1. ANTIPLATELET DRUGS

2. Activation of platelets is considered an essential process for arterial thrombosis. Thus, treatment with platelet-inhibiting drugs is indicated in patients with TIAs and strokes or unstable angina and acute myocardial infarction.
Physiologically;when platelets are activated, they undergo a sequence of reactions that are essential for hemostasis & important for the healing of damaged blood vessels. These reactions include:
Adhesion following vascular damage (via von Willebrand factor bridging between subendothelial macromolecules and glycoprotein [GP] Ib receptors on the platelet surface and between collagen and GP Ia receptor)
Change of shape :from smooth discs to spiny spheres
with protruding pseudopodia.
Secretion of platelet granule contents {including platelet agonists, such as ADP (Adenosine diphosphate) and serotonin and coagulation factors and growth factors}

3. Biosynthesis of labile mediators such as platelet-activating factor and thromboxane (TX)A2 .
Aggregation, which is promoted by various agonists, including collagen, thrombin, ADP, serotonin and TXA2, acting on specific receptors on the platelet surface; activation by agonists leads to conformational change in GPIIb/IIIa receptors of platelets lead to binding of fibrinogen, which links adjacent platelets to form aggregates.
Exposure of acidic phospholipid on the platelet
surface, promoting thrombin formation.
These actions are mediated by several messenger systems that ultimately result in elevated levels of calcium and a decreased concentration of cAMP within the platelet.

5. Several targets for platelet inhibitory drugs have been identified:
Inhibition of thromboxane A2 synthesis (aspirin),
Inhibition of ADP-induced platelet aggregation ,Adenosine receptor antagonists.
(ticlopidine ,clopidogrel, prasugrel and ticagrelor)
Blockade of glycoprotein IIb/IIIa receptors on platelets (abciximab, tirofiban, and eptifibatide).
Dipyridamole and cilostazol are additional antiplatelet drugs.
Because these agents have different mechanisms of actions, synergistic or additive effects may be achieved when agents from different classes are combined.
These agents are beneficial in the prevention and treatment of occlusive cardiovascular diseases, in the maintenance of vascular grafts and arterial patency, and as adjuncts to thrombin inhibitors or thrombolytic therapy in MI.

6. Aspirin(Acetyl salicylic acid,ASA)
Mechanism of action
Aspirin is NSAID (Non-steroidal anti-inflammatory drug) that alters the balance between TXA2, which promotes aggregation, and PGI2, which inhibits it.
Aspirin inactivates or inhibits the cyclo-oxygenase (COX) enzyme responsible for synthesis of prostaglandins(PGs) from arachidonic acid acting mainly on the constitutive form (COX-1)-by irreversibly acetylating a serine residue in its active site.
TXA2 produced by platelet COX-1 plays an important role in amplifying aggregation. Before it is deacetylated in liver, aspirin acetylates COX-1 in platelets while they are in portal circulation. Further, platelets are unable to regenerate fresh COX-1 (lack nucleus: do not synthesize protein), while vessel wall is able to do so (fresh enzyme is synthesized within hours). Thus, in low doses, aspirin selectively inhibits TXA2 production and has antithrombotic effect lasting for the life of platelets (7-10 days)

7. Clinical uses
Aspirin is the main antiplatelet drug ,other drugs with distinct actions can have additive effects, or be used in patients who are intolerant of aspirin.
Aspirin is currently employed in:
Prophylactic treatment of transient cerebral ischemia
To reduce the incidence of myocardial infarction in patients with high risk of myocardial infarction, including a history of myocardial infarction, angina or intermittent claudication.
Unstable coronary syndromes & following coronary artery bypass grafting
To decrease mortality in pre and post myocardial infarct patients.
The recommended dose of aspirin ranges from 75 to 325 mg.

8. Pharmacokinetics: When given orally, aspirin is absorbed by passive diffusion and quickly hydrolyzed to salicylic acid in the liver. Salicylic acid is further metabolized in the liver, and some is excreted unchanged in the urine. The half-life of aspirin ranges from 15 to 20 minutes and for salicylic acid is 3 to 12 hours.
Adverse effects of aspirin:
GI irritation and increase the incidence bleeding from the GI tract
Increase the incidence of hemorrhagic stroke
Treatment failure due to a syndrome of 'aspirin resistance' in some patients.
NSAIDs such as ibuprofen, inhibit COX-1 by transiently competing at the catalytic site. Ibuprofen, if taken within the 2 hours prior to aspirin, can obstruct the access of aspirin to the serine residue and, thereby, antagonize platelet inhibition by aspirin. Therefore, immediate release aspirin should be taken at least 60 minutes before or at least 8 hours after ibuprofen.

9. Adenosine Receptor Antagonists
Ticlopidine was the first to be introduced, but causes neutropenia and thrombocytopenia. Other agents are clopidogrel, prasugrel and ticagrelor
These drugs are thienopyridine derivatives that achieve their antiplatelet effects by irreversibly inhibit the binding of ADP to its receptors on platelets preventing further platelet activation. Ticagrelor is a reversible but non-competitive inhibitor of the adenosine receptor.
These drugs report efficacy in the prevention of vascular events among patients with transient ischemic attacks, completed strokes, and unstable angina pectoris & they are now considered standard practice in patients undergoing placement of a coronary stent.

10. Clinical uses :
Clopidogrel is approved for prevention of atherosclerotic events in patients with a recent MI or stroke and in those with established peripheral arterial disease. It is also approved for prophylaxis of thrombotic events in acute coronary syndromes & with percutaneous coronary intervention (PCI) with or without coronary stenting.
Ticlopidine is similar in structure to clopidogrel. It is indicated for the prevention of transient ischemic attacks (TIA) and strokes in patients with a prior cerebral thrombotic event. However, due to life-threatening hematologic adverse reactions and common GI adverse reactions, ticlopidine is generally reserved for patients who are intolerant to other therapies.
Prasugrel is approved to decrease thrombotic cardiovascular events in patients with acute coronary syndromes. Prasugrel is contraindicated in patients with history of TIA or stroke because of increased bleeding risk.
Ticagrelor is approved for the prevention of arterial thrombo-embolism in patients with unstable angina and acute MI, including those undergoing PCI.

11. Pharmacokinetics:
These agents require loading doses for quicker antiplatelet effect.
Food interferes with the absorption of ticlopidine but not with the other agents.
After oral ingestion, the drugs are extensively bound to plasma proteins.
They undergo hepatic metabolism by the cytochrome P450 (CYP) system to active metabolites.
Elimination of the drugs and metabolites occurs by both the renal and fecal routes.
Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on its active metabolite, “Poor metabolizers” of clopidogrel have reduced clinical response to the drug & also enzyme inhibitors as esomeprazole should not be administered concurrently with clopidogrel.

12. Unwanted effects
These drugs predictably increase the risk of hemorrhage. Clopidogrel can cause dyspepsia, rash or diarrhea. The serious blood dyscrasias caused by ticlopidine are very rare with clopidogrel.
Prasugrel can cause rash or, rarely hypersensitivity reactions and angioedema.
Ticagrelor can cause dyspnea or, less commonly, gastrointestinal symptoms.

13. Blockers of Platelet Glycoprotein IIb/IIIa Receptors (Abciximab, Tirofiban, and Eptifibatide)
These glycoprotein IIb/IIIa antagonists are used in patients with acute coronary syndromes. They target the platelet IIb/IIIa receptor complex . Activation of this receptor complex is the "final common pathway" for platelet aggregation.
Abciximab is a monoclonal antibody directed against the IIb/IIIa complex. It is used in high-risk patients undergoing coronary angioplasty, as an adjunct to heparin and aspirin. It reduces the risk of restenosis at the expense of an increased risk of bleeding.
Eptifibatide is a cyclic peptide that binds to GPIIb/IIIa at the site that interacts with fibrinogen. Tirofiban is a synthetic non-peptide. They are used with aspirin and heparin to reduce early events in acute coronary syndrome
The three agents described above are administered intravenously by continuous infusion.
S.ES: They may cause bleeding.

14. Dipyridamole
Dipyridamole is a vasodilator that inhibits platelet function by inhibiting cyclic nucleotide phosphodiesterase ,this increases intracellular levels of cAMP & decreasing calcium resulting in decreased thromboxane A2 synthesis.
Dipyridamole by itself has little beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboembolism in patients with prosthetic heart valves.
The main side effects of dipyridamole are dizziness, headache and gastrointestinal disturbances; unlike aspirin, it does not increase the risk of bleeding.

15. Cilostazol is an oral antiplatelet agent that also has vasodilating activity. Cilostazol and its active metabolites inhibit phosphodiesterase type III, which prevents the degradation of cAMP, thereby increasing levels of cAMP in platelets and vascular tissues
Cilostazol is used primarily to treat intermittent claudication in peripheral vascular disease .
S.Es: Headache and GI side effects (diarrhea, abnormal stools, dyspepsia, and abdominal pain). Phosphodiesterase type III inhibitors have been shown to increase mortality in patients with advanced heart failure. As such, cilostazol is contraindicated in patients with heart failure.

16. FIBRINOLYSIS (THROMBOLYSIS)
When the coagulation system is activated, the fibrinolytic system is also set in motion via several endogenous plasminogen activators, including tPA(tissue Plasminogen Activator), urokinase-type plasminogen activator.
Plasminogen is deposited on the fibrin strands within a thrombus. Plasminogen activators are serine proteases and are unstable in circulating blood. They diffuse into thrombus and cleave plasminogen to release plasmin
Plasmin is a trypsin-like protease that digests fibrin as well as fibrinogen, factors II, V and VIII, and many other proteins. It is formed locally and acts on the fibrin meshwork, generating fibrin degradation products and lysing the clot. Its action is localized to the clot; any plasmin that escapes into the circulation is inactivated by plasmin inhibitors .

18. If the coagulation and fibrinolytic systems are pathologically activated, the hemostatic system may become out of control, leading to generalized intravascular clotting and bleeding. This process is called disseminated intravascular coagulation (DIC) and may follow massive tissue injury, advanced cancers, obstetric emergencies such as abruptio placentae or retained products of conception, or bacterial sepsis. The treatment of DIC is to control the underlying disease process; if this is not possible, DIC is often fatal.
Regulation of the fibrinolytic system is useful in therapeutics. Increased fibrinolysis is effective therapy for thrombotic disease. Tissue plasminogen activator, urokinase, and streptokinase all activate the fibrinolytic system. Conversely, decreased fibrinolysis protects clots from lysis and reduces the bleeding of hemostatic failure. Aminocaproic acid is a clinically useful inhibitor of fibrinolysis. Heparin and the oral anticoagulant drugs do not affect the fibrinolytic mechanism.

19. FIBRINOLYTIC or THROMBOLYTIC DRUGS
Fibrinolytic drugs can lyse thrombi rapidly by their ability to activate plasmin from its precursor plasminogen.
Several fibrinolytic drugs used clinically to re-open the occluded coronary artery in patients with acute myocardial infarction or stroke and less commonly in patient with deep vein thrombosis and pulmonary embolism.
Clot dissolution and reperfusion occur with a higher frequency when therapy is initiated early after clot formation (within 2- to 6-hours) because clots become more resistant to lysis as they age. Unfortunately, increased local thrombi may occur as the clot dissolves, leading to enhanced platelet aggregation and thrombosis. Strategies to prevent this include administration of antiplatelet drugs, such as aspirin, or antithrombotics such as heparin.
Streptokinase is a protein extracted from cultures of streptococci. It forms an active one-to-one complex with plasminogen converting it to plasmin. Infused intravenously, it reduces mortality in acute myocardial infarction and this beneficial effect is additive with aspirin. Its action is blocked by antibodies, which appear about 4 days or more after the initial dose. So, at least 1 year must elapse before it is used again.

20. Urokinase is produced naturally in the body by the kidneys
Urokinase is produced naturally in the body by the kidneys. Therapeutic urokinase is isolated from human kidney cells and has low antigenicity. is only approved for lysis of pulmonary emboli.
 Recobinant human tissue plasminogen activators (t-PA): Alteplase is a serine protease obtained as a product of recombinant DNA technology. Reteplase is a genetically engineered, smaller derivative of recombinant tPA. Tenecteplase is another recombinant tPA with a longer half-life and greater binding affinity for fibrin than alteplase. Alteplase has a low affinity for free plasminogen in the plasma, but it rapidly activates plasminogen that is bound to fibrin in a thrombus or a hemostatic plug. Thus, alteplase is said to be “fibrin selective” at low doses. Alteplase is approved for the treatment of MI, massive PE, and acute ischemic stroke. Reteplase and tenecteplase are approved only for use in acute MI.
Alteplase has a very short half-life (5 to 30 minutes), and therefore, 10% of the total dose is injected intravenously as a bolus and the remaining drug is administered over 60 minutes. Both reteplase and tenecteplase have longer half-lives and, therefore, may be administered as an intravenous bolus. Alteplase may cause orolingual angioedema, and there may be an increased risk of this effect when combined with angiotensin-converting enzyme (ACE) inhibitors.

21. Unwanted effects and contraindications
The main hazard of all fibrinolytic agents is bleeding, including gastrointestinal hemorrhage and stroke. If serious, this can be treated with tranexamic acid (see below), fresh plasma or coagulation factors. Streptokinase can cause allergic reactions , low-grade fever and hypotension.
Contraindications to the use of these agents are:
Active internal bleeding or healing wounds
Hemorrhagic cerebrovascular disease
Bleeding abnormalities
Pregnancy
Uncontrolled hypertension
Recent trauma
brain tumor

22. ANTIFIBRINOLYTIC AND HAEMOSTATIC DRUGS
Aminocaproic acid is a synthetic inhibitor of fibrinolysis. It competitively inhibits plasminogen activation . It is rapidly absorbed orally and is cleared from the body by the kidney. It can be administered intravenously.
Tranexamic acid is an analog of aminocaproic acid but 10 times more potent than it. It can be given orally or by intravenous injection.
Both are used to treat various conditions in which there is bleeding or risk of bleeding, such as hemorrhage following prostatectomy or dental extraction, in menorrhagia (excessive menstrual blood loss) , for life-threatening bleeding following thrombolytic drug administration,they are also used as adjunctive therapy in hemophilia and as prophylaxis for rebleeding from intracranial aneurysms.

23. Adverse effects: include intravascular thrombosis from inhibition of plasminogen activator, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness. They should not be used in patients with disseminated intravascular coagulation or genitourinary bleeding of the upper tract, eg, kidney and ureters, because of the potential for excessive clotting.

24. Vitamin K
Vitamin K is a fat-soluble substance found primarily in leafy green vegetables. It is essential for the formation of clotting factors II, VII, IX and X. The dietary requirement is low, because the vitamin is additionally synthesized by bacteria that colonize the human intestine.
Two natural forms exist: vitamins K1 and K2. Vitamin K1 (phytonadione) is found in food. Vitamin K2 (menaquinone) is found in human tissues and is synthesized by intestinal bacteria.
Vitamins K1 and K2 require bile salts for absorption from the intestinal tract.

25. Vitamin K1 is available clinically in oral and parenteral forms
Vitamin K1 is available clinically in oral and parenteral forms. Onset of effect is delayed for 6 hours but the effect is complete by 24 hours when treating depression of prothrombin activity by excess warfarin or vitamin K deficiency.
Vitamin K1 is currently administered to newborns to prevent the hemorrhagic disease of vitamin K deficiency, which is especially common in premature infants.
Unwanted effect: hypersensitivity or anaphylactoid reactions.