Medicinal Chemistry

CARDIOVASKULAR DRUGS

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ANTIANGINAL AGENTS

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Classes of Drugs Used to Treat Angina
Classes of drugs used in the treatment of angina and myocardial
infarction are given below. Clicking on the drug class will link you to
the page describing the pharmacology of that drug class.

• Vasodilators (dilate arteries and veins)

- nitrodilators
- calcium-channel blockers

• Cardioinhibitory drugs (reduce heart rate and contractility)

- beta-blockers
- calcium-channel blockers

• Ranolazine (FDA approved 1/06 - blocker of late sodium currents)

• Anti-thrombotic drugs (prevent thrombus formation)

- anticoagulants
- anti-platelet drugs

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 Nitrates
• It was known from the time of its discovery in 1847 that the
tasting or close handling of nitroglycerin could cause sudden
intense headaches, which indicated some form of vasodilation
effect. “Nitrate handlers headache”

• Following discoveries that amyl nitrite helped to alleviate

chest pain, Doctor William Murrell experimented with the use
of nitrogylcerin to alleviate angina pectoris and reduce blood
pressure. He began treating patients with small doses in 1878,
and it was soon adopted into widespread use after he
published his results in The Lancet in 1879. The medical
establishment used the name "glyceryl trinitrate" or "trinitrin"
to avoid alarming patients who associated nitroglycerin with
explosions.

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• Alfred Nobel in 1851
recognized the potential of
NG. He began
manufacturing NG in
Sweden, overcoming
handling problems with his
patented mixture of NG &
diatomaceous earth
(dynamite). Nobel suffered
acutely from angina and
was later to refuse NG as a
treatment.

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• Mechanism of action of Nitrates and nitrites
• These act by the formation free radical nitric
oxide (NO), which interact with and activate
guanylate cyclase. Nitric oxide forms a
reductive nitrothiol intermediate activate a
soluble cytosolic form of the enzyme
guanylate cyclase and cGMP formation is
thereby increased. The guanylate cyclase
increases 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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Nitroglyserin
• It is a clear, colorless to pale yellow solution.
Glyceryl trinitrate (nitroglycerin; nitro glycerol;
trinitrin; trinitroglycerin) is the nitric acid ester
of glycerin, and may be prepared by treating
dehydrated glycerin with a mixture of fuming
nitric acid and sulphuric acid.
• Flammable, explosive liquid.
• It is slightly soluble in water.

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Glyceryl trinitrate is rapidly absorbed from the oral
mucosa.
It is also well absorbed from the gastrointestinal tract, but
since it undergoes extensive first-pass metabolism in the
liver its bioavailability is reduced.
As it has short plasma half-life different long-acting
formulations are available.
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Isosorbid dinitrate

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 Properties of Isosobide dinitrate

• Isosorbide dinitrate is 1, 4:3, 6-dianhydro-D-

glucitol 2, 5-dinitrate.
• It is a white crystalline powder; slightly soluble
in water.
• Diluted isosorbide dinitrate is a dry mixture of
isosorbide dinitrate with lactose, mannitol or
any other suitable inert excipient, which
permits safe handling.

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• Its major metabolites are isosorbide 2-
mononitrate and isosorbide 5-mononitrate,
both of which possess vasodilatory activity
and may contribute to the activity of the
parent compound.
• Isosorbide dinitrate is also absorbed through
the skin from an ointment base.
• Isosorbide dinitrate is suitable for sublingual
as well as oral administration.
• The usual dose in acute angina is 2.5 to 10 mg
sublingually
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 Adverse effects:
1. The most common side effect of nitrates is headache due to
veno-dilation, patients whom intermittently used nitrate
preparation should be asked about headaches after nitrate
use; lack of headache often indicates degradation of agent
with a loss of therapeutic effect.
2. Postural hypotension & syncope particularly with sublingual
use.
3. Tachycardia induced by decreased PVR may itself induce
anginal symptoms especially with unstable symptoms.
4. Methemaglobinemia can occur with chronic use of long term
agents, this may occur when sublingual use is combined with
long acting agents.
5. Withdrawal symptoms may occur (an indication of tolerance)
when nitrate agents are tapered or discontinued, this may
precipitate anginal attacks.
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Anticoagulants and Antiplatelets

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 Terminologies
• Antithrombotics = Drugs which interfere with
platelet functions

• Anticoagulants = Drugs used to reduce the

coagulability of blood

• Thrombolytics (Fibrinolytics) = Drugs used to

lyse thrombin clot (mainly therapeutic)
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The need for anticoagulation
 Why do thromboses occur?
 How are they treated?
 How are they prevented?

 Thrombosis and haemostasis

What is haemostasis?
 Balance between four major components
 Vascular endothelium

 Platelets

 Coagulation pathway

 Procoagulant
 Anticoagulant
 Fibrinolysis
Coagulation pathway
 Procoagulant proteins
 Anticoagulant proteins

 Balance between activation and control

of coagulation
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 1. Anticoagulant Drugs
• Reduce the formation of fibrin clots.
• Oral anticoagulant drugs : Coumarin
anticoagulants (warfarin - dicumarol)
• Parenteral anticoagulant drugs:
Heparin - Hirudin)

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 A. Oral anticoagulants
(Coumarin and warfarin)

• Chemistry and mechanisms:

– They are structurally related to vitamin k
– These drug inhibit the synthesis of clotting
factors II (prothrombin), VII, IX, and X.
– Warfarin blocks the reduction of oxidized vitamin
K and thereby prevents the posttranscriptional
carboxylation of the above four factors.

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Pathway of Vitamin K

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Oral anticoagulants – 4-hydroxycoumarins

Vitamin K

Coumarins
Coumarins act here
act here
Coumarins are
competitive inhibitors
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 Warfarin - Mechanism of Action
– By inhibiting vitamin K epoxide reductase and
vitamin K reductase, warfarin leads to the
accumulation of vitamin K epoxide in the liver
and plasma and the depletion of reduced vitamin
K (active form, KH2)
– Reduced vitamin K is necessary for carboxylation
of glutamate residues
– Decrease in KH2 limits the gamma-carboxylation
of vitamin K dependent coagulant proteins -
– Prothrombin (Factor II)
– Factors VII, IX, X
– Protein C and Protein S
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 O O

CH WARFARIN SODIUM

ONa CH2

CO

CH3

O O O O

DICUMAROL

CH2

OH OH 30
Synthesis of coumarin and warfarin

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Cont.

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 Warfarin - Pharmacokinetics -
Pharmacodynamics

•Racemic mixture of two optical isomers

•Absorbed rapidly from GI tract
•Maximal plasma concentration in 90 min
•Plasma t1/2 of 36 to 42 hours
•Circulates bound to plasma proteins
•Administered orally

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Warfarin therapy
 Inter-individual differences
 Narrow therapeutic range
 Bleeding risk
 Outside anticoagulation range
 Higher mortality
 Increased risk of stroke
 Increased rate of hospitalisation
Warfarin interactions
 Pharmacokinetic interactions
 Drugs which interfere with clearance
 Antibiotics which affect intestinal flora
 Pharmacodynamic interactions
 Drugs which have anti-platelet effect
(aspirin and NSAIDS)
 Drugs associated with falls in the elderly
 Drug Interactions with Warfarin:
Potentiation
Level of
Evidence Potentiation
Alcohol (if concomitant liver disease) amiodarone (anabolic steroids,
cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600
I mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam,
propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)
Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram,
II itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen,
tetracycline, flu vaccine
Acetylsalicylic acid, disopyramide, fluorouracil, ifosfamide, ketoprofen,
simvastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin,
III propoxyphene, sulindac, tolmetin, topical salicylates
Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
IV
†In a small number of volunteer subjects, an inhibitory drug interaction occurred.
 Drug Interactions with Warfarin:
Inhibition

Level of
Evidence Inhibition
Barbiturates, carbamazepine, chlordiazepoxide,
I cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate
II Dicloxacillin
III Azathioprine, cyclosporine, etretinate, trazodone