Anesthesia Pharmacology: Drugs that Influence Coagulation
Anticoagulant Drugs: Pharmacology
Sulfated mucopolysaccharides (heterogenous)
Binds to endothelial cell surface membrane.
Heparin activity dependent on: plasma protease inhibitor antithrombin III
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
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)
Obtained from:
Porcine intestinal mucosa
Bovine lung
Enoxaparin (Lovenox) -- same sources; amount specified in milligrams
Dalteparin (Fragmin)and danaproid (Orgaran)-- amounts specified in anti-factor Xa units
Major adverse/toxic effect: bleeding
Risk managed by attention to:
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
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
Heparin hypersensitivity
Hematologic disease:
Hemophilia, thrombocytopenia, purpura,
Cardiovascular:
Severe hypertension, intracranial hemorrhage, infective endocarditis
Active tuberculosis
Gastrointestinal tract
Ulcerative lesions
Visceral carcinoma
Advanced hepatic/renal dysfunction
Threatened abortion
Related to medical procedures:
After brain, spinal cord, or eye surgery
Lumbar puncture/regional anesthesia blocks
Drug discontinuation
Use specific antagonist, e.g. protamine sulfate (note!- excess protamine also has an anticoagulant effect)
Warfarin and Coumarin Structures
|
|
Coumarin: produces plasma prothrombin deficiency
Active agent --: bishydroxycoumarin (synthesis -- dicumarol)
Rodenticide
Humans: antithrombotic agent
Warfarin
High bioavailability; most bound to plasma albumin (99%)
Racemate-- equal amounts of two enantiomorphs
Levorotatory-S-warfarin: four times more potent than dextrorotatory- R-warfarin
Mechanism of Action: coumarin anticoagulants
Blockade of γ-carboxylation of glutamate residues in:
Prothrombin
Factors: VII, IX, X
Endogenous anticoagulant protein C
γ-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
Partially inhibited synthesis of the four vitamin K-dependent clotting factors and
Unaltered degradation rates of these factors.
Higher initial doses (loading doses) speed onset by maximally inhibiting synthesis
Toxicity: coumarin anticoagulants
Warfarin: crosses the placenta → hemorrhagic fetal disorder
Fetal abnormal bone formation (Warfarin effects on fetal proteins with g-carboxylglutamate 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
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 and sulfinpyrazone-- effects: a
Added hypoprothrombinemia
Platelet function inhibition
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 and 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:
Dscontinue drug administration
Administer vitamin K1 (phytonadione) and 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)
Dicumarol -- incompletely absorbed; GI symptoms
Phenprocoumon: extended half-life; adverse renal/hepatic effects.
Primary Reference: O'Reilly, R.A. Drugs Used in Disorders of Coagulation, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 916-940
Handlin, R.I. Bleeding and Thrombosis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 339-344.
This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information. Medical or other information thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals. |