Anticoagulant drugs

Blood drugs

Anticoagulant

Presented by: Mamona Waheed

Presented to : Prof. Dr Shoaib

Drugs that are useful in treating three important dysfunctions of blood:

▪ Thrombosis

▪ Bleeding

▪ anemia

Thrombosis▪ The formation of an unwanted clot within

a blood vessel is the most common abnormality of hemostasis.

▪ Thrombotic disorders include acute myocardial infarction, deep-vein thrombosis, pulmonary embolism, and acute ischemic stroke. These are treated with drugs such as anticoagulants and fibrinolytics.

Thrombus VS. Embolus

▪ A clot that adheres to a vessel wall is called a thrombus, whereas an intravascular clot that floats in the blood is termed an embolus.

HAEMOSTASIS?

HAEMOSTASIS

The term haemostasis means prevention of

blood loss.

Haemostasis is the process of forming clots in the walls of damaged blood vessels and preventing blood loss, while maintaining blood in a fluid state within the vascular system

Mechanism

1. Vascular spasm2. Platelets reaction3. Formation of platelet plug3. Blood coagulation

Blood Coagulation

The clotting mechanism involves a cascade of reactions in which clotting factors are activated. Most of them are plasma proteins synthesized by the liver (vitamin K is needed for the synthesis of factor II, VII, IX and X). They are always present in the plasma in an inactive form. When activated they act as proteolytic enzymes which activate other inactive enzymes. Several of these steps require Ca++ and platelet phospholipid.

The ultimate step in clot formation is the conversion of fibrinogen → fibrin.

Definition of Anticoagulation

▪ Therapeutic interference ("blood-thinning") with the clotting mechanism of the blood to prevent or treat thrombosis and embolism.

▪The anticoagulant drugs either inhibit the action of the coagulation factors (the thrombin inhibitors, such as heparin and heparin-related agents) or interfere with the synthesis of the coagulation factors (the vitamin K antagonists, such as warfarin).

▪The fibrinolytic system dissolves intravascular clots as a result of the action of plasmin, an enzyme that digests fibrin. Plasminogen, an inactive precursor, is converted to plasmin by cleavage of a single peptide bond.

Plasmin

▪ Plasmin is a relatively nonspecific protease,it digests fibrin clots and other plasma proteins, including several coagulation factors. Therapy with thrombolytic drugs can dissolve both pathological thrombi and fibrin deposits at sites of vascular injury, thus, such drugs also may promote also hemorrhage.

Indications of Anticoagulant Therapy

▪ Treatment and Prevention of Deep Venous Thrombosis

▪ Pulmonary Emboli

▪ Prevention of stroke in patients with atrial fibrillation, artificial heart valves, cardiac thrombus.

▪ Ischaemic heart disease

▪During procedures such as cardiac catheterisation and apheresis.

NATURAL ANTICOAGULANT MECHANISMS

▪ Platelet activation and coagulation normally do not occur within an intact blood vessel. Thrombosis is prevented by several regulatory mechanisms that require a normal vascular endothelium.

▪ Prostacyclin (prostaglandin I2; PGI2) is synthesized by endothelial cells and inhibits platelet aggregation and secretion

▪ Heparan sulfate proteoglycans synthesized by endothelial cells stimulate the activity of antithrombin.

▪ Protein C is a plasma zymogen that is homologous to factors II, VII, IX, and X; its activity depends on the binding of Ca2+ to g carboxyglutamate (Gla) residues within its aminoterminal domain.

▪ Activated protein C, in combination with its nonenzymatic Gla-containing cofactor (protein S), degrades cofactors Va and VIIIa and thereby greatly diminishes the activation of prothrombin and factor X

▪ Protein C is activated by thrombin only in the presence of thrombomodulin, an integral membrane protein of endothelial cells. Like antithrombin, protein C exerts an anticoagulant effect in the vicinity of intact endothelial cells. Tissue factor pathway inhibitor (TFPI) is found in the lipoprotein fraction of plasma. When bound to factor Xa, TFPI inhibits factor Xa and the factor VIIa–tissue factor complex. By this mechanism, factor Xa may regulate its own production.

PARENTERALANTICOAGULANTS

Heparin…..,SOURCE :

▪Heparin is commonly extracted from porcine intestinal mucosa or bovine lung. Despite the heterogeneity in composition among different commercial preparations of heparin, their biological activities are similar (~150 USP units/mg).

▪ The USP unit is the quantity of heparin that prevents 1 mL of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 mL of 1% CaCl2.

▪ Low-molecular-weight heparins (~ 4500 Da, or 15 monosaccharide units) are isolated from standard heparin by gel filtration chromatography, precipitation with ethanol, or partial depolymerization with nitrous acid and other chemical or enzymatic reagents.

▪Low-molecular-weight heparins differ from standard heparin and from each other in their pharmacokinetic properties and mechanism of action

MECHANISM OF ACTION

▪Heparin catalyzes the inhibition of several coagulation proteases by antithrombin, a glycosylated, single-chain polypeptide

▪Antithrombin is synthesized in the liver and circulates in plasma inhibition occurs when the protease attacks a specific Arg-Ser peptide bond in the reactive site of antithrombin and becomes trapped as a stable 1:1 complex.

▪ Heparin increases the rate of the thrombin-antithrombin reaction at least 1000-fold by serving as a catalytic template to which both the inhibitor and the protease bind. Binding of heparin also induces a conformational change in antithrombin that makes the reactive site more accessible to the protease. Once thrombin has become bound to antithrombin, the heparin molecule is released from the complex.

Miscellaneous Pharmacological Effects▪Prolong bleeding time.

CLINICAL USE▪Treatment of venous thrombosis and pulmonary embolism because of its rapid onset of action. An oral anticoagulant usually is started concurrently, and heparin is continued for at least 4–5 days to allow the oral anticoagulant to achieve its full therapeutic effect.

Management of patients with unstable angina or acute myocardial infarction, during and after coronary angioplasty or stent placement, and during surgery requiring cardiopulmonary bypass.

TOXICITIES

▪Bleeding Bleeding is the primary untoward effect of heparin. the effect of heparin can be reversed quickly by the slow intravenous infusion of protamine sulfate, a mixture of basic polypeptides that bind tightly to heparin and thereby neutralize its anticoagulant effect. ~1 mg of protamine for every 100 units of heparin

▪Anaphylactic reactions▪Thrombocytopenia

Other Parenteral Anticoagulants

LEPIRUDIN:▪ Lepirudin (REFLUDAN) is a recombinant derivative

(Leu1-Thr2-63-desulfohirudin) of hirudin, a direct thrombin inhibitor present in the salivary glands of the medicinal leech. It is a 65-amino-acid protein that binds tightly to both the catalytic site and the extended substrate recognition site of thrombin.

BIVALIRUDIN▪ Bivalirudin (ANGIOMAX) is a synthetic,

20-amino-acid polypeptide that directly inhibits thrombin.

ARGATROBAN Binds reversibly to the catalytic site of thrombin.

Administered intravenously, it has an immediate onset of action and a t1/2 of 40–50 minutes. Argatroban can be used as an alternative to lepirudin for prophylaxis or treatment of patients with or at risk of developing heparin-induced thrombocytopenia.

ORALANTICOAGULANTS

MECHANISM OF ACTION

▪ The oral anticoagulants are antagonists of vitamin K . Coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S are synthesized mainly in the liver and are biologically inactive unless 9–13 of the amino-terminal glutamate residues are carboxylated to form the Ca2+-binding g-carboxyglutamate (Gla) residues

▪ . This reaction of the descarboxy precursor protein requires CO2, O2, and reduced vitamin K, and is catalyzed by g-glutamyl carboxylase in the rough endoplasmic reticulum. Carboxylation is directly coupled to the oxidation of vitamin K to its corresponding epoxide.

▪ The vitamin K cycle: G-glutamyl carboxylation of vitamin K–dependent proteins. The enzyme g-glutamyl carboxylase couples the oxidation of the reduced hydroquinone form (KH2) of vitamin K1 or K2, to g-carboxylation of Glu residues on vitamin K–dependent proteins, generating the epoxide of vitamin K (KO) and g-carboxyglutamate (Gla) residues in vitamin K–dependent precursor proteins in the endoplasmic reticulum. A 2,3-epoxide reductase regenerates vitamin KH2 and is the warfarin-sensitive step. The R on the vitamin K molecule represents a 20-carbon phytyl side chain in vitamin K1 and a 5- to 65-carbon prenyl side chain in vitamin K2.

▪DOSAGE :

▪ The usual adult dose of warfarin (COUMADIN) is 5 mg/day for 2–4 days, followed by 2–10 mg/day as indicated by measurements of the INR.

TOXICITIES▪Bleeding Bleeding is the major toxicity of oral anticoagulant drugs. The risk of bleeding increases with the intensity and duration of anticoagulant therapy, the use of other medications that interfere with hemostasis, and the presence of a potential anatomical source of bleeding.

Purple toe syndrome:▪ A reversible, sometimes painful, bluish

discoloration of the plantar surfaces and sides of the toes that blanches with pressure and fades with elevation may develop 3–8 weeks after initiation of therapy with warfarin

Clinical Use…

▪ To prevent the progression or recurrence of acute deep vein thrombosis

▪ Pulmonary embolism following an initial course of heparin.

▪Orthopedic or gynecological surgery and

▪ In preventing systemic embolization in patients with acute myocardial infarction, prosthetic heart

▪ Valves, or chronic atrial fibrillation.