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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
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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
nodes.
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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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
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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.
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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
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.
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Methyldopa (Aldomet)
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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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
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
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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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(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
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Fosinopril Fosinoprilate
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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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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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