Antiplatelet drugs

Antiplatelet drugs

Aspirin
Mechanism of action
Inhibits thromboxane A2 synthesis from arachidonic acid in platelets by irreversible acetlyation of a serine, preventing arachidonate from binding to the active site, thus, inhibition of COX-1. The aspirin induced suppression of thromboxane A2 synthetase and the resulting suppression of platelet aggregation last for the life of the anucleate platelet, which is approximately 7 to 10 days.
Indications
Prophylactic treatment of transient cerebral ischemia
Reduce the incidence of recurrent myocardial infarction
Decrease mortality in pre and post myocardial infarct patients.
Adverse effects
Increase the incidence of hemorrhagic stroke ,and Gastrointestinal bleeding.
Ticlopidine, Clopidogrel, and prasugrel
Mechanism of action
These drugs irreversibly inhibit the binding of Adenosine Diphosphate (ADP) to its receptors on platelets and, thereby, inhibit the activation of the GP ІІb/ІІІa receptors required for platelet to bind to fibrinogen and to each other.
Therapeutic use
Although ticlopidine and clopidogrel are similar in both structure and mechanism of action , their therapeutic uses are different.
Ticlopidine is approved for the prevention of transient ischemia attack and strokes for patients with a prior cerebral thrombotic event. In addition it is also used as adjunct therapy with aspirin following coronary stent implantation to decrease the incidence of stent thrombosis (however due to its life-threatening hematologic adverse reaction,ticlopidine reserved for patients who are intolerant to other therapies.
Clopidogrel is approved for prevention of atherosclerotic events following recent myocardial infarction, stroke, and established peripheral arterial disease. It is also approved for prophylaxis of thrombotic events in acute coronary syndrome (unstable angina, non-Q wave myocardial infarction). Clopidogrel is used to prevent thrombotic events associated with percutaneous coronary intervention with or without coronary stent.
Prasugrel is the newest ADP receptor antagonist . It is approved to decrease thrombotic cardiovascular events in patients with acute coronary syndrome (unstable angina, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction that is managed with percutaneous coronary intervention). In clinical trials, prasugrel was more effective than clopidogrel in reducing cardiovascular death, nonfatal heart attack, and nonfatal stroke.
Adverse effects
Ticlopidine is generally reserved for patient who are intolerant to other therapies due to its life-threatening hematologic adverse reactions, including neutropenia/agranulocutosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia. Clopidogrel has better over-all side effect profile, although TTP may also occur with this agent. Although not reported for Prasugrel, TTP is possible.
Abciximab
Is chimeric monoclonal antibody that block the final common pathway of platelet activation (GP ІІb/ІІІa receptor).abciximab is given intravenously along with either heparin or aspirin as an adjunct to percutaneous coronary intervention for their prevention of cardiac ischemic complications. It is also approved for unresponsive unstable angina and for prophylactic use in myocardial infarction. The major side effect of the use of abciximab is potential for bleeding.
Dipyridamole
coronary vasodilator, is used prophylactically to treat angina pectoris. It is usually given in combination with aspirin or warfarin. Although Dipyridamole increases intracellular levels of cAMP by inhibiting cyclic nucleotide phosphodiesterase, resulting in decreased thromboxane A2 synthesis, it has only a marginal contribution to the antithrombotic action compare to that of aspirin. The major adverse effect is GI disturbance and orthostatic problems.
Cilostazol
Is an oral antiplatelet agent that also has vasodilating activity. It is FDA approved to reduce the symptoms of intermittent claudication. It inhibit phosphodiesterase typeІІІ, which prevents the degradationof cAMP, thereby increasing levels of cAMP in platelets and vascular tissues. Adverse effects is GI symptoms like diarrhea dyspepsia, abnormal stools.


Anticoagulant drugs
There are two group of anticoagulant drugs. The first inhibits the action of coagulant factors like heparin while the second one interfere with the synthesis of coagulant factors like warfarin.
Anticoagulant drugs inhibits the action of coagulant factors
Unfractionated Heparin and low molecular weight heparin
Is an injectable, rapidly acting anticoagulant that is often used acutely to interfere with the formation of thrombi. Unfractionated heparin is a mixture of straight-chain, anionic glycosaminoglycans with a wide range of molecular weights. It is strongly acidic, its antidote is protamin sulfate which very basic protein that forms neutral complex with heparin. The LMWHs are heterogeneous compounds replacing the use of heparin in many clinical situations, because of they are free of some of the drawbacks associated with the unfractionated heparin.
Mechanism of action
Heparin's anticoagulant effect is a consequence of binding to antithrombin ІІІ, with the subsequent rapid inactivation of coagulation factors. antithrombin ІІІ inhibits serine proteases, including several of the clotting factors, most importantly, thrombin and factor xa. heparin molecules bind to antithrombin ІІІ lead to conformational changes that accelerates its rate of action about 1000-fold.
Therapeutic uses
Limit the expansion of thrombi by preventing fibrin formation
Is the major antithrombotic drug for treatment of acute deep vein thrombosis and pulmonary embolism
Heparin is used prophylactically to prevent postoperative venous thrombosis in patients undergoing elective surgery.
Those in acute phase of myocardial infarction.
Coronary artery rethrombosis after thrombolytic treatment is reduced with heparin.
Heparin is anticoagulants of choice for treating pregnant women with prosthetic heart valves or venous thromboembolism. Because these agents do not cross the placenta.

Adverse effects

Despite the early hopes that the LMWHs have fewer side effects. the complication proved that have the same side effects profile except thromboembolic disorder which fewer with LMWHs
the major side effect with heparin therapy is hemorrhage. Careful monitoring of the bleeding time is required to minimize this problem.
Heparin preparations are obtained from procine sources and therefore, may be antigenic. Possible adverse reaction include chills, fever, urticaria, anaphylactic shock.
Chronic or intermittent administration of heparin cam lead to a reduction in antithrombin ІІІ activity, thus decreasing the inactivation of coagulation factors, to minimize this risk, low-dose heparin therapy is typically used.
Thrombocytopenia is a common abnormality among hospital patients receiving heparin. Heparin therapy should be discontinued in patients that show severe thromobocytopenia. heparin can be replaced by another anticoagulant such as dabigatran, or lepirudin. In addition heparin may cause osteoporosis if it used for long time, reversible alopecia was reported, and due to its effect on aldosteron synthesis it may lead to hyperkalemia.
Direct thrombin inhibitor: dabigatran etexilate, lepirudin
Is the first oral anticoagulant after warfarin. Is the produrg of the active moiety dabigatran which is a direct thrombin inhibitor currently approved for prevention of stroke and systemic embolism in patients with atrial fibrillation. It not required routine monitoring (INR) and fewer drug interaction in compare with warfarin. However like any anticoagulant the major side effect is bleeding.
lepirudin is parentral anticoagulants highly specific, direct thrombin antagonist it polypeptide that is closely related to hirudin, which derived from medicinal leech saliva. lepirudin produced in yeast cells by recombinant DNA technology.
Fondaparinux is indirect Xa inhibitor, and the first in a new class of pentasaccharide anticoagulants that is synthetically derived with no variable biologic activity.
Vitamin K antagonist: warfarin
Is the only therapeutically relevant coumarin anticoagulant.
Mechanism of action
Several of the protein coagulation factors (including factor ІІ, VІІ, ІX, and X in required vitamin K as a cofactor for their synthesis by the liver. These factor to be active, it should be carboxlyated at glutamate residue and this reaction depend on vitamin K, in its reduced form, warfarin inhibit vitamin K epoxide reductase, the enzyme that responsible for reduction of vitamin K epoxide. So warfarin treatment results in production of clotting factors with diminished activity. Unlike heparin, th anticoagulant effects of warfarin are not observed unitl 8 to 12 hours after drug administration, but peak effects may be delyayed for 72 to 96 hours.
Therapeutic uses
warfarin is used to prevent the progression or recurrence of acute deep vein thrombosis or pulmonary embolism after initial heparin treatment. It is also used for the prevention of venous thromboembolism during orthopedic. Prophylactically, it is used in patients with acute myocardial infarction, prosthetic heart valves, and chronic atrial fibrillation.
Side effect
the principal untoward reaction casued by warfarin treatment is hemorrhage. Therefore, it is importrant to freguently monitor and adjust the anticoagulant effect.
Warfarin has numerous durg interactions that may potentiate or attenuate its anticoagulant effect.
Vitamin K deficiency, hepatic diseases that impair synthesis of the clotting factors or affects warfarin metabolism, hypermetabolic states that increase catabolism of thevitamin K-dependent clotting factors can all influence the hypoprothrombinemic state of the patient and augment the response to the oral anticoagulants.
Thrombolytic drugs
Acute thromboembolic disease in selected patients may be treatedny the administration of agents that activate the conversion of plasminogen to plasmin, a serine protease that hydrolyzes fibrin and , thus, dissolves clots. This group include Streptokinase, alteplase (more locally on the thrombotic fibrin to produce fibrinolysis, and Urokinase ( is produced naturally in human kidneys and directly converts plasminogen into active plasmin).
Therapeutic use
As second line for treatment of acute myocardial infarction or peripheral arterial thrombosis.
Used in treatment of acute thrombotic stroke


Adverse effects
The thrombolytic agents do not distinguish between the fibrin of an unwanted thrombus and the fibrin of a beneficial haemostatic plug. Thus, hemorrhage is a major side effect.
Drugs used to treat bleeding
Aminocaproic acid and tranexamic acid
These drugs act by inhibit plasminogen activation
Protamine
Is fish protein which strongly positive in charge that neutralize heparin
Vitamine K (phytonadione)
It not surprising that vitamin K reverse the action of warfarin however it need 24 hours to produce new active coagulant factors, so for immediate action frozen plasma is indicated.