Lecture Notes on Anticoagulants (Heparin & Warfarin)

Overview of the Topics
Anticoagulant Drugs

Anticoagulant drugs: 

- Drugs that inhibit the development and enlargement of clots by action on the coagulation phase. 
- Do not lyse clots or affect the fibrinolytic pathways 

Clinical Indication for Anticoagulant therapy
- Deep Vein Thrombosis
- Arterial Embolism
- Arterial Fibrillation 
- Unstable angina and myocardial infarction

Heparin (Intravenous or subcutaneous administration)

- Heparin is a sulfated acidic mucopolysaccharide that is widely distributed in the body
- Two types of heparin are used clinically
- Standard Unfractionated Heparin
- Low Molecular Weight Heparin

Standard Unfractionated Heparin

- Heparin (heparin sodium) is a mixture of highly electronegative acidic mucopolysaccharides that contain numerous N- and O-sulfate linkages. 
- The unfractionated preparation is extracted from the lung or intestine of ox, pig, and is a mixture of polymers of variable molecular weight.
- Unfractionated heparin is rarely used and is now replaced by lower molecular weight heparin 
- But it is still administered to patients with impaired or rapidly changing renal function,
- For prophylaxis, a low dose is injected subcutaneously into the fatty layer of the lower abdomen 8- or 12 hourly. 

Lower Molecular Weight Heparin (LMWH)

- Lower molecular weight heparin is produced by chemical depolymerization and extraction of standard heparin
- Molecular weight ranges from 2000 to 9000 
- The LMWH has 2-4 fold greater anti-factor Xa activity than antithrombin activity
- LMWH has greater bioavailability than standard heparin and dose-dependent clearance pharmacokinetics

Mechanism of action
- Heparin binds to the serine protease inhibitor, antithrombin III
- It induces a conformational change that accelerates the interaction of antithrombin to coagulation factors (IIa, IXa, Xa, XIa, and XIIa) resulting in rapid inactivation 
- Heparin also catalyzes the inhibition thrombin by heparin cofactor II
- Monitoring of the treatment effect is done by measurement of Partial thromboplastin time (PTT)

Absorption, Metabolism, and Excretion
- Heparin is not absorbed from the gastrointestinal tract, therefore, must be given parenterally
- Intravenous administration results in an almost rapid immediate anticoagulant effect 
- Half-life of unfractionated heparin range from 0.5-2.5 hour, and is dose-dependent
- Unfractionated heparin is rapidly taken up by the reticuloendothelial system for degradation and renal excretion
- The LMWH are solely cleared through urine, therefore, the unfractionated heparin is recommended to an individual with renal dysfunction
- Both forms of heparin do not cross the placental barrier, therefore, the anticoagulant of choice during pregnancy 

Indication (Rapid Anticoagulation -intensive)
- Deep Vein Thrombosis
- Arterial Embolism
- Arterial Fibrillation 
- Unstable angina and myocardial infarction

Other Pharmacological Effects
- Exerts antilipemic effects by releasing lipoprotein lipase from endothelial cells
- Decreases platelet aggregation and inflammatory cell adhesiveness to endothelial cells.
- Reduces platelet like growth factors and exert an antiproliferative effect on smooth muscle 

Bleeding, -
- Osteoporosis, -
- Heparin-induced thrombocytopenia, 
- Hypersensitivity

Warfarin (Oral Administration)

- Warfarin is a fat-soluble derivative of 4-hydroxycoumarin and they serve as Vitamin K antagonists
- Decreases blood coagulation by inhibiting the synthesis of coagulation factors

Mechanisms of Action:
- Warfarin inhibits the hepatic synthesis of vitamin K dependent coagulation factors II, VII, IX & X 
- Vitamin K dependent carboxylation of glutamic acid residue at the N terminal end these coagulation factors precursors are blocked by warfarin
- Warfarin specifically targets epoxide reductase, thereby inhibiting the recycling of active hydroxyquinone that is required for carboxylation. 

Absorption, Metabolism, and Excretion
- Complete reabsorption after oral administration of warfarin
- Maximal plasma concentration is reached within 2-8 hours, and approximately 95% of the drugs are bound to plasma proteins
- Warfarin is metabolized and inactivated by the hepatic microsomal P450 enzyme
- Hydroxylated metabolites are excreted into bile and into the intestine
- Monitoring of the treatment effect is done by measurement of Prothrombin time (PT)

Indications  (Longer-term regimen)
-Deep vein Thrombosis 
-Pulmonary Embolism
-Arterial Fibrillation
-Mitral Stenosis
-Prosthetic valve replacement 

- Hemorrhage and bleeding
- Warfarin does not cross the blood-brain barrier but it crosses the placental barrier 
- Causes teratogenesis to the fetus
- Causes hypercoagulability in individuals with impaired hepatic function
- Interaction with drugs that binds to plasma proteins and are metabolized by P450 enzymes 
    - Inducers: Barbiturates, Carbamazepine, Rifampin
    - Inhibitors: Cimetidine, Macrolides, Azole