Pharmacology Test 4: Anticoagulants And Anti-Anemia Drugs

Front 1

Hemostasis

Back 1

The process of forming clots in the walls of damaged blood vessels to prevent blood loss while maintaining blood in a fluid state within a vessel

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Thrombosis

Back 2

- Emboli (a dislodged thrombus) break off and travel in the bloodstream to distant sites and damage other organs (ex: PE)
- Caused by: Endothelial injury (atherosclerosis, diabetes, smoking); abnormal blood flow- stasis (common after surgery); hypercoaguability (genetic, acquired, oral contraceptives)

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Pharmacological Interventions to Treat Thrombosis

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1. Antiplatelets- prevent platelet activation and thus prevent clot formation
2. Anticoagulants- inhibit clotting cascade to ultimately prevent fibrin clot formation
3. Thrombolytics- dissolve an existing clot by digesting fibrin

Front 4

Antiplatelet Drugs

Back 4

- Block platelet aggregation and adhesion
- Cannot dissolve or remove a thrombus that has already formed
- Indications:
1. Prevent or treat occlusive cadiovascular dz
2. Maintain patent arteries, vascular grafts, shunts
3. Adjuncts to thrombolytic therapy for MI pts.
4. Cerebrovascular dz/stroke
5. Peripheral vascular dz

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The Antiplatelet Drugs are:

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1. Aspirin (ASA)
2. Dipyridamole (Persantine, Aggrenox)
3. Clopidogrel (Plavix)
4. Ticlopidine (Ticlid)
5. Abciximab (ReoPro)
6. Eptifibatide (Integrillin)

Front 6

Aspirin (ASA)

Back 6

- Antiplatelet Drug
- Low Dose (81-325mg/day)- selectively inhibits TXA2 production without affecting prostacyclin
- High Dose ASA inhibits prostacyclin synthesis, which normally prevents platelet aggregation
- Effect of ASA persists for as long as lifespan of platelet (about 10 days)
- Side Effects: increased incidence of hemorrhagic stroke, GI bleeding
- Typically the drug of choice unless pt. is allergic or intolerant

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Dipyridamole (Persantine, Aggrenox)

Back 7

- Antiplatelet Drug
- Inhibits phosphodiesterase (PDE) which increases cAMP and blocks platelet aggregation; also inhibits TXA2 production
- Short duration of action; repeated dosing or slow-release preps. needed to achieve long-term platelet inhibition
- Typically given in combo. with anticoagulant (warfarin) to prevent emboli from prosthetic heart valves or with ASA to prevent strokes in pts. with history of stroke

Front 8

Clopidogrel (Plavix) and Ticlopidine (Ticlid)

Back 8

- Antiplatelet Drug
- ADP receptor blocker: dec. ADP-induced platelet aggregation
- Long onset of action: only metabolites are biologically active
- Used to prevent secondary strokes, angina and during angioplasty
- Loading dose may be required to decrease onset time
- Maximum inhibition 8-11 days
- Side Effects: prolonged bleeding, neutropenia
- Clopidogrel is less toxic (so used for acute cerebral ischemia)

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Abciximab (ReoPro) and Eptifibatide (Integrillin)

Back 9

- Anitplatelet Drugs
- Abciximab- antibody fragment that blocks fibrinogen binding to GPIIb/IIIa
- Eptifibatide- GPIIb/IIIa competitive inhibitor
- Prevent aggregation and cross-linking of platelets
- Onset of action: 30 min, peak 2 hours, platelet fxn restored after 2 days
- Used mainly for prevention of thrombosis during coronary angioplasty in combo with ASA and heparin
- Side Effects: hemorrhage; concurrent use of warfarin is contraindicated
- ReoPro- $1500 per dose

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Anticoagulants

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Oral:
1. WARFARIN (Coumadin)
2. Anisindione/Phenindione (toxic, so no longer used)

Parenteral:
1. HEPARIN
2. LMW HEPARINS
3. Hirudin

- cannot dissolve an already formed thrombus
- Indicated for pts. with thromboembolic disorders: PE, MI, DVT, CVD/stroke, a. fib

Front 11

Heparin

Back 11

- Anticoagulant
- Inactivates clotting factors XIIa, XIa, IXa, Xa, and thrombin by greatly enhancing antithrombin III activity
- Administered only IV or SC
- Immediate onset of action when given IV; 1-2 hours SC
- T 1/2= 90 min
- Testing required to determine dose effect on coagulation
- Side Effects: hemorrhage, thrombocytopenia
- Antagonist: Protamine Sulfate

Front 12

Low Molecular Weight (LMW) Heparins

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- Anticoagulant
Commonly used are: Dalteparin (Fragmin) and Enoxaparin (Lovenox)
- Advantages over unfractioned heparin:
1. Longer half-life (4hrs) and faster absorption time
2. Much lower risk of thrombocytopenia and osteoporosis
3. Twice daily SC injections in outpt. setting
4. Less frequent monitoring required due to more predictable response

Front 13

Warfarin (Coumadin)

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- Most widely used oral anticoagulant
- Slow onset of action (12-48 hrs); max. effect 3-5 days after admin.
- Administered orally
- Used for long-term management of thromboembolic disorders (ex: a. fib., and DVT)
- Side Effects: hemorrhage; can cross the placenta
- Testing required to determine dose effect on coagulation
- Drug Interactions:
1. Increase Effects: anabolic steroids, antibiotics, tamoxifen, oral hypoglycemics
2. Decrease Effects: chronic alcohol, oral contraceptives, corticosteroids

** Phytonadione (Vitamin K) used to reverse bleeding associated with warfarin

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Thrombolytics

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- Effective only if used rapidly after onset of thrombosis- b/c after a few hrs. clot hardens and becomes resistant to breakdown by plasmin
- Use: treatment of acute MI, stroke, PE, or DVT
- Almost always used in conjunction with ASA and heparin
- Beta-blockers and ACE inhibitors sometimes given in conjunction to reduce heart damage and control arrhythmias
- Inhibitor of thrombolytics: Aminocaproic acid- inhibits the conversion of plasminogen to plasmin
- Most dangerous Side Effect: hemorrhage, particularly intracranial hemorrhage
- Contraindications: brain tumor; aneurysm; stroke w/in last 3-6 months; major surgery w/in last 2 weeks; active bleeding in GI or urinary tract; severe platelet shortage or coagulation disorder; severe uncontrolled hypertension

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The Thrombolytics are

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1. Streptokinase (Streptase)
2. Tissue Plasminogen Activator (tPA, Altepase, Activase)
3. Reteplase (Retavase)
4. Tenecteplase (TNKase)

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Streptokinase (Streptase)

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- Thrombolytic
- Enzyme derived from bacteria; first thrombo. available
- converts plasminogen to plasmin throughout circulation
- administered as a constant infusion IV for 1 hr; serum T 1/2= 20min
- must be reconstituted
- can cause allergic reaction- often Diphenhydramine (ex: Benadryl) pretreatment is given
- cheaper alternative to most thrombos

Front 17

Tissue Plasminogen Activator (tPA, Altepase, Activase)

Back 17

- Endogenous thrombolytic; human gene cloned, expressed and purified from bacteria
- Acts on plasminogen only at the site of the clot
- Administered as a small initial bolus followed by constant infusion IV for 90 min
- Serum T 1/2= 5 min
- must be reconstituted
- 8-10x more expensive than Strep.

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Reteplase (Retavase)

Back 18

- 2nd-generation thrombolytic
- Fragment of human tPA gene cloned, expressed and purified from bacteria
- Acts on plasminogen (like tPA) only at the site of the clot
- Convenience in dosing- 2 bolus injections 30 min apart
- Serum T 1/2= 18 min
- Must be reconstituted, but takes less time than tPA or SK (only about 1 min to recon)
- Expensive (comparable to tPA)

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Tenecteplase (TNKase)

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- 2nd-generation thrombolytic
- Fragment of human tPA gene cloned, genetically modified, expressed and purified from hamster cells
- More clot-specific than tPA and has some resistance to plasminogen inhibitors
- Convenience in dosing- single IV bolus over 5 sec
- Serum T 1/2= 20 min
- Must be reconstituted, but takes less time than tPA or SK (about 1 min)
- Expensive (comparable to tPA)

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Anemia

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- Decrease in number of RBCs (Hct 40-52% (men) 35-47% (female)
- Production defects: nutritional deficiences; inflammation/chronic dz; primary marrow disorders; decreased erythropoietin; chemotherapy
- Dilutional
- Blood Loss (ex: injury, surgeru, GI bleeding, heavy menstruation, clotting deficiency, colon cancer)
- Blood Destruction- increased destruction of RBCs (hemolytic anemia)

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Iron Deficiency Anemia

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- Caused by pregnancy, bleeding, impaired iron absorption, colon cancer
- RBCs are abnormally small and pale
- Treatment:
1. Ferrous fumarate (PO)
2. Ferrous gluconate (PO)
3. Ferrous sulfate (PO)
4. Polysaccharide-iron complex (PO)
5. Iron Dextran (IV or IM)
- Replaces iron necessary for RBCs to transport oxygen
- Antacids may inhibit the absorption of ferrous compounds
- Side Effects: GI upset, constipation, nausea

Front 22

Vitamin B12 Deficiency

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- B12 is required for RBC maturation
- Usually due to lack of intrinsic factor (pernicious anemia), which is needed to absorb B12 from the diet
- RBCs are abnormally large (magaloblastic anemia)
- Treatment: Vitamin B12 given IM or SC (for pernicious anemia) or orally as a dietary supplement

Front 23

Folic Acid Deficiency

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- Folic acid is required for maturation of pre-RBCs
- Cause- inadequate levels of folic acid in diet or impaired folic acid absorption (ex: intestinal dz or small bowel resection)
- Often seen in alcoholics with poor diet, during pregnancy and lactation, pts taking methotrexate, pts w/ hemolytic anemia or cancer
- RBCs are abnormally large
- Treatment: folic acid (PO or IM) or folinic acid (leucovorin calcium)