1. bind to antithrombin III
2. opens up the active site of antithrombin III
3. acelerates the rate of formation of ATIII:X and ATIII:II
4. decrease the amount of active X, II
5. decreases formation of fibrin clot

• strongly acidic
• repeating units of D-glucoronic acid and sulfated D-glucosamine or L-iduronic acid
• naturally occuring polysaccharide
• prepared from porcine intestines or bovine lung

• parenteral administration
  • with immediate onset when given IV
  • never give orally
• cleared and degraded mainly by reticuloendothelial system
• metabolized by liver
• distribution- does NOT cross placenta (SAFE IN PREGNANCY)
• plasma half life is dose dependent: 1-5 hrs

• bleeding (MAJOR)
• hypersensitivity rxn- fever, rash urticaria
  • rare- anaphylaxis
• transient thrombocytopenia
• heparin induced thrombocytopenia
  • rare- severe thrombocytopenia

Monitor anticoagulant action by seeing if you can keep aPTT at 2x its control

• Process
  1. produce Ab's directed against heparin-platelet factor 4 complexes
  2. they will bind to Fc receptors on adjacent platelets, activating them causing
     • aggregation
     • thromboembolism
• solution- warfarin is also CI in HIT, so we use a direct thrombin inhibitor

• prevent DVT/PE esp. in hip surgery
• acute MI
• unstable angina
• prevent thrombosis in extracorporeal devices (ex: stents)

• hypersensitivity
• active bleeding
  • intracranial hemorrhage
  • GI ulceration
• threatened abortion
• infective endocarditis
• surgical procedures in general

• chemistry- highly basic peptide (positive charge, and remember, heparin has a negative charge)
• mechanism- heparin antagonist
  1. ion pairs with heparin to form a stable complex devoid of anticoagulant activity
• adverse effects
  • dyspnea
  • bradycardia
  • hypotension
• toxicity- excessively by itself, produces anticoagulant activity

Enoxaparin

Dalteparin

same as unfractionated heparin, but it is highly selective for factor Xa because of its lower molecular weight

• longer half life than generic heparin
  • improved bioavailability after subQ administration permits use of fixed dosage without much need for routine monitoring of acitivity
  • half life: 3-6 hrs
  • QD dosing
• excreted in urine

px of DVT/PE

• bleeding (same as unfractionated)
• HIT (less frequent than unfractionated)
  • CI: h/o HIT
• allergic rxns- urticaris, skin necrosis at injection site

• synthetic analog of heparin
  • due to pentasaccharide binding sequence
  • allows it to inhibit X with no effect on II
  • also does not bind platelet 4, so does not cause HIT

• px of PE/DVT
• thrombopx for patients undergoing hip or knee surgery

• adverse effects
  • bleeding
  • thrombocytopenia
• PK
  • half life: 17-21 hrs
  • QD dosing
  • subQ administration
  • no monitoring needed

1. directly complex with thrombin (1:1) with little effect on related serine proteases (ex: X)
   • also no need for ATIII
2. inhibits fibrin bound thrombin and soluble thrombin

Remember, this is the recombinant form of hirudin (from leeches)

• indications- thrombosis related to HIT
• PK
  • parenterally administered
  • short half life: 1-2 hrs (accumulate in renal insufficiency, so dosage adjust)
• adverse rxn
  • Ab formed to it (thrombin-lepirudin complex) that are not cleared

• mechanism of action- like lepirudin, direct inhibitor derived from hirudin
• PK
  • short acting half life: 25 minutes
  • coagulation time returns to baseline one hr after drug is stopped
• indication- angioplasty

• chemistry- synthetic derivative of arginine
• indication- anticoagulant in pts with h/o HIT
• mechanism- reversibly block catalytic site of thrombin (both soluble and clot bound)
• PK- metabolized by P450
  • dosage adjust- liver disease
• adverse rxn
  • hematuria
  • allergic rxns
  • hemorrhage

1. inhibits VKORCI (as structural analong of vitamin K)
2. this decreases the amount of vitamin K that is reduced and can be used
3. this decreases carboxylation of viatmin K dependent factors leading to the decrease of:
   1. first, VII
   2. second, IX
   3. thrid, X
   4. and finally, II
4. this will as well decrease protein C in the first few weeks

Most active in S enantiomer form.

• bleeding
• hemorrhagic disorder in fetus
  • serious birth defects due to abnormal bone formation
  • CI: pregnancy
• cutaneous necrosis with reduced activity of protein C in first few weeks of pregnancy (leads to procoagulant state)

• 100% bioavailable (99% protein bound)
• half life: 36 hrs
• extensively metabolized via CYP29 to hydroxylated metabolites and excreted in urine
• distribution: cross placenta
  • CI: pregnancy
• administered as sodium salt

• phenobarbitol induces P450 leading to increase in metabolism, decrease warfarin levels
• sulfonamides inhibit P450 leading to decrease metabolism, increase warfarin levels
• sulfonamides also decrease binding of plasma protein, leading to increase in free warfarin
• aspirin interferes with normal platelet function, so we would get an intensified anticoagulant function
• cholestyramine binds to warfarin and blocks its absorption from the GI tract, decrease warfarin levels
• vitamin K in large doses can restore normal activity of clotting factors, leading to reversal of warfarin action

1. irreversible acetylation of Ser residdues at COX-1 and COX-2
2. leads to blocking access of arachidonic acid to active site of cyclooxygenases
3. decrease cyclooxygenase activity
4. decrease TXA activity, which inhibit platelet adhesion and aggregation
   • effect last 7-10 days (platelets have no nucleus)

• px/therapy of thromboembolism
• MI
• post MI
• transient cerebral ischemia
• unstable angina
• coronary bypass surgery

Ticlodipine

Clopidogrel

1. inhibits P2Y₁ OR P2Y₁₂ (separate purine R's)
2. inhibits ADP mediated activation of platelets

Synergy with aspirin

• alternative for those who cannot tolerate aspirin (this drug has no effect on PG path)

• very few (replaced ticlopidine as alternative to aspirin)
  • lower risk of neutropenia
• rash
• abdominal pain and dyspepsia
• thrombotic thrombocytopenia

• well absorbed
• extensively metabolized by liver
• half life= 8 hrs
• urine and fecal elimination

• antacids decrease its absorption
• cimitidine decrease clearance
• increases the half life of theophyline

1. block GP_IIb/IIIa
2. leads to decrease in anchoring of platelets
3. decrease in receptors for fibrinogen and vWF
4. decrease aggregation

• indications- angioplasty adjunct therapy to prevent re-stenosis of treated coronary artery
• adverse reactions
  • bleeding at arterial access site
  • GI, GU, retroperitoneal bleeding

streptokinase

alteplase (aka tPA)

1. increase tPA
2. this will increase activation of plasminogen to plasmin (must overcome PAI and alpha 2 antiplasmin to do this)
   1. degrade fibrin to fibrin split products
   2. degrade fibrinogen
3. leads to lysing of thrombosis
4. cause restoration of tissue perforation

1. form stable 1:1 complex with plasminogen
2. confirmation change to expose plasminogen active site leading to activation to plasmin

1. bind fibrin and activate plasminogen bound to fibrin-tPA complex (show clot specificity)
   • cause increase in activation of circulating plasminogen
   • cause increase in activation of clot bound plasmin

• half life: 5-15 minutes due to hepatitic proteolytic degradation being rapid
• IV adminstration

• hemorrhagic stroke
  • CI: active bleeding, recent stroke, recent major surgery, severe HTN
  • lysis of protective thrombi can also occur
• allergy (streptokinase only because Ab's are developed leading to HS rxns)- only use this drug every 6-12 months
  • fever
  • rash
  • anaphylatic rxn