Description
BP501T. MEDICINAL CHEMISTRY — II (Theory)
UNIT- III Notes
Author Details
SP PANDEY
Assistant Professor
Department of Pharmaceutical Chemistry, Knimt Faculty of Pharmacy
Sultanpur.
Course Content:
UNIT- III
10 Hours
Study of the development of the following classes of drugs, Classification, mechanism of action,
uses of drugs mentioned in the course, Structure activity relationship of selective class of
drugs as specified in the course and synthesis of drugs superscripted (*)
Anti-arrhythmic Drugs:
Quinidine sulphate, Procainamide hydrochloride, Disopyramide phosphate*, Phenytoin sodium,
Lidocaine hydrochloride, Tocainide hydrochloride, Mexiletine hydrochloride, Lorcainide
hydrochloride, Amiodarone, Sotalol.
Anti-hyperlipidemic agents:
Clofibrate, Lovastatin, Cholesteramine and Cholestipol
Coagulant & Anticoagulants:
Menadione, Acetomenadione, Warfarin*, Anisindione, clopidogrel
Drugs used in Congestive Heart Failure:
Digoxin, Digitoxin, Nesiritide, Bosentan, Tezosentan.
1
ANTI-ARRHYTHMIC DRUGS
Introduction
Cardiac arrhythmias remain a major source of morbidity and mortality in developed
countries. Cardiac arrhythmia is a disturbance in the conduction of impulse
through the myocardial tissue. These cardiac arrhythmias may be caused from disorders
in pacemaker function of the sinoatrial node thereby resulting into tachycardia,
bradycardia, cardiac arrest, atrial flutter, atrial fibrillation and ventricular
fibrillation. Hence, the antiarrhythmic agents are also termed as ‘antidysrhythmic drugs’ or
‘antifibrillatory drugs’.
Antiarrythmic drugs (AADs) may be defined as the “drugs that are capable of reverting any
irregular cardiac rhythm or rate to normal”.
Development
During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia
mechanisms has increased significantly, resulting in the identification of new
potential targets for mechanism-based antiarrhythmic therapy. However, antiarrhythmic drug
development has remained slow, despite much effort given our limited understanding of
what role various ionic currents play in arrhythmogenesis and how they are modified by
arrhythmias. Multichannel blockade, atrial selectivity, and the reduction of the risk of adverse
events have all constituted the main theme of modern atrial fibrillation (AF) drug development.
The increasing appreciation of ventricular arrhythmias as a marker of underlying heart disease
and, therefore, a potential drug target, led to the development of multiple new
antiarrhythmic drugs in the late 1970’s and early 1980’s. Most currently available AADs
have been derived from naturally available compounds (e.g., quinidine adapted from a
compound from the bark of the cinchona tree) or were originally developed for other purposes
(e.g., amiodarone and sotalol were initially developed for the treatment of angina). The multiple
electrophysiological effects of each of these compounds make mechanism-based therapy difficult.
Classification
The anti-arrhythmic drugs are categorized according to the Vaughan-Williams (VW)
classification system. The VW classification anti-arrhythmic drugs are divided into four
main categories based on their dominant electrophysiological properties. Recently it is being
updated to more subcategories. They are as follows:
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Table 1. Updated classification of anti-arrhythmic drugs.
HCN channel blockers
0 – Ivabradine
Voltage-gated Na+ channel blockers
la
I 1b
1c
Id
Ha IIb
II IIc
IId He
IIIa
III IIIb IIIc
IVa
IV
IVb
V VI
VII
Quinidine, ajmaline, disopyramide Lidocaine, mexiletine, phenytoin sodium Propafenone, flecainide
Ranolazine
Autonomic inhibitors and activators
Nonselective b inhibitors: carvedilol, propranolol
Selective b1-adrenergic receptor inhibitors: atenolol, esmolol, metoprolol Isoproterenol
Atropine, anisodamine, scopolamine Carbachol, pilocarpine, methacholine, Adenosine, aminophylline
K+ channel blockers and openers
Nonselective K“ channel blockers: Ambasilide, amiodarone, dronedarone Selective K+ channel
blockers: Dofetilide, sotalol, vernakalant, tedisamil Nicorandil, pinacidil
BMS 914392
Ca2“ handling modulators
Nonselective Ca²“ channel blockers: Bepridil Selective Ca²“ channel blockers: Verapamil, diltiazem
Intracellular Ca²“ channel blockers: Flecainide, propafenone Mechanosensitive channel blockers
N-(p-amylcinnamoyl)anthranilic acid
Gap junction channel blockers
Carbenoxolone
Upstream target modulators
Angiotensin-converting enzyme inhibitors: Captopril, enalapril, imidapril Angiotensin receptor
blockers: Losartan, candesartan, telmisartan
Omega-3 fatty acids: eicosapentaenoic acid, docosahexaenoic acid Statins: Atorvastatin, lovastatin
3
Quinidine sulphate
• Quinidine is a class la (voltage-gated Na+ channel blockers) anti-arrhythmic drug.
• It is a member of a family of alkaloids found in Cinchona bark (Cinchona officinalis L.).
• It is the dextrorotatory diastereomer of quinine.
• Quinidine and quinine are structurally similarity, but differ in their effects on the cardiac
muscles, with the effects of quinidine being much more pronounced.
• The structure contains two basic nitrogens, of which the quinuclidine nitrogen is stronger
base (pea = 10).
• Because of the basic character of quinidine, it is always used as water -soluble salt forms.
These salts include quinidine sulfate, gluconate, and polygalacturonate.
• The gluconate salt is particularly suited for parenteral use because of its high water
solubility and lower irritant potential.
Mechanism of action
• Quinidine is a membrane stabilizing agent. It interferes directly with depolarization of the
cardiac membrane.
• Quinidine binds with the voltage-gated sodium channels and inhibits the sodium
influx required for the initiation and conduction of impulses.
• This results in an increase of the threshold for excitation and decreased
depolarization during phase 0 of the action potential.
• In addition, the effective refractory period (ERP), action potential duration
(APD), and ERP/APD ratios are increased, resulting in decreased conduction velocity
of nerve impulses in the myocardium.
Uses
Quinidine should be used only after alternative measures have been found to be inadequate.
• Quinidine is used to treat and prevent atrial fibrillation or flutter and ventricular
arrhythmias.
• Quinidine is also used to treat short QT syndrome.
• Quinidine is an intra-erythrocytic schizonticide, used to treat malaria.
Procainamide hydrochloride
• Procainamide is a class 1a (voltage-gated Na+ channel blockers) anti-arrhythmic drug.
4
• It is the amide bio- isostere of local anesthetic procaine.
• Because of its amide structure, procainamide is more resistant to both enzymatic and
chemical hydrolysis. It is orally active.
Mechanism of action
• Procainamide hydrochloride has mechanism of action similar to that of quinidine.
• Due to its charged and hydrophilic form, procainamide has its effect from the
internal side, where it causes blockage of voltage-dependent, open channels.
• It reversibly binds to and blocks activated (open) voltage-gated sodium channels, thereby
block the influx of sodium ions into the cell, which leads to an increase in threshold for
excitation and inhibit depolarization during phase 0 of the action potential.
• The lasting action potential may also be due to blockage of outward K+ currents.
• The result is a decrease in automaticity, increase in refractory period and slowing
of impulse conduction.
Uses
• Procainamide hydrochloride is used to suppress ventricular extrasystoles and paroxysmal
ventricular tachycardia.
• It is also useful in the control and management of atrial fibrillation and premature atrial
contractions.
• It has been also been used as a chromatography resin because it somewhat binds protein.
Disopyramide phosphate*
• Disopyramide phosphate is a Type 1a anti-arrhythmic drug. O N
• It is marketed as a racemic mixture H2N
N
. H3 04
IUPAC name:
• 4-Diisopropylamino-2-pheny1-2-(2-pyridyl) butyramide phosphate
• 4-[di(propan-2-yl) amino]-2-phenyl-2-pyridin-2-y1butanamide; phosphoric acid.
Mechanism of action
• Disopyramide phosphate has similar mechanism of action like procainamide and
quinidine.
5
• It targets sodium channels to inhibit conduction.
• It decreases the rate of diastolic depolarization (phase 4) in cells with
augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action
potential duration of normal cardiac cells, decreases the disparity in
refractoriness between infracted and adjacent normally perfused myocardium.
• Disopyramide also has an anticholinergic effect on the heart which accounts for
many adverse side effects.
Synthesis
CN ” ‘
N CI
NaNHz
NC
i. (iPr)zNCHzCHzCI
N
NC CH CH N(iPr)
N
Benzyl cyanide
2-ChIoropyridine
Phenyl-(2-pyridyI)acetonitrile
Uses
• It is used orally as a prophylaxis of either unifocal or multifocal premature
ventricular contractions and ventricular tachycardia.
• It also exhibits both anticholinergic and local anesthetic properties.
Phenytoin sodium
4-DiisopropyIamino-2-phenyI- (2-pyridyI)butyronitriIe
i. Conc. HzSO‹
ii. H POS
HzNOC GH2GH2N(iP#)2
N .H PO,
Disopyramide phosphate
• Phenytoin sodium is the sodium salt form of phenytoin, a hydantoin derivate.
• It is a Type Ib anti-arrhythmic drug.
Mechanism of action
• Phenytoin sodium targets the voltage gated sodium channels in cardiac myocyte and purkinje
fibre cell membranes.
• Phenytoin binds preferentially to the inactive form of the sodium channel.
• Because it takes time for the bound drug to dissociate from the inactive channel, there is a
time dependent block of the channel.
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• Since the fraction of inactive channels is increased by membrane depolarization as
well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce
voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials.
• It reduces the maximum rate of depolarisation of the cardiac action potential
and increases the effective refractory period.
• Therefore, it is particularly effective in inhibiting ventricular ectopy, especially
in an ischaemic or damaged myocardium.
Uses
• Phenytoin sodium is a potential option for patients with refractory ventricular arrhythmia
when other agents are contraindicated or unavailable.
Lidocaine hydrochloride
• Lignocaine is an amino amide class of drug also known as lidocaine.
• It is a class- lb antiarrhythmic drug.
Mechanism of action
• Lignocaine’s cardiac effects, however, are distinctly different from those of procainamide
or quinidine.
• It binds with equal affinity to both active and inactive sodium channels.
• It depresses diastolic depolarization and automaticity (depress Na+ influx during
the diastole) in the Purkinje fibre network and increases the functional refractory
period relative to action potential duration.
• It does not decrease the conduction velocity and increase membrane responsiveness
to stimulation.
Uses
Lidocaine hydrochloride is administered intravenously in the acute management of
• Ventricular arrhythmias occurring during digitalis toxicity, cardiac surgery, or cardiac
catheterization.
• Life-threatening arrhythmias, particularly those which are ventricular in origin, such as
those which occur during acute myocardial infarction.
7
Tocainide hydrochloride
• Tocainide Hydrochloride is the hydrochloride salt form of tocainide.
• It is a primary amine analog of lidocaine exhibiting class lb antiarrhythmic property.
• It is an o-methyl analogue structurally related to monoethylglycinexylide, the active
metabolite of lidocaine.
• The o-methyl group slows the rate of metabolism and, thereby, to contribute to oral activity.
Mechanism of action
• Tocainide hydrochloride stabilizes the neuronal membrane by reversibly binding to and
blocking open and inactivated voltage-gated sodium channels.
• This inhibits the inward sodium current required for the initiation and conduction of
impulses and reduces the excitability of myocardial cells.
• This agent reduces the rate of rise and amplitude, and shortens the action-potential duration
(APD) in both the Purkinje and muscle fibers.
• Tocainide also shortens the effective refractory period (ERP) of Purkinje fibers resulting in
an increased the ERP/APD ratio.
• Overall these effects lead to the slowing of nerve impulses and stabilization of the
heartbeat.
Uses
• It is used in ventricular arrhythmias, such as sustained ventricular tachycardia, that, in
the judgment of the physician, are life-threatening.
Mexiletine hydrochloride
• Mexiletine hydrochloride is a class 1b anti-arrhythmic drug.
• It has a xylyl group like lidocaine in its structure.
• Chemically it is an ether, so it is comparatively resistant to hydrolysis during
metabolism.
Mechanism of action
• Mexiletine hydrochloride works as a non-selective voltage-gated sodium channel blocker.
Mexiletine, like lidocaine, inhibits the inward sodium current required for the
initiation and conduction of impulses, thus reducing the rate of rise of the action potential,
Phase 0.
• It achieves this reduced sodium current by inhibiting sodium channels.
• Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers in the heart.
The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD),
which results in an increase in the ERP/APD ratio.
• It does not significantly affect resting membrane potential or sinus node automaticity, left
ventricular function, systolic arterial blood pressure, atrioventricular (AV) conduction
velocity, or QRS or QT intervals.
Uses
• It is used for the treatment of ventricular tachycardia and symptomatic
premature ventricular beats, and prevention of ventricular fibrillation.
• It is used to treat muscle stiffness resulting from myotonic dystrophy (Steinert’s
disease) or nondystrophic myotonias such as myotonia congenita (Thomsen syndrome or Becker
syndrome).
Lorcainide hydrochloride
• Lorcainide hydrochloride is a Class 1c antiarrhythmic agent.
• It is a member of acetamides.
Mechanism of action
• Lorcainide hydrochloride targets Voltage-gated Na“ channel blockers in the inactivated state.
This leads to marked block of open Na channels (decreases Phase 0).
• It has little effect on the repolarization phase and increases the PR and QRS interval.
• It decreases automaticity, conduction in depolarized cells.
• It decreases the rate of change of the depolarization phage of the action potential.
Uses
• It is used to help restore normal heart rhythm and conduction in patients with premature
ventricular contractions, ventricular tachycardiac and Wolff-Parkinson-White syndrome.
• It is very effective particularly during chronic therapy perhaps due to its inherent high
first-pass metabolism orally.
Amiodarone
• Amiodarone is a class IIIa antiarrhythmic drug.
• Chemically it is a benzofuran derivative.
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• The molecular structure of amiodarone has some similarities with iodothyronines.
Mechanism of action
• Amiodarone is a nonselective K“ channel blockers.
• It works primarily by blocking potassium rectifier currents that are responsible for the
repolarization of the heart during phase 3 of the cardiac action potential.
• This potassium channel-blocking effect results in increased action potential duration and a
prolonged effective refractory period in cardiac myocytes.
• Myocyte excitability is decreased, preventing reentry mechanisms and ectopic foci from
perpetuating tachyarrhythmias.
• Electrocardiographic evidence of these effects is evident as prolongation of the QRS
duration and QT interval.
• Unlike other class III agents, amiodarone also interferes with beta-adrenergic receptors,
calcium channels, and sodium channels.
Uses
• Amiodarone is one of the most commonly used and prescribed antiarrhythmic drugs.
• It is frequently employed in the control and management of ventricular and supraventricular
arrhythmias, and also in the treatment of angina pectoris.
Sotalol.
• Sotalol is a class IIIa antiarrhythmic drug.
• It has effects that are related to class II drugs.
• Chemically it is a sulfonamide that is N-phenylmethanesulfonamide.
• It contains a chiral centre and marketed as the racemic mixture.
Mechanism of action
• The levo enantiomer of satolol has both Q-blocking (class II) and potassium channel blocking
(class III) activities. The dextro enantiomer has class III properties.
• Sotalol is a nonselective beta-adrenergic receptor and competitive inhibitor of the rapid
potassium channel potassium channel.
• In the heart, this agent inhibits chronotropic and inotropic effects thereby slowing the
heart rate and decreasing myocardial contractility.
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• This agent also reduces sinus rate, slows conduction in the atria and in the atrioventricular
(AV) node and increases the functional refractory period of the AV node.
Uses
• Sotalol is used to treat life threatening ventricular arrhytmias and maintain normal
sinus rhythm in patients with atrial fibrillation or flutter.
• Due to the risk of serious side effects, the FDA states that sotalol should
generally be reserved for patients whose ventricular arrhythmias are
life-threatening, or whose fibrillation/flutter cannot be resolved using simple methods.
ANTI-HYPERLIPIDEMIC AGENTS
Introduction
The major lipids found in the bloodstream are cholesterol, cholesterol
esters, triglycerides, and phospholipids. An excess plasma concentration of one or more
of these compounds is known as hyperlipidemia. This disease is usually chronic and requires
continuous medication to control blood lipid levels. Hyperlipidemias are classified according to
which types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or
both in combined hyperlipidemia. Hyperlipoproteinemia has been strongly associated with
atherosclerotic lesions and coronary heart disease (CHD).
Antihyperlipidemic agents promote reduction of lipid levels in the blood. Some
antihyperlipidemic agents aim to lower the levels of low-density lipoprotein (LDL)
cholesterol, some reduce triglyceride levels, and some help raise the high-density
lipoprotein (HDL) cholesterol.
Classification of antihyperlipidemic agents
• Hydroxymethylglutaryl-CoA (HMGCoA) reductase inhibitors Ex. Statins (Atrovastatin,
lovastatin, Metastatin, Pravastatin, Fluvastatin)
• Phenoxyisobutyric acid derivatives Ex. Fibrates (Clofibrates, Gemfibrozil)
• Pyridine derivatives Ex. Nicotinic acid, Nicotinamide
• Bile acid sequestrans Ex. Cholestyramine, Colestipol
• Cholesterol absorption inhibitors Ex. Ezetimibe
• LDL oxidation inhibitors Ex. Probucol
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Ex. Alirocumab
11
• Miscellaneous Antihyperlipidemic Agents Ex. b-Sitostero1, Dextrothyroxine
Strateqy for Controllinq Hyperlipidemia
STATINS
Diet
Ezetimibe
Biosynthesis
Cellular Cholesterol
bile Acids
Intestine
Feces
Re-absorption
BILE ACID
SEQUESTRANTS
Lipoprotein cotobolism
Conversion to hormones within cells or storage as granules
FIBRATES
Figure 1. Mechanism of actions of antihyperlipidemic agents.
Clofibrate (CLOF)
• Clofibrate is an ester of phenoxyisobutyric acid (fibric acid).
• It is regarded as a broad spectrum lipid lowering drug.
• It is a prodrug, metabolized to chlorophenoxyisobutyric acid (CPIB) which is the active form
of the drug.
Mechanism of action
• Clofibrate increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing
lipoprotein triglyceride lipolysis.
• Chylomicrons are degraded, VLDLs (Very low density lipoprotein) are converted to LDLs, and
LDLs are converted to HDL.
• This is accompanied by a slight increase in secretion of lipids into the bile and ultimately
the intestine.
• Clofibrate also inhibits the synthesis and increases the clearance of apolipoprotein B, a
carrier molecule for VLDL.
12
• Also, as a fibrate, clofibrate is an agonist of the PPAR-e receptor
(peroxisome proliferator-activated receptor alpha) in muscle, liver, and other tissues.
• This agonism ultimately leads to modification in gene expression resulting in
increased beta-oxidation, decreased triglyceride secretion, increased HDL, and
increased lipoprotein lipase activity.
Uses
• It is used as an anticholesteremic agents or antilipemic agents.
• It is also used to treat xanthoma tuberosum and type III hyperlipidemia that doesn’t respond
adequately to diet.
• Clofibrate was discontinued in 2002 due to adverse effects.
Lovastatin
• Lovastatin is a fungal polyketide derived synthetically from a fermentation product of
Aspergillus terreus.
• It is a prodrug.
• The inactive gamma-lactone closed ring form is hydrolysed in vivo to the active §- hydroxy
acid open ring form.
• Lovastatin was the first specific inhibitor of HMG CoA reductase to receive approval for the
treatment of hypercholesterolemia.
Mechanism of action
• Lovastatin is a potent competitive reversible inhibitors of HMG-CoA reductase.
• HMH-CoA reductase enzyme is required for mevalonate synthesis which an important
building blocks in cholesterol biosynthesis.
• Lovastatin acts primarily in the liver, where decreased hepatic cholesterol
concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL)
receptors which increase hepatic uptake of LDL.
• Lovastatin also inhibits hepatic synthesis of very low density lipoprotein(VLDL).
• The overall effect is a decrease in plasma LDL and VLDL and a significant reduction in the
risk of development of CVD and all-cause mortality.
13
Uses
• Lovastatin is used to reduce the risk of myocardial infarction, unstable angina,
and the need for coronary revascularization procedures in individuals without
symptomatic cardiovascular disease
• Lovastatin is also used to slow the progression of coronary atherosclerosis in
patients with coronary heart disease.
Cholesteramine
• Cholestyramine or colestyramine is a bile acid sequestrant.
• Cholesteramine is the chloride form a highly basic anion exchange resin.
• It is a styrene copolymer with divinylbenzene with quaternary ammonium groups.
• Cholestyramine resin is quite hydrophilic, but insoluble in water.
Mechanism of action
• Cholestyramine limits the reabsorption of bile acids in the gastrointestinal tract.
• Cholestyramine resin is a strong anion exchange resin, allowing it to exchange its chloride
anions with anionic bile acids present in the gastrointestinal tract.
• Forms an insoluble complex resin matrix in the intestine which is excreted in the feces.
• This results in a partial removal of bile acids from the enterohepatic circulation by
preventing their absorption.
Uses
• Cholestyramine is used to lower high levels of cholesterol in the blood, especially LDL.
• Cholestyramine powder is also used to treat itching caused by a blockage in the bile ducts of
the gallbladder.
Cholestipol
• Colestipol is a bile acid sequestrant.
• It is an anion exchange resin.
• It is hydrophilic, but it is water-insoluble (99.75%).
Mechanism of action
• Colestipol is a water insoluble and high molecular weight polymer.
• It binds with bile acids to forms complex in the intestine.
14
• This complex cannot be reabsorbed due to its high molecular weight and low solubility and
ultimately excreted in the feces.
• This increased fecal loss of bile acids due to colestipol interrupt the enterohepatic
circulation of bile acids. Hence, cholesterol conversion to bile acids is enhanced.
• This results in an increased uptake of LDL and a decrease in serum/plasma beta lipoprotein or
total and LDL cholesterol levels.
Uses
• Colestipol is indicated as adjunctive therapy to diet for the reduction of elevated
serum total and low-density lipoprotein cholesterol (LDL-C) in patients with
primary hypercholesterolemia who do not respond adequately to dietary changes.
COAGULANT & ANTICOAGULANTS
Blood must remain fluid within the vessels and yet clot quickly when exposed to
subendothelial surfaces at sites of vascular injury. Under normal circumstances, a
delicate balance between coagulation and fibrinolysis prevents both thrombosis and
hemorrhage. Alteration of this balance in favor of coagulation results in thrombosis.
Blood Coagulation
It is a complex process of enzymatic reactions in which clotting factors activate other clotting
factors in a fixed sequence until a clot is formed. It depends on the existence of
a complex system of reactions involving plasma proteins, platelets, tissue factors and
calcium ion. The coagulation process can be activated and proceed through one of
two possible sequential pathways:
• Intrinsic system path: components present within the circulating blood,
• Extrinsic system: components present in the extravascular and
intravascular compartment.
Cooperative integration of these two systems, along with circulating platelets, maintains
vascular integrity and preserves hemostasis.
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Blood clo i g mechanism Three stages H Vascular spasm
Platelets plug formation Coagulation
Stages of blood clotting
liljttred tissue
,neleases
(i)
Ca+’ roteins
(ii)
D Formation of prothrombinase:
l. Intrinsic pathway
2. Extrinsic pathway
R Prothrombine —> Thrombine (enzyme) Fibrinogen (soluble) Fibrin (insoluble)
Blood platelets
$Disiittegrate aitcf release
Platelet factor – 3 (= Platelet thromboplastin)
Ca++ proteins
Prothrombin
Fibrinogeii
In.ictivates heparin and catalyses
Thrombin
(iii) q catalyses
Fibrin +B1ood c ells
Figure 2. Stages and mechanism of blood clotting.
Bleeding disorders or hemorrhages like Haemophilia, Von willibrands result when the blood
lacks certain clotting factors. A variety of pathological and toxicological condi tions can
result in excessive bleeding from inadequate coagulation. Depending on the etiology and severity
of the hemorrhagic episode, several possible blood coagulation inducers can be
therapeutically employed.
Coagulants
Coagulants are substances which promote coagulation indicated in hemorrhagic states like
Haemophi1ia,Von willibrands disease, etc.
16
Classification of anticoagulants
Vitamin K KI (from p\ants fat-sDILIbIe): Phytonadione
(Phylloquinone)
K3 (synthetic)
— Fat-solub Ie:
— Water—soluble:
Menadlone,
Acetomenaphthone
Menadione sod. Bisulfite, Menadione, sod. Diphosphate
Misceilaneous
F ibrinogen (human), Anti hae vophillc factor, Desmopressin, Adrenochrome monosemicarbazone, Ruti
n, E thamsylate
Menadione
• Menadione is a synthetic naphthoquinone (analog of 1,4-naphthoquinone).
• It is also called as vitamin Ks.
• It is a prothrombin activator.
Mechanism of action
• Menadione (Vitamin Ks) is a fat-soluble vitamin precursor that is converted into
active menaquinone (vitamin K2) after alkylation in the liver.
• It acts as a cofactor in the synthesis of coagulation proteins; prothrombin, factors VII, IX,
and X by liver.
• Vitamin K helps in gama-carboxylation of these clotting factors where their descarboxy-
forms get converted in to active forms.
• Now this active form of clotting factors have the capacity to bind with Ca²+ and
to get bound to the phospholipid surfaces which are essential properties for participation in
the coagulation process.
Vitamin K1 (Phylloquinone) Vitamin K2 (Menaquinone) Vitamin K3 (Menadione)
17
Uses
• It is used in the treatment of hypoprothrombinemia.
• It may also play a role in normal bone calcification.
Acetomenadione
• Acetomenadione is a member of naphthalenes.
• It is a synthetic vitamin.
• It is also known as davitamon-K or acetomenaphthone.
• Acetomenaphthone is an extremely weak basic
Mechanism of action
Refer the mechanism of action of menadione.
Uses
Acetomenadione is used for the treatment, control, prevention, & improvement of the following
diseases, conditions and symptoms:
• Coagulation disorders due to vitamin K deficiency
• Anticoagulant-induced prothrombin deficiency
Anticoagulants
Drugs that interfere with blood coagulation (anticoagulants) are known as anticoagulants. They
are the mainstay of cardiovascular therapy. Anticoagulants eliminate or reduce the risk of blood
clots. They’re often called blood thinners, but these medications don’t really thin
your blood. Instead, they help prevent or break up dangerous blood clots that form in
your blood vessels or heart.
Classification
1. Used in vivo
a. Parenteral anticoagulants
i. Indirect thrombin inhibitors Ex. Heparin, Danaparoid, Fondaparinux
ii. Direct thrombin inhibitors Ex. Lepirudin, Bivalirudin, Argatroban
b. Oral anticoagulants
i. Coumarin derivatives Ex. Warfarin, Bishydroxycoumarin, Acenocoumarol
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2. Used in vitro
i. Indanedione derivatives Ex. Phenindione
ii. Direct factor Xa inhibitors Ex. Rivaroxaban
iii. Ora1 direct thrombin inhibitors Ex. Dabigatran,
Warfarin
Heparin
Calcium complexing agents
i. Oxalate compounds Ex. Calcium oxalate
ii. Citrate compounds Ex. Sodium citrate
OH
• Warfarin is a synthetic anticoagulant.
• IUPAC Name. 4-hydrox j -3-(3-oxo-1-phenylbutyl )chromen-2-one.
• The name warfarin came from its discovery at the, WARF (Wisconsin Alumni Research Foundation)
and the ending -arin, indicates its link with coumarin.
• Warfarin exists in tautomeric form.
• Hemiketal must tautomerise to the 4-hydroxy form in order for warfarin to be active.
• Warfarin contains a stereocenter and consists of two enantiomers. This is a racemate.
• Anticoagulant activity of S-warfarin is 2-5 times more than the R-isomer.
Mechanism of action
I lp»m chuii i
• Warfarin acts by antagonizing vitamin K and reduction of the factors involved directly or
indirectly in blood clotting.
• Warfarin inhibits vitamin K reductase enzyme, which results in decrease amount of reduced
form of vitamin K.
• Reduction in vitamin K (reduced) lowers down the glutamate residues carboxylation in the
N-terminal regions of coagulant proteins.
19
• This inhibits the synthesis of vitamin K-dependent coagulation factors (factors II, VII, IX,
and X) and anticoagulant proteins (regulatory factors) C and S by the liver.
• Decrease in the coagulation factors causes lowering in the prothrombin levels.
• Reduce prothrombin affects production of thrombin and fibrin bound thrombin,which ultimately
reduces blood clotting.
Precursor-mooting
Warfarin
Vitamin K(Reduced)
Warfarin
Active-Hooting protein
Vitamin K(Oxidized)
Vitamin K Reductase
Figure 2. Mechanism of action of warfarin.
Synthesis
OH
4-Hydroxycoumarin Benzalacetone
Warfarin
Pyridine
OH
Racemic Warfarin
Base/acid catalysed Michael condensation reaction of 4-hydroxycoumarin with benzalacetone.
Pyridine is usually used as the catalyst for this reaction to afford racemic warfarin.
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Uses
• Prophylaxis and treatment of venous thromboembolism and related pulmonary embolism.
• Prophylaxis and treatment of thromboembolism associated with atrial fibrillation.
• Prophylaxis and treatment of thromboembolism associated with cardiac
valve replacement.
• Used as adjunct therapy to reduce mortality, recurrent myocardial infarction, and
thromboembolic events post myocardial infarction.
• Secondary prevention of stroke and transient ischemic attacks in patients with rheumatic
mitral valve disease but without atrial fibrillation.
Anisindione
• Anisindione is a synthetic indanedione anticoagulant.
Mechanism of action
• Anisindione inhibits the vitamin K—mediated gamma-carboxylation of precursor proteins.
• This prevents the formation of active procoagulation factors II, VII, IX, and X, as well as
the anticoagulant proteins C and S.
• The consequential effects of this inhibition include a reduced activity of these
clotting factors and prolonged blood clotting time.
• Anisindione has no direct thrombolytic effect and does not reverse ischemic
tissue damage, although it may limit extension of existing thrombi and prevent secondary
thromboembolic complications.
Uses
• For the prophylaxis and treatment of venous thrombosis and its extension, the treatment
of atrial fibrillation with embolization, the prophylaxis and treatment of pulmonary
embolism, and as an adjunct in the treatment of coronary occlusion.
• It is prescribed only if coumarin-type anticoagulants cannot be taken.
Clopidogrel
• Clopidogrel is a prodrug of the thienopyridine family.
Mechanism of action
• Clopidogrel is a prodrug and its thiol metabolite is a platelet inhibitor.
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• Clopidogrel is metabolized to its active form in two steps in the liver by cytochrome P450
enzymes.
• The active thiol metabolite irreversibly inhibits the P2Y i subtype of ADP (adenosine
diphosphate) receptor on the platelet surface.
• This leads to disruption of resulting in platelet aggregation.
Actlve metsbollte
{Act-Met)
dDP
plytg
bled)
VG protein gnalling
P2Y12
(activated)
CP IIb/IIIa
(activated)
Fibrinogen
vWF
Figure 3. Mechanism of action of clopidogrel.
Uses
• Used to reduce the risk of heart disease and stroke in those at high risk.
• It is also used together with aspirin in heart attacks and following the placement of
a coronary artery stent (dual antiplatelet therapy).
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DRUGS USED IN CONGESTIVE HEART FAILURE
Congestive heart failure is a condition in which the heart is unable to pump
sufficient blood to meet the metabolic demand of the body and also unable to receive it back
because every time after a systole. This is the direct result of a reduced contractility
of the cardiac muscles, especially those of the ventricles, which causes a decrease in cardiac
output, increasing the blood volume of the heart (hence the term “ congested”). As a result, the
systemic blood pressure and the renal blood flow are both reduced, which often lead to
the development of edema in the lower extremities and the lung (pulmonary edema) as
well as renal failure. A group of drugs known as the cardiac glycosides were found to
reverse most of these symptoms and complications.
Oruga uaed in congeetive hegrt failure
VasodlJBtors Miscellaneous drugs for chronic tailore
Cardiac Beta
giycos<tes agonists
(digoxin) (dobutamine)
POE inhibitors
Nlroprussido Loop d uretics Niiraiss ACE inhibitors
Hydrsiazine Nesiritide
B0ta bickers Spirondactone Thiazides
Digoxin
• Digoxin is a cardiac glycoside extracted from foxglove leaves (Digitalis lanata, Family
Scrophulariaceae).
• Digoxin includes a steroid nucleus and a lactone ring; most also have one or more sugar
residues. The side chain of digoxin is made up of three molecules of digitoxose in a glycosidic
linkage, which upon hydrolysis yields the aglycone, digoxigenin.
• It differs from digitoxin in that it has an additional hydroxyl group
at Ci6 Of the steroid skeleton.
• The 17- lactone and the steroid (A-B-C-D) ring system are essential for cardiac glycoside
activity.
Mechanism of action
• The process of membrane depolarization/repolarization is controlled mainly by the
movement of the three ions, Na“, K“, Ca²“ in and out of the myocardial cells.
• The Na“/K“ exchange requires energy and is catalyzed by the enzymeNa“/K“-ATPase.
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• Digoxin inhibits Na“/K“-ATPase enzyme, with a net result of reduced odium exchange with
potassium (i.e. increased intracellular sodium), which in turn results in increased
intracellular calcium.
• Elevated intracellular calcium concentration triggers a series of intracellular
biochemical events that ultimately result in an increase in the force of the myocardial
contraction, or a positive inotropic effect.
• Digitalis also modifies autonomic outflow, and this action has effects on the
electrical properties of the heart.
Na*/Ca-*
e
Digoxin NTpaKe
Ca**
Na’
TnC Ca** I cardiac
binding contraction
Figure 4. Mechanism of action of digoxin.
Uses
• It is the drug of choice for “low output HF” due to HT, IHD or arrhythm as.
• Treatment of paroxysmal supraventricular tachycardia (arrhythmia due to reentry
phenomenon taking place at SA or AV node).
• Treatment of atrial flutter and atrial fibrillation.
• It is helpful in restoring cardiac compensation.
• Digitalis glycosides are no longer considered first-line drugs in the treatment of heart
failure.
Digitoxin
• Digitoxin is a lipid soluble cardiac glycoside obtained from Digitalis purpurea, Digitalis
lanata and other suitable species of Digitalis.
• It is a phytosteroid and is similar in structure and effects to digoxin.
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• Its side chain is comprised of three molecules of digitoxose in a glycosidic linkage.
• Its hydrolysis affects removal of the side chain to yield the aglycone, digitoxigenin.
• It has a longer half-life than digoxin.
Mechanism of action
Refer the mechanism of action of Digoxin.
Uses
• Digitoxin is used for chronic cardiac insufficiency, tachyarrhythmia form of atrial
fibrillation, paroxysmal ciliary arrhythmia, and paroxysmal supraventricular tachycaria.
• It is eliminated hepatically making it useful in patients with poor or erratic kidney
function.
• Digitoxin lacks the strength of evidence that digoxin has in the management of heart failure.
Nesiritide
• Nesiritide is a recombinant human B-type natriuretic peptide (BNP).
• It is identical to the endogenous hormone produced in E. coli.
• It is a new drug class for the treatment of congestive heart failure.
Mechanism of action
• Human B-type natriuretic peptide (BNP) is normally produced by the
ventricular cardiomyocytes.
• Human BNP binds to the particulate guanylate cyclase receptor of vascular smooth
muscle and endothelial cells, leading to increased intracellular concentrations
of guanosine 3′, 5′-cyclic monophosphate (cGMP) and smooth muscle cell relaxation.
• cGMP serves as a second messenger to dilate veins and arteries.
• Nesiritide mimics the actions of endogenous BNP by binding to and stimulating receptors in
the heart, kidney and vasculature.
• Nesiritide has venous, arterial, and coronary vasodilatory
properties that reduce preload and afterload, and increase cardiac output without direct
inotropic effects.
Uses
• For the intravenous treatment of patients with acutely congestive heart failure who have
dyspnea at rest or with minimal activity.
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Bosentan
• Bosentan is an oral dual endothelin receptor antagonist.
• It is a sulfonamide-derived compound.
Mechanism of action
• Bosentan is a specific and competitive antagonist at endothelin receptor types endothelin A
(ETA) and endothelin B (ETB).
• It has slightly higher affinity for the ETAreceptor than endothelin ETB.
• Endothelin 1 is an extremely potent endogenous vasoconstrictor and bronchoconstrictor.
Bosentan blocks the action of endothelin 1 by binding to endothelin A and endothelin B
receptors in the endothelium and vascular smooth muscle.
• Thus Bosentan decreases both pulmonary and systemic vascular resistance.
Uses
• It is used in the treatment of pulmonary arterial hypertension (PAH).
• It is used to reduce the number of active digital ulcers.
Tezosentan
• Tezosentan is an intravenous endothelin receptor A/B antagonist.
• It has pyrldinylpyrimidine skeleton.
Mechanism of action
• Tezosentan competitively antagonizes the specific binding of endothelin-1 (ET-1) and
endothelin-1 (ET-3) on cells and tissues carrying ETAand ETBreceptors.
• This results in vasodilatory responses leading to an improvement in cardiac index.
Uses
• It acts as a vasodilator and was designed as a therapy for patients with acute heart failure.
• It is used to treat pulmonary arterial hypertension.
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ea both eiin
eododNeWo receptor.GB
for ph¿ st logical
Figure S. Mechanism of action of tezosentan.
References
1. Wilson CO, Gisvold O, Doerge RF. Text book of Organic Medicinal and Pharmaceutical Chemistry,
12th ed., Philadelphia: Lippincott Williams & Wilkins; 2011.
2. Lemke TL, Williams, DA, Roche VF, Zito SW. Foye’s Principles of Medicinal Chemistry: 1 lth
ed., Philadelphia: Lippincott Williams & Wilkins; 2012.
3. Kar A. Medicinal Chemistry, 7th ed.; New Age International Publishers; 2018.
4. Heijman J, Ghezelbash S, Dobrev D. Investigational antiarrhythmic agents: promising
drugs in early clinical development. Expert Opinion on Investigational Drugs, 2017; 26 (8):
897-907.
5. Estrada JC, Darbar, D. Clinical use of and future perspectives on antiarrhythmic drugs.
European journal of clinical pharmacology, 2008; 64(12): 1139-1146.
6. Lei M, Wu L, Terrar DA, Huang CL. Modernized classification of cardiac antiarrhythmic drugs.
Circulation, 2018; 138: 1879-1896.
7. https://www.drugbank.ca/drugs
8. https://pubchem.ncbi.n1m.nih.gov
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