Coagulation Modifier Drugs

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Anticoagulants: Warfarin - Overview

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Warfarin (Coumadin):

- Is a vitamin K antagonist and is the most commonly prescribed oral anticoagulant.

- It is a potent rodenticide (used to kill rats)

- Similar to Heparin it is used to prevent thrombosis

- Has a delayed onset of action thus making it inappropriate for emergency use

- Does NOT require injection, ideal for long-term prophylactic treatment

- Significant risk for hemorrhage - a number of drug interactions which can contribute to hemorrhage risk

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Warfarin: Mechanism of Action

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Warfarin supresses vitamin K dependent clotting factors (ie. VII, IX, X, prothrombin)

- Inhibits Vit. K epoxide reductase complex 1 (enzyme) needed to convert vit. K to its active form - reduces vit K dependant factors by 30-50%

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Warfarin: Pharmacokinetics

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Oral:

- Half life: 0.5-3 days; Onset: 12-24 hrs; Peak 3-4 days; Duration 3-5 days

- Delayed onset as Warfarin has no effect on clotting factors already present in circulation

- Coagulation remains inhibited for 2-5 days after discontinuation because of long half life

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Warfarin: Indications

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Most frequently prescribed for the long-term prophylactic treatment of thrombosis.

- Prevention/tx of venous thrombosis and associated PE (ie. DVT)

- Prevention of thromboembolism in pt.'s with prosthetic heart valves

- Prevention of thrombosis in pt.'s with atrial fibrillation

- Atrial fibrillation = high risk of CVA secondary to clot formation in artiums -- if dislodged can cause artery blockage = ischemic stroke

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Warfarin: Contraindications

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a) Active bleeding process or high risk of such occurence

b) Thrombocytopenia - low platelets

- Normal range: 150-400 x10^9/L

- Leukemia

- Small cohort of women develop thrombocytopenia during pregnancy

c) Surgery: warfarin should be dc days prior to elective surgery; vit. K given prior to emergent cases for those on warfarin (antidote)

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Warfarin: Adverse Effects

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a) Hemorrhage: considered a major complication of therapy and can occur at any time.

- Monitor for bleeding: BP, HR, bruising, petechiae, hematomas, black/red stool, discolored urine, pelvic pain, lumbar pain (ie. adrenal hemorrhage), headache (cerebral hemorrhage)

- Bleeding: dc warfarin, antidote = vit. K, avoid razors; soft toothbrush

b) Fetal hemorrhage and teratogenesis (pregnancy): FDA classification = risk outweighs benefit of drug administration.

- Warfarin crosses placenta and can result in fetal hemorrhage, malformation, CNS defects, optis atrophy and death.

- Women of child-bearing age and considering pregnancy should be aware of teratogenic effects: postpone pregnancy? termination of pregnancy if on warfarin? warfarin enters breast milk ie. can't breast feed

- Heparin is an alternative as it doesn't cross placental barrier

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International Normalized Ratio (INR)

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Internationally recognized blood test that measures the effectiveness of warfarin therapy.

- Objective of warfarin therapy is to increase INR = less chance for thrombus formation

INR levels vary for the condition being treated:

- Acute MI, atrial fib., valvular heart disease, PE, & venous thrombosis = 2-3

- Mechanical heart valves = 3- 4.5

- Systemic embolism - prevention = 2-3

- Systemic embolism - recurrent = 3- 4.5

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Warfarin: Interactions

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Subject to a large number of clinically significant drug interactions:

- Drugs that incr. the effect of warfarin: Asprin, acetaminophen, cimetidine, trimethoprim- sulfamethoxazole, cephalosporins

- Drugs that promote bleeding:

Aspirin, clopidogrel (plavix), heparins, glucocorticoids, indomethacin

- Drugs that decrease the effect of warfarin:

Dilantin, rifampin, phenobarbital, oral contraceptives, vitamin K

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Anticoagulants: Heparin (Hepalean) -Overview

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Rapid acting anticoagulant (SC/IV only) NOT IM!

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Heparin: Mechanism of Action

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Heparin administration --> activation of anti-thrombin --> promotes inactivation of thrombin factor Xa = supression of fibrin

- Fibrin forms the framework of thrombi in veins. Heparin is therefore useful in prophylactic tx. of venous thrombosis

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Heparin: Pharmacokinetics

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Half-life:1-2hrs

Onset: SC - 20-60mins; IV - immediate

Peak: 2-4 hrs

Duration: dose dependent

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Heparin: Indications

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a) Anticoagulant of choice for pregnancy as it does not cross the placenta

b) Critical/emergent situations: PE, evolving CVA (stroke), DVT, adjunct to acute MI management

c) Open heart surgery & renal dialysis: heparin prevents coagulation in devices (ie. heart/lung machines)

d) Post-operative prevention of venous thrombosis

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Heparin: Contraindications

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In those at high risk for bleeding:

- Hemophilia, severe hypertension, dissecting aneurysm, peptic ulcer disease

- Thrombocytopenia

- during/immediately after eye, brain, spinal cord injury

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Heparin: Adverse Effects

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a) Hemorrhage:

- bleeding occurs in aprox. 10% of pt.'s

- bleeding can occur at any site - monitor pt. carefully for blood loss: BP, HR, bruising, petechiae, hematomas, black/red stool, discolored urine, pelvic pain, lumbar pain (ie. adrenal hemorrhage), headache (cerebral hemorrhage)

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Activated Partial Thromboplastin Time (aPTT):

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- normal: 27-38 seconds

- Therapeutic goal is 1.5-2 times the normal (ie. 60-80 seconds)

- Heparin drip- frequent lab tests to determine therapeutic effect

- protamine sulfate is antidote for heparin

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Heparin: Interactions

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Platelet aggregation is the only remaining defense in those treated with heparin

- Avoid aspirin or other antiplatelet medications

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Antiplatelet: Aspirin - Overview

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- Anti-inflammatory, analgesic, anti-pyretic, clot prevention

- Prevention of thrombosis in arteries - where as warfarin and heparin prevent formation of thrombus in veins

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Aspirin: Mechanism of Action

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-Suppresses platelet aggregation by causing irreversable inhibition of cyclooxygenase (enzyme) that is required by paltelets to synthesize thromboxane A2.

- Thromboxane A2 promotes platelet aggregation and vasoconstriction

- Asprin supresses vasoconstriction, and platelet aggregation, thus reducing risk for arterial thrombosis

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Aspirin: Pharmocokinetics

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Oral:

- Half-life: 3.5-4.5 hours

- Onset: 15-30 mins

- Peak: 1-2 hours

- Duration: 4-6 hours

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Aspirin: Indications

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a) Ischemic stroke and TIA: reduce the risk of death and non-fatal stroke

b) Chronic stable angina, unstable angina, previous MI: Reduce risk of MI and death

c) Coronanry Stent Placement: to prevent re-occlusion

d) Acute MI: reduce risk of vascular death

e) Primary prevention of MI: prevent first MI in men and in women over 65 years old

- Research (2002) - in those at risk for cardiovascular event in next 5 years, aspirin lowers the risk of MI by 28%, it doesn't however, reduce the risk of death

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Aspirin: Contraindications

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- Thrombocytopenia

- Active bleeding

- Leukemia

- Traumatic Injury

- Gastric ulcer

- Vitamin K deficiency

- Recent stroke (CVA)

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Aspirin: Adverse Effects

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a) Increase risk of GI bleed and hemorrhagic stroke: even at low doses

- study - apsirin usage for at least 5 yrs:

2-4 bleeding episodes per 1000 pt.'s;

0-2 hemorrhagic strokes per 1000 pt.'s

b) Enteric coated aspirin may not reduce risk of GI bleeding: may need proton pump inhibitor - pantoprazole (protonix) - AKA GI protection

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Aspirin: Interactions

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a) NSAIDS/heparin: additive anti-platelet activity and increased bleeding potential

b) Hypoglycemic medications: large doses of aspirin may enhance the effect of oral hypogylcemic drugs

c) Steroids: Can increase risk of gastric ulcers/bleeding

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Thrombolytic: Alteplase (tPA) - Overview

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- Clot buster

- AKA Tissue Plasminogen Activator is made through recombinant DNA and modified hamster ovary cells

- Clot specific: doesn't produce systemic lyses

- Naturally occurring in body, therefore does not induce antibody-antigen response

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Alteplase (tPA): Mechanism of action

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Alteplase binds with plasminogen to form an active complex (alteplase-plasminogen complex)

- Complex converts other plasminogen molecules into plasmin (enzyme) that breaks down fibrin -- essentially it is a fibrinolytic

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Alteplase (tPA): Parmacokinetics

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IV:

Half-life: 5 mins

Onset: unknown

Peak: varies with dose

Duration: unknown - 80% cleared within 10 mins after stopping infusion

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Alteplase (tPA): Indications

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- Acute MI

- Acute ischemic stroke

- Acute massive PE

Global utilization of Streptokinase and tPA for Occluded Coronary Artery - large trial looked at benefits of thrombolytic drugs in pt.'s with MI:

- treated within 2 hrs of symptom onset - death rate 5.4%

- treated 2-4 hrs after symptom onset - death rate 6.6%

- treated 4-6 hrs after symptom onset - Death rate 9.4%

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Alteplase (tPA): Contraindications

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- Other medications altering clotting

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Alteplase (tPA): Adverse Effects

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Bleeding:

- Destroys pre-existing clots from recent injuries that have healed and can interfere with new clot formation -- Intracranial hemorrhage (ICH) is the most concerning -- recent wounds, needle punture sites, invasive?

- Management: Pressure dressings, Blood products (PRBCs), IV aminocaporic acid (prevents activation of plasminogen and inhibits plasmin)

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Alteplase (tPA): Interactions

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- Minimize physical manipulation

- Avoid SC and IM injections

- Minimize invasive procedures

- Minimize anticoagulant and antiplatelet use