhibiting phase 0 of the action potential.
They decrease the maximal rate of depolarization without changing the
resting potential.
Class I is subdivided into class IA, IB and IC based on the primary
pharmacological effects.
Quinidine(Duraquin, Cardioquin sulfate)
Isomerization of quinine is presently
the largest source of quinidine.
Quinidine exerts both a direct action on
the cardiac membrane and indirect
(anticholinergic effect).
It is useful in supraventricular and
ventricular tachyarrhythmias. For long-
term therapy it is often preferred to
(6-Methoxyquinolin-4-yl)-
procaiamide.
(5-vinylquinuclidin-2-yl)-methanol
Assay Or (8a,9R )-6`-Methoxycinchonan-9-ol
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Non-aqueous titration with 0.1M perchloric

Procainamide HCl (Pronestyl)

4-Amino-N-[2-(diethylamino)ethyl]
benzamide monohydrochloride

Synthesis

Usese
Procaiamide is useful in supraventricular and severe tachyarrythmias.
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Also it is used in treatment of arrhythmias associated with alcohol withdrawal.


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Biotransformation
The major active metabolite is, N-acetylprocainamide. It is recently introduced in
therapeutics under the name of acecainide, has a longer half-life than the parent compound.
Assay
Titration with 0.1 M sodium nitrite
Lidocaine
Usese
It is the drug of choice for emergency treatment of
ventricular arrhythmias, due to the rapid onset of N-Diethylaminomethyl-2,
its action after i.v. administration. 6-dimethylbenzamide
The antiarrhythmic activity is not observed after
oral administration due to the rapid and efficient
first-pass metabolism by the liver. Hepatic
metabolism is rapid (plasma half life is about 15-30
min) and involves deethylation to yield
monoethylglyciexylide, followed by amidase-
catalyzed hydrolysis into N-ethylglycine and 2,6-
dimethylaniline. Monoethylglyciexylide has good
antiarrhythmic activity, but is not clinically useful,
because it undergoes rapid enzymatic hydrolysis. 13

Class II. Beta-Adrenergic Blocking Agents


Mode of action
block the role of sympathetic nervous system in the genesis of certain cardiac
arrhythmias. Their dominant electrophysiological effect is to depress adrenergically
enhanced calcium influx through -receptor blockade.
At higher dosed, these drugs may also exhibit anesthetic properties, which cause
decreased excitability, decreased conduction velocity and prolonged effective
refractory period. Propranolol is the prototype of this group.

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Class III
Mode of action
Causes a homogenous prolongation of the duration of the action potential. This
results in prolongation of the effective refractory period.
It is believed that most drugs of this class of compounds act by blocking
potassium channels.

Amiodarone
Amiodarone exerts antiadrenergic
effects and both antianginal and
antiarrhythmic actions. It is used in
treatment of refractory supraventricular (2-butyl-3-benzofuranyl){4-[2-(diethyl-amino)
ethoxy]-3,5-diiodophenyl}methanone
arrhythmias.
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Class IV
Mode of action
Selectively block the slow inward current carried by calcium. i.e. calcium
channel blockers.
It has been suggested that this inward current is involved in the genesis of
certain types of cardiac arrhythmias.
Verapamil is the prototype of this group of compounds.

Verapamil Diltiazem Nifedipine


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Antihypertensive Agents
Defenision
Hypertension a condition in which systolic blood pressure exceeds 160 mm Hg or
diastolic pressure exceeds 95 mm Hg.
Classification
Essential or primary hypertension, where the cause cannot clearly determined.
Essential hypertension affects about 10 % of the world population and constitutes
approximately 80% of the total cases of hypertension.
Secondary hypertension results from known causes. It may be divided into four
different forms: renal, neurogenic, endocrine and cardiovascular.
Renal hypertension

Angiotensin II by loss of aspartic acid gives angiotensin III (heptapeptide),


angiotensin III stimulates the release of aldosterone, the hormone involved in sodium
retention, which leads to increase in blood pressure.
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Neurogenic hypertension
Due to lesions of the vasomotor center leading to an increase in cerebrospinal fluid.
Endocrine hypertension
Results from endocrine disorders, such as pheochromocytoma.
Cardiovascular hypertension
Due to constriction of the aorta and usually is treated by surgery.
Treatment of hypertension
Approach for treatment of chronic hypertension include:
1. Oral diuretic (usually thiazide type) or -blocker as alternative, in special cases.
2. If needed, an antiadrenergic agent (reserpine, -blocker, labetalol,
methyldopa, clonidine or prazosin is added.
3. If needed, a vasodilator (hydralazine), or nifedipine or angiotensin-converting
enzyme inhibitor is added).
4. If needed, guanthidine or as alternative, an angiotensin converting enzyme
inhibitor (captopril, enalapril) or a calcium channel blocker (diltiazem, nifedipine,
verapamil).
5. In hypertensive crises, the most potent and effective agent is sodium
nitroprusside. Other alternatives are diazoxide, trimethaphan, hydralazine, for long-term
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control of blood pressure, phenoxybenzamine, prazosin, are used.


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Classification of antihypertensives
Antihypertensives could be classified into
Diuretics
Vasodilators
Sympathetic tone depressants
Angiotensin converting enzyme inhibitors
Calcium channel blockers
Miscellaneous agents
Sympathetic Depressant Agents
This class includes the following groups:
a- Agents which deplete Neurotransmitter stores
e.g.Reserpine and related compounds, Guanethedine and related compounds.
Guanethedine (Ismelin sulphate)
It produces a gradual, prolonged fall
in blood pressure; it has a slow onset
and prolonged duration of action
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only a single dose is required.

b-Selective- -Adrenergic Antagonists


Main use of these agents is treatment of catecholamine-dependant hypertension
Classic drugs like phentolamine and phenoxybenzamine are non-specific blocking
agents of both 1 and 2.
Specific antagonists of 1-receptors are effective antihypertensive agents.

Prazosin HCl (Hytrin)

The antihypertensive effect of prazosin is due to its peripheral vasodilatation as a


result of its blockade of 1-adrenergic receptors. 20


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c- Centrally acting adrenergic drugs


E.g. Azepoxide, clonidine hydrochloride, guanfacine hydrochloride, Lofexidine,
methyldopa, monoxidine and tolinidine.

Methyldopa (Aldomet)

Structurally related to L-dopa and the catecholamines.


To increase its water solubility for parenteral administration, the zwiterion
methyldopa is esterified and converted to the hydrochloride salt, methyldopate
ethyl ester hydrochloride.
Methyldopa is unstable in the presence of oxidizing agents, alkaline pH and light.
Metabisulfite/sulfite may be added to dosage formulation to prevent oxidation. 21

Mechanism of action
Antihypertensive effect of the prodrug methyldopa is not due to its inhibition of
norepinephrin biosynthesis, but rather to its metabolism in the CNS to -
methylnorepinephrin, which acts on 2-adrenergic receptors to inhibit the release of
norepinephrine, resulting in decrease in sympathetic outflow from the central nervous
system.

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Clonidine hydrochloride (Catapress)

Synthesis

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Mode of action
Acts by both peripheral and central mechanisms to affect blood pressure. It stimulates
the peripheral -adrenergic receptors to produce vasoconstriction, resulting in a brief
period of hypertension. It acts centrally to inhibit the sympathetic tone and cause
hypotension that is much more longer duration of action than the initial hypertension.

Metabolism
Clonidine hydrochloride is metabolized by the body to form two major metabolites,
P-hydroxyclonidine and its glucuronoide., P-hydroxyclonidine does not cross the
blood brain barrier and has no hypotensive effect in humans.

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Guanabenz Acetate

Mode of action
Guanabenz is a central 2-arenergic agonist that reduces the release of norepinephrine
from the neuron when stimulated.
Guanfacine Hydrochloride

Guanafacine HCl is structurally related to clonidine hydrochloride and


guanabenz acetate. It has longer duration of action than either clonidine HCl or
guanabenz acetate. 25

2-Vasodilatory Antihypertensives
Arterial Vasodilators
Very important and numerically expanding. e.g. diazoxide, hydralazine and minoxidil.

Minoxidil

It is direct acting peripheral vasodilator used for long-term therapy of patients with
hypertension unresponsive to standard therapy. It should be administered
concomitantly with a -blocker to control fluid retention, prevent tachycardia and
augment the response. It has shown some activity in alopecia. The mechanism is
unknown. Topical minoxidil is believed to increase cutaneous blood flow, which
may stimulate hair growth. Minioxidil requires metabolic conversion to produce
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antihypertensive effects. It is converted into minoxidil sulphate by sulfotransferase.


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Hydralazine Hydrochloride
Mode of action
The mechanism of action is unclear.
It interferes with Ca++ entry and
Ca++ release from intracellular
stores
It has been reported to cause activation of guanylate cyclase, resulting in increases
levels of cGMP leading to vasodilatation.
Metabolism
Mainly benzylic oxidation, glucuronoid formation followed by N-acetylatio

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Diazoxide

Sodium, 7-Chloro3-methyl-2H-1,2,4benzothiadiazine-1,1-dioxide

It is the des-sulfamoyl analogue of the benzothiazine diuretics and has a closed


structural similarity to chlorothiazide.
It is used by i.v. route as a rapidly acting antihypertensive agent in emergency
lowering of blood pressure in hospitalized patients.
The injection has a pH of 11.5, which is necessary to convert the drug to its
soluble sodium salt. 28


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b- Arterial and venous vasodilators


Sodium nitroprusside (Sodium nitroferricyanide), Nipride

Pentakis (Cyano-C) nitrosylferrate (2-) Disodium dihydrate

Drug of choice for treatment of most hypertensive crises requiring parenteral


therapy. It is used to control hypertension during surgery and in congestive heart
failure.

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Metabolism
It is converted by erythrocytes to cyanide, which is then catalytically metabolized in the liver
by rhodanese to thiocyanate and slowly excreted in the urine. It should be protected from light
and not be used more than 4 hr after preparation.
Assay
By titration with 0.1M AgNO3
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3-Drugs Acting Through the Renin-Angiotensin System


The rennin-angiotensin system is a hormonal system that plays a central role in
the control of sodium excretion and body fluid volume. It interacts closely with
the sympathetic nervous system and aldosterone secretion in the regulation of
blood pressure.
ACE is a membrane bound enzyme anchored to the cell membrane. The enzyme
is a zinc containing glycoprotein with a molecular weight about 130,000.
ACE inhibitors are used in treatment of mild to moderate essential and renal
hypertension especially when plasma rennin activity is high.
The important binding points at the active site of ACE are thought to be an
arginine residue, which provides a cationic site that attracts a carboxylate ion, and
a zinc ion, which can polarize a carbonyl group of an amide function to make it
more susceptible to hydrolysis.

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a- Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors)


ACE inhibitors could be classified according to their chemistry into three categories:
I-Sulfhydryl Containing ACE Inhibitors
II-Dicarboxylate containing Inhibitors
III-Phosphate containing ACE Inhibitor

I-Sulfhydryl Containing ACE Inhibitors


Captopril (Capoten)
First orally active inhibitor of angiotensin I converting
enzyme (ACE), the enzyme that is responsible for conversion
Captopril is used in treatment of essential and renovascular
hypertension.
It should be given concomitantly with a thiazide (S)-1-(3-Mercapto-2-methyl
diuretic. -1-oxopropyl)-L -proline
Sulfhydryl group of captopril is proved to be responsible for
ACE inhibition activity and the most common two side
effects, skin rashes and taste disturbances (metallic taste and
loss of taste). 32


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II-Dicarboxylate containing Inhibitors


Enalapril Maleate (Vasotec).

(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-1-alanyl]-L-proline

Two carboxylate groups and the secondary amine are responsible for its overall
low lipophilicity and poor oral bioavailability.
Zwitterion formation has been suggested to contribute to the low oral activity.
Esterification of enalaprilate produced enalapril with good oral bioavailability.

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Benazepril Hydrochloride

[(3S)-3-({(1S)-1-[(ethyloxy)carbonyl]-3-phenylpropyl}amino)
-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid

Metabolized rapidly to the active diacid benazeprilate

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III-Phosphate containing ACE Inhibitor


Also lack the sulfhydryl group. The phosphinic acid is capable of binding to ACE
in a manner similar to enalapril. The interaction of the zinc atom with the
phosphinic acid is similar to that seen with sulfhydryl and carboxylate groups.
Similar to the dicarboxylate, fosinoprilate was too hydrophilic and exhibited poor
oral bioavailability.
Fosinopril
Fosinopril is aprodrug contains an (acyloxy) alkyl group, which allows for better
lipid solubility and improved bioavailability. Bioactivation by esterases in the liver
and intestinal wall produces fosinoprilate.

Fosinopril Fosinoprilate
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SAR of ACE Inhibitors

1. The N-ring must contain a carboxylic acid to mimic the C-terminal carboxylate of
ACE inhibitors.
2. Large hydrophobic heterocyclic rings in the N-ring increase potency and alter
pharmacokinetic parameters.
3. Groups A,B or C can serve as zinc binding groups.
4. The SH group shows superior binding to zinc (Ph in carboxylate and phosphinic
acid side chain compensates for SH group). 36


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5. SH containing compounds produce high incidence of skin rash and taste


disturbrnces and can form disulfides, which may shorten duration of action.
6. Esterification of the carboxylate or phosphinates produces an orally bioavailable
prodrugs.
7. X- is usually methyl to mimic the side chain of alanine. When X equals n-
butylamine (lysine side chain), this produces a compound, which is orally active
without being a prodrug.
8. Optimal activity occurs when stereochemistry of inhibitor is consistent with l-amino
acid stereochemistry 37

b- Angiotensin II Receptor Antagonists


Inhibition of angiotensin II produce a vasodilatory effect can be accomplished by
administration of the competitive antagonist.
Saralasine, an octapetide that differs from angiotensin by two amino acids.
Saralasine is not a pure competitive antagonist, but it is a partial agonist.
It is effective only in patients with rennin-dependent form of hypertension. It is use
is limited because it may be administered. i.v. and has a short duration of action
Losartan

Orally active non-peptidic antihypertensive acting through high affinity to


angiotensin II receptors.
Losartin does not inhibit angiotensin-converting enzyme, avoiding the side effects of
ACE inhibitors.
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SAR of angiotensin II Inhibitors


All the commercially available angiotemsin II antagonists are analogues of the
following general structure:

In the biphenyl series, the tetrazole and carboxylate groups must be in the ortho
position for optimal activity. The n-butyl group of the model compound provides
hydrophobic binding.

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