HEPARIN INDICATION Atrial fibrillation with embolization Treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation)

tion) Prevention of clotting in arterial and heart surgery Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and itsextension (In a low-dose regimen) for prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdomino-thoracic surgery or who for other reasons are at risk of developing thromboembolic Prophylaxis and treatment of pulmonary embolism Prophylaxis and treatment of peripheral arterial embolism

MECHANISM OF ACTION Under normal circumstances, antithrombin III (ATIII) inactivates thrombin (factor IIa) and factor Xa. This process occurs at a slow rate. Administered heparin binds reversibly to ATIII and leads to almost instantaneous inactivation of factors IIa and Xa The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin. The mechanism of action of heparin is ATIII-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. The antithrombotic effect of heparin is well correlated to the inhibition of factor Xa. Heparin is not a thrombolytic or fibrinolytic. It prevents progression of existing clots by inhibiting further clotting. The lysis of existing clots relies on endogenous thrombolytics. DOSAGE

SIDE EFFECTS

Bleeding & Miscellaneous Effects The major adverse effect of heparin is bleeding. This risk can be decreased by scrupulous patient selection, careful control of dosage, and close monitoring. Elderly women and patients with renal failure are more prone to hemorrhage. Heparin is of animal origin and should be used cautiously in patients with allergy. Increased loss of hair and reversible alopecia have been reported. Long-term heparin therapy is associated with osteoporosis and spontaneous fractures. Heparin accelerates the clearing of postprandial lipemia by causing the release of lipoprotein lipase from tissues, and long-term use is associated with mineralocorticoid deficiency. Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) is a systemic hypercoagulable state that occurs in 14% of individuals treated with UFH for a minimum of 7 days. Surgical patients are at greatest risk. The reported incidence of HIT is lower in pediatric populations outside the critical care setting and is relatively rare in pregnant women. The risk of HIT may be higher in individuals treated with UFH of bovine origin compared with porcine heparin and is lower in those treated exclusively with LMWH. Morbidity and mortality in HIT are related to thrombotic events. Venous thrombosis occurs most commonly, but occlusion of peripheral or central arteries is not infrequent. If an indwelling catheter is present, the risk of thrombosis is increased in that extremity. Skin necrosis has been described, particularly in individuals treated with warfarin in the absence of a direct thrombin inhibitor, presumably due to acute depletion of the vitamin K-dependent anticoagulant protein C occurring in the presence of high levels of procoagulant proteins and an active hypercoagulable state. The following points should be considered in all patients receiving heparin: Platelet counts should be performed frequently; thrombocytopenia appearing in a time frame consistent with an immune response to heparin should be considered suspicious for HIT; and any new thrombus occurring in a patient receiving heparin therapy should raise suspicion of HIT. Patients who develop HIT are treated by discontinuance of heparin and administration of a direct thrombin inhibitor or fondaparinux
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Reversal of Heparin Action Excessive anticoagulant action of heparin is treated by discontinuance of the drug. If bleeding occurs, administration of a specific antagonist such as protamine sulfate is indicated. CONTRAINDICATION

Hypersensitive to drug/class/compon. hypersensitive to pork products thrombocytopenia, severe hemorrhage active bleeding (except if DIC) neonates or infants pregnant patients breastfeeding patients caution if bleeding risk caution if severe hypertension caution if recent major surgery caution in elderly patients especially women

WARFARIN

INDICATION Warfarin is a commonly used medication for the prevention and treatment atrial fibrillation, venous thromboembolism and prosthetic heart valves. Atrial fibrillation is probably the most common indication for warfarin therapy in our community. There is a large body of evidence in the literature showing the high efficacy of warfarin in preventing ischaemic stroke in AF patients (6070% relative risk reduction). The target INR range is 2.03.0. It is important to realise that not all patients with AF need to be anticoagulated. A scoring system the CHADS2 score has been devised to help decision making regarding which patients with AF to warfarinise. Patients score 1 point for having either of the following: o Cardiac failure
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o Hypertension o Age 75 years or more o Diabetes mellitus and they score 2 points for prior history of Stroke or transient ischaemic attack. It is recommended that patients with a CHADS2 score of zero not be warfarinised. Patients with a score of 2 or more should be considered for warfarinisation if there are no contraindications (based on the riskbenefit ratio) and those with a score of 1 can either be treated with aspirin or warfarin. The role of warfarin therapy in patients with deep venous thrombosis (DVT) or pulmonary embolism (PE) istwofold. In treating the current episode anticoagulation aims at limiting clot extension thus allowing the fibrinolytic system to resolve the clot, a process which may take up to 6 weeks. In this setting, parenteral heparins are used together with warfarin during warfarin initiation. The second aim of anticoagulation in venous thromboembolism is prevention of thrombus recurrence. For this reason, anticoagulation needs to continue for a period of time beyond what is needed to allow for clot resolution. Several factors need to be considered in order to decide on the appropriate length of anticoagulation. In the presence of a prosthetic heart valve, the aim of anticoagulation is prevention of valve thrombosis and systemic embolisation. The risk of major embolism without antithrombotic therapy has been shown to be around 4 per 100 patient years, and this risk is reduced to about 1 per 100 patient years with oral anticoagulation. Therefore, patients with prosthetic heart valves need to be anticoagulated indefinitely. The target INR is 2.03.0 for aortic valve replacement in the absence of other risk factors for thrombosis (AF, previous embolism and low left ventricular ejection fraction). For prosthetic mitral valves or prosthetic aortic valves with risk factors the recommended target INR is 2.53.5

MECHANISM

SIDE EFFECT Patients taking warfarin bleed easily. This can produce serious, life-threatening side effects. A rare side effect of warfarin is skin tissue death and gangrene that may occur in the first three to eight days of starting treatment. This requires immediate medical attention to prevent the onset
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of gangrene infection. Also seek immediate medical attention if, at any time while taking warfarin, you experience severe bleeding, chest pain or pressure, nausea, diarrhea, vomiting, fever or flu-like symptoms. Rectal bleeding or dark-colored stools also require emergency medical care. Numbness, tingling, swelling and difficulty moving may indicate a serious complication. Seek medical attention for painful erections that last four hours or longer.

The most common side effect of warfarin is bleeding. This is most likely to occur if your INR is too high, and if you put yourself at risk of injury. The risk of bleeding is greatly reduced by managing your therapy well and keeping your INR inside your target range.

Signs of slight bleeding that you may notice from time to time: o Gum bleeding while brushing teeth. o Occasional nose bleeds. o Easy bruising. o Bleeding after a minor cut that stops within a few minutes. o Menstrual bleeding that is a little heavier than normal. Signs and symptoms of more serious bleeding to watch for include: o Severe bruising that gets worse. o Any bleeding that take a long time to stop. o Unexplained bleeding or bruising o Menstrual bleeding that is much heavier than usual. o Red or dark urine. o Red or black bowel motions. o Coughing up blood, or anything red. o Bloody or dark stained vomit. o Severe headache or dizziness. o Weakness or lethargy. o Unusual pain or swelling. If any of the above symptoms occur you should contact your doctor immediately. If your doctor is unavailable, go to your nearest hospital emergency department.

Other Side Effects Occasionally people may experience other side effects associated with taking warfarin. These side effects are rare but include: o Unusual skin lesions. These usually appears within 3 to 10 days of starting warfarin, and the risk is reduced if heparin is used when warfarin treatment is commenced. o Purple discolouration of the toes. This usually appears within 3 to 8 weeks of starting warfarin. o Hair loss o Rash If you notice any of the above, or something else that you feel may be caused by your medication, even if it's not on the list above, speak to your healthcare professional.

CONTRA INDICATION Current guidelines do not recommend warfarin use in patients with systolic heart failure unless indicated for other cardiovascular conditions.

The most obvious contraindication to warfarin therapy is recent haemorrhage. Bleeding tendencies due to congenital or acquired disorders of the clotting system are also important. The presence of severe liver disease may predispose to bleeding. Warfarin is teratogenic and should be avoided during pregnancy. This should be discussed with all women of childbearing potential. Heparins (both unfractionated and low molecular weight) can be prescribed during pregnancy and provide a safe alternative.

ALTEPLASE INDICATION Alteplase is used to treat persons with heart attacks (acute myocardial infarctions), strokes, chest pain at rest (unstable angina), blood clots in the lungs (pulmonary thrombosis or embolism), and other less common conditions involving blood clots. It is also used for clearing blood clots from blocked venous catheters.

1. Acute Myocardial Infarction Activase (alteplase) (Alteplase) is indicated for use in the management of acute myocardial infarction in adults for the improvement of ventricular function following AMI, the reduction of the incidence of congestive heart failure, and the reduction of mortality associated with AMI. Treatment should be initiated as soon as possible after the onset of AMI symptoms. 2. Acute Ischemic Stroke Activase (Alteplase) is indicated for the management of acute ischemic stroke in adults for improving neurological recovery and reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage. 3. Pulmonary Embolism Activase (Alteplase) is indicated in the management of acute massive pulmonary embolism (PE) in adults: For the lysis of acute pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple segments of the lungs. For the lysis of pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures. The diagnosis should be confirmed by objective means, such as pulmonary angiography or noninvasive procedures such as lung scanning. MECHANISM OF ACTION Activase (alteplase) is an enzyme (serine protease) which has the property of fibrin-enhanced conversion of plasminogen to plasmin. It produces limited conversion of plasminogen in the absence of fibrin. When introduced into the systemic circulation at pharmacologic concentration, Activase (alteplase) binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis. Following administration of 100 mg Activase (alteplase) , there is a decrease (16%-36%) in circulating
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fibrinogen. In a controlled trial, 8 of 73 patients (11%) receiving Activase (alteplase) (1.25 mg/kg body weight over 3 hours) experienced a decrease in fibrinogen to below 100 mg/dL.2 The clearance of Alteplase in AMI patients has shown that it is rapidly cleared from the plasma with an initial half-life of less than 5 minutes. There is no difference in the dominant initial plasma half-life between the 3-Hour and accelerated regimens for AMI. The plasma clearance of Alteplase is 380-570 mL/min. The clearance is mediated primarily by the liver. The initial volume of distribution approximates plasma volume. CONTRAINDICATION Known hypersensitivity to this drug, active internal bleeding, recent cerebrovascular accident, severe uncontrolled hypertension, intracranial trauma or surgery, intraspinal trauma or surgery, aneurysm, and brain tumor prohibit the use of this drug. 1. Acute Myocardial Infarction or Pulmonary Embolism Activase (alteplase) therapy in patients with acute myocardial infarction or pulmonary embolism is contraindicated in the following situations because of an increased risk of bleeding: Active internal bleeding History of cerebrovascular accident Recent intracranial or intraspinal surgery or trauma Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis Severe uncontrolled hypertension

2. Acute Ischemic Stroke Activase (alteplase) therapy in patients with acute ischemic stroke is contraindicated in the following situations because of an increased risk of bleeding, which could result in significant disability or death: Evidence of intracranial hemorrhage on pretreatment evaluation Suspicion of subarachnoid hemorrhage on pretreatment evaluation

Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or previous stroke History of intracranial hemorrhage Uncontrolled hypertension at time of treatment (e.g., > 185 mm Hg systolic or > 110 mm Hg diastolic) Seizure at the onset of stroke Active internal bleeding Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis including but not limited to: Current use of oral anticoagulants (e.g., warfarin sodium) or an International Normalized Ratio (INR) > 1.7 or a prothrombin time (PT) > 15 seconds

Administration of heparin within 48 hours preceding the onset of stroke and have an elevated activated partial thromboplastin time (aPTT) at presentation Platelet count < 100,000/mm3

SIDE EFFECTS The most common and serious side effect with alteplase is bleeding. Minor bleeding is more common, but significant bleeding such as into the brain or fatal bleeding also occurs. Nausea, vomiting, and allergic reactions also occur.It is not known whether alteplase passes into breast milk. 1. Bleeding The most frequent adverse reaction associated with Activase (alteplase) in all approved indications is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories: Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.

Superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g., venous cutdowns, arterial punctures, sites of recent surgical intervention).

Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, Activase (alteplase) therapy should be discontinued immediately, along with any concomitant therapy with heparin. Death and permanent disability are not uncommonly reported in patients that have experienced stroke (including intracranial bleeding) and other serious bleeding episodes. For the 3-hour infusion regimen, the incidence of significant internal bleeding (estimated as > 250 cc blood loss) has been reported in studies in over 800 patients. These data do not include patients treated with the Alteplase accelerated infusion. TOTAL DOSE 100 MG gastrointestinal genitourinary ecchymosis retroperitoneal epistaxis gingival 5% 4% 1% < 1% < 1% < 1%

2. Allergic Reactions Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual angioedema, rash, and urticaria have been reported. A cause and effect relationship to Activase (alteplase) therapy has not been established. When such reactions occur, they usually respond to conventional therapy. There have been post-marketing reports of orolingual angioedema associated with the use of Activase (alteplase) . Most reports were of patients treated for acute ischemic stroke, some reports were of patients treated for acute myocardial infarctions. Many of these patients received concomitant angiotensin-converting enzyme inhibitors. Most cases
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resolved with prompt treatment; there have been rare fatalities as a result of upper airway hemorrhage from intubation trauma. 3. Other Adverse Reactions The following adverse reactions have been reported among patients receiving Activase (alteplase) in clinical trials and in post-marketing experience. These reactions are frequent sequelae of the underlying disease and the effect of Activase (alteplase) on the incidence of these events is unknown. Use in Acute Myocardial Infarction: Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema. These events may be life threatening and may lead to death. Nausea and/or vomiting, hypotension and fever have also been reported. CLOPIDOGREL INDICATION

Clopidogrel is used to prevent heart attacks and strokes in persons with heart disease (recent heart attack), recent stroke, or blood circulation disease (peripheral vascular disease).

It is also used with aspirin to treat new/worsening chest pain (new heart attack, unstable angina) and to keep blood vessels open and prevent blood clots after certain procedures (such as cardiac stent, coronary artery bypass graft-CABG, balloon angioplasty).

MECHANISM OF ACTION The active metabolite of clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. DOSAGE
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First dose 300 mg followed by 75mg per oral Take once per day SIDE EFFECTS Gastrointestinal effect: nausea, vomiting, indigestion, gastritis, diarrhea and constipation. Haematological effects: gastrointestinal bleeding, intracranial bleeding, brusing, purpura, epitaxis, hematoma, hematuria. Dermatological (rash and itching).

CONTRAINDICATION

Hypersensitivity to the drug substance or any component of the product. Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

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