Anticoagulant Drugs: Pharmacology Heparin

Composition:
o

sulfated mucopolysaccharides (heterogenous)

Mechanism of Action: Binds to endothelial cell surface membrane. Heparin activity dependent on: plasma protease inhibitor antithrombin III

1. 2.

Antithrombin III -- inhibitor of clotting factors proteases (forming 1:1 stable complexes) Complex forming reactions normally slow -- accelerated by three orders of magnitude (1000 times) by heparin acceleration mechanism: heparin binding induces a change in antithrombin III inhibitor form resulting in increased complex formation activity Following antithrombin-protease complex formation, heparin is released; available for binding to other antithrombin molecules
o

{a heparin high-molecular-weight (HMW) fraction has higher affinity for antithrombin compared to other fractions} {a heparin low-molecular-weight (LMW) fraction has a lower affinity for antithrombin but inhibits factor Xa (activated)}

a low-molecular-weight fraction (LMW), enoxaparin (Lovenox) is FDA approved for primary prevention of deep venous thrombosis following hip replacement surgery. Dalteparin and danaproid have been also approved for prevention of the venous thrombosis following hip replacement surgery

Heparin (HMW): standardized by bioassay (units)

o

obtained from:

porcine intestinal mucosa bovine lung

o o

Enoxaparin (Lovenox) -- same sources; amount specified in milligrams Dalteparin (Fragmin)& danaproid (Orgaran)-- amounts specified in anti-factor Xa units

Toxicity:heparin
o

major adverse/toxic effect: bleeding

Risk managed by attention to:

1. 2. 3.

patient selection dosage control monitoring of partial thromboplastin time (PTT)

Factors predisposing to hemorrhage:

elderly renal failure patients

Long-term heparin use-- increased incidence of:

osteoporosis spontaneous fractures

o o o o

Transient thrombocytopenia: frequency = 25% Severe thrombocytopenia: frequency = 5% Paradoxical thromboembolism heparin-induced platelet aggregation Patients on heparin:

thrombocytopenia that causes bleeding: probably due to heparin new thrombus: may be due to heparin if thromboembolic disease may be heparin-induced: discontinue heparin

Contraindications:heparin
o o

Heparin hypersensitivity Hematologic disease:

hemophilia, thrombocytopenia, purpura,

Cardiovascular:

severe hypertension, intracranial hemorrhage, infective endocarditis

o o

Active tuberculosis Gastrointestinal tract

ulcerative lesions visceral carcinoma

o o o

Advanced hepatic/renal dysfunction Threatened abortion Related to medical procedures:

after brain, spinal cord, or eye surgery lumbar puncture/regional anesthesia blocks

Reversal of Heparin Effects: 0. drug discontinuation 1. Use specific antagonist, e.g. protamine sulfate (note!- excess protamine also has an anticoagulant effect)

Warfarin & Coumarin Coumarin

Warfarin

Chemistry/Pharmacokinetics:Warfarin & Coumarin

o o o

Coumarin: produces plasma prothrombin deficiency active agent --: bishydroxycoumarin (synthesis -- dicumarol) Uses:

rodenticide humans: antithrombotic agent

Oral anticoagulants:

Warfarin -- agent in use high bioavailability; most bound to plasma albumin (99%) racemate-- equal amounts of two enantiomorphs

levorotatory-S-warfarin: four times more potent than dextrorotatory- Rwarfarin

Mechanism of Action:coumarin anticoagulants

o

Blockade of g-carboxylation of glutamate residues in:

prothrombin factors: VII, IX, X endogenous anticoagulant protein C

o o

g-carboxylation results in biologically inactive molecules Carboxylation reaction is coupled with oxidative deactivation of vitamin K

anticoagulant prevents reductive metabolism of inactive vitamin K epoxide regenerating active hydroquinone.

Anticoagulant effect dependent on two considerations A. partially inhibited synthesis of the four vitamin K-dependent clotting factors and B. naltered degradation rates of these factors.

Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis

Toxicity:coumarin anticoagulants
o

Warfarin: crosses the placenta hemorrhagic fetal disorder

Fetal abnormal bone formation (Warfarin effects on fetal proteins with gcarboxylglutamate residues). Never administer Warfarin during pregnancy

Other Adverse Effects:coumarin anticoagulants

Cutaneous necrosis related to reduced protein C activity Rare: reduced protein C activity breast, fatty tissues, intestine, extremity infarction

Drug-Drug Interactions:oral anticoagulants

o

Pharmacokinetic effects include:

enzyme induction enzyme induction reduced plasma protein binding

Pharmacodynamic effects include:

synergistic interactions with Warfarin

impaired hemostasis, diminish clotting factor synthesis (e.g. hepatic disease)

competitive antagonism (vitamin K) abnormal physiologic vitamin K control loop (hereditary oral anticoagulant resistance)

Most serious interaction:-- interactions that increase anti-coagulation (promote bleeding risk)

most dangerous: pharmacokinetic interactions with:

pyrazolones phenylbutazone & sulfinpyrazone-- effects: a 1. added hypoprothrombinemia 2. platelet function inhibition 3. promotion: peptic ulcer disease

Metronidazole, fluconazole, trimethoprim-sulfamethoxazole:

stereoselective in addition of S-warfarin metabolism

Amiodarone, disulfram, cimetadine:

inhibit metabolism of Warfarin (both enantiomorphs)

Aspirin, hepatic disease, hypothyroidism -- enhance Warfarin effects {pharmacodynamic}

Aspirin:effects on platelets hepatic disease/hypothyroidism: increasing clotting factors turnover rates

Third-generation cephalosporins -

kill intestinal bacteria that produce vitamin K directly inhibit vitamin K epoxide reductase

Decrease of anticoagulant action:

Barbiturates & rifampin: anticoagulant reduction by increasing liver enzymes that transform racemic Warfarin. Cholestyramine: promotes intestinal Warfarin binding

Pharmacodynamic-mediated reduction of anticoagulant effects:

vitamin K -- {increased clotting factors synthesis} diuretics -- chlorthalidone, spironolactone {affect clotting factor concentration} genetics -- {molecular mutations of vitamin K reactivation cycle components}

hypothyroidism -- {reduced clotting factors turnover rate}

Reversal of Warfarin anticoagulant effects:

o o

discontinue drug administration administer vitamin K1 (phytonadione) & fresh-frozen plasma or factor IX concentrates {Konyne-80 and Proplex which contained prothrombin complex} Objective of intervention: establishing normal clotting factor activity

serious bleeding: large amounts of vitamin K1 (intravenous administration), factor IX concentrates, and possibly whole blood transfusion

Other related agents:(seldom used due to unfavorable toxicity/pharmacologic properties)

o o

dicumarol -- incompletely absorbed; GI symptoms Phenprocoumon:extended half-life; adverse renal/hepatic effects.