Pharmacology Flashcards
Heparin
MECHANISM Cofactor for the activation of antithrombin, decr thrombin, and decr factor Xa. Short half-life.
CLINICAL USE Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT. Used during pregnancy (does not cross placenta). Follow PTT.
TOXICITY Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin).
NOTES Low-molecular-weight heparins (e.g., enoxaparin, dalteparin) act more on factor Xa, have better bioavailability and 2–4 times longer half-life. Can be administered subcutaneously and without laboratory monitoring. Not easily reversible.
Heparin-induced thrombocytopenia (HIT)—development of IgG antibodies against heparin bound to platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets–> thrombosis and thrombocytopenia.
Argatroban, bivalirudin
Derivatives of hirudin, the anticoagulant used by leeches; inhibit thrombin directly. Used instead of heparin for anticoagulating patients with HIT.
Warfarin (Coumadin)
MECHANISM Interferes with normal synthesis and
γ-carboxylation of vitamin K–dependent clotting factors II, VII, IX, and X and proteins C and S. Metabolized by the cytochrome P-450 pathway. In laboratory assay, has effect
on EXtrinsic pathway and incr PT. Long half-life.
The EX-PresidenT went to war(farin).
CLINICAL USE Chronic anticoagulation (after STEMI, venous
thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation). Not used in pregnant women (because warfarin, unlike heparin, can cross the placenta).
Follow PT/INR values.
TOXICITY Bleeding, teratogenic, skin/tissue necrosis,
drug-drug interactions.
For reversal of warfarin overdose, give vitamin K. For rapid reversal of severe warfarin overdose, give fresh frozen plasma.
Warfarin (Coumadin)
MECHANISM Interferes with normal synthesis and
γ-carboxylation of vitamin K–dependent clotting factors II, VII, IX, and X and proteins C and S. Metabolized by the cytochrome P-450 pathway. In laboratory assay, has effect
on EXtrinsic pathway and incr PT. Long half-life.
The EX-PresidenT went to war(farin).
CLINICAL USE Chronic anticoagulation (after STEMI, venous
thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation). Not used in pregnant women (because warfarin, unlike heparin, can cross the placenta).
Follow PT/INR values.
TOXICITY Bleeding, teratogenic, skin/tissue necrosis,
drug-drug interactions.
For reversal of warfarin overdose, give vitamin K. For rapid reversal of severe warfarin overdose, give fresh frozen plasma.
Direct factor Xa inhibitors
Apixaban, rivaroxaban.
MECHANISM Bind and directly inhibit the activity of factor Xa.
CLINICAL USE Treatment and prophylaxis of DVT and PE (rivaroxaban), stroke prophylaxis in patients with atrial
fibrillation.
Oral agents do not usually require coagulation monitoring.
TOXICITY Bleeding (no specific reversal agent available).
Heparin
Heparin
STRUCTURE Large anionic, acidic polymer
ROUTE OF ADMINISTRATION Parenteral (IV, SC)
SITE OF ACTION Blood
ONSET OF ACTION Rapid (seconds)
MECHANISM OF ACTION Activates antithrombin, which decr the action of IIa (thrombin) and factor Xa.
DURATION OF ACTION Acute (hours)
INHIBITS COAGULATION IN VITRO Yes
TREATMENT OF ACUTE OVERDOSE Protamine sulfate
MONITORING PTT (intrinsic pathway)
CROSSES PLACENTA No
Warfarin
Heparin STRUCTURE Small lipid-soluble molecule ROUTE OF ADMINISTRATION Oral SITE OF ACTION Liver ONSET OF ACTION Slow, limited by half-lives of normal clotting factors MECHANISM OF ACTION Impairs the synthesis of vitamin K–dependent clotting factors II, VII, IX, and X (vitamin K antagonist) DURATION OF ACTION Chronic (days) INHIBITS COAGULATION IN VITRO No TREATMENT OF ACUTE OVERDOSE IV vitamin K and fresh frozen plasma MONITORING PT/INR (extrinsic pathway) CROSSES PLACENTA Yes (teratogenic)
Thrombolytics
Alteplase (tPA), reteplase (rPA), tenecteplase (TNK-tPA).
MECHANISM Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin
clots. Incr PT, incr PTT, no change in platelet count.
CLINICAL USE Early MI, early ischemic stroke, direct thrombolysis of severe PE.
TOXICITY Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension.
Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.
Thrombolytics
Alteplase (tPA), reteplase (rPA), tenecteplase (TNK-tPA).
MECHANISM Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin
clots. Incr PT, incr PTT, no change in platelet count.
CLINICAL USE Early MI, early ischemic stroke, direct thrombolysis of severe PE.
TOXICITY Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension.
Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.
Aspirin (asa)
MECHANISM Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) enzyme by covalent acetylation.
Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced: incr bleeding time, decr TXA2 and prostaglandins. No effect on PT or PTT.
CLINICAL USE Antipyretic, analgesic, anti-inflammatory, antiplatelet (decr aggregation).
TOXICITY Gastric ulceration, tinnitus (CN VIII). Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding. Reye syndrome in children with viral infection.
Overdose causes respiratory alkalosis initially, which is then superimposed by metabolic acidosis.
ADP receptor inhibitors
Clopidogrel, ticlopidine, prasugrel, ticagrelor.
MECHANISM Inhibit platelet aggregation by irreversibly blocking ADP receptors. Inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa from binding to fibrinogen.
CLINICAL USE Acute coronary syndrome; coronary stenting. decr incidence or recurrence of thrombotic stroke.
TOXICITY Neutropenia (ticlopidine). TTP/HUS may be seen.
Cilostazol, dipyridamole
MECHANISM Phosphodiesterase III inhibitor; Incr cAMP in platelets, thus inhibiting platelet aggregation; vasodilators.
CLINICAL USE Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with
aspirin), angina prophylaxis.
TOXICITY Nausea, headache, facial flushing, hypotension, abdominal pain.
GP IIb/IIIa inhibitors
Abciximab, eptifibatide, tirofiban.
MECHANISM Bind to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Abciximab
is made from monoclonal antibody Fab fragments.
CLINICAL USE Unstable angina, percutaneous transluminal coronary angioplasty.
TOXICITY Bleeding, thrombocytopenia.
Methotrexate (MTX) - antimetabolite
MECHANISM
Folic acid analog that inhibits dihidrofolate reductase –> decr dTMP –> decr DNA and decr protein synthesis.
CLINICAL USE
Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas.
Non-neoplastic: abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis, IBD.
TOXICITY
Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue.”
Macrovesicular fatty change in liver.
Mucositis.
Teratogenic.
5-fluorouracil (5-FU)
MECHANISM
Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid.
This complex inhibits thymidylate synthase–> decr dTMP –> decr DNA and decr protein synthesis.
CLINICAL USE
Colon cancer, pancreatic cancer, basal cell carcinoma (topical).
TOXICITY
Myelosuppression, which is not reversible with leucovorin.
Overdose: “rescue” with uridine.
Photosensitivity.
Methotrexate (MTX)
Antimetabolite, S-phase specific
MECHANISM
Folic acid analog that inhibits dihidrofolate reductase –> decr dTMP –> decr DNA and decr protein synthesis.
CLINICAL USE
Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas.
Non-neoplastic: abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis, IBD.
TOXICITY
Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue.”
Macrovesicular fatty change in liver.
Mucositis.
Teratogenic.
