B.2 Flashcards
Drugs influencing blood coagulation II: Anticoagulant
Heparin,
Dalteparin,
Warfarin,
Dabigatran-etexilate,
Rivaroxaban,
Fondaparinux
Anticoagulants protocol
For massive embolization we prefer to give UFH (initially), but for prophylaxis we give LMWH.
now we use LMWH also for embolization bc it is easier to dose correctly
note: Heparin chains longer than 18 monosaccharide units (typical of UFH) inactivate both thrombin and F Xa
Heparin chains shorter than 18 monosaccharide units (characteristic of LMWH) inactivates primarily F Xa
HIT- Heprin induced thrombocytopenia types
- Type I: 5-10% - reversible, transient (usually within the 4th day of treatment)
- Type II: 0.5-3% - extremely dangerous (fatal in 30% of cases), antibody mediated platelet aggregation paradoxically
Stopping the HIT effect of heparin
Protamine sulphate
Note: Protamine sulphate: isolated from salmon sperm, strongly basic protein, neutralized by acid heparin in blood
non-specific antidotes
Fresh frozen plasma (FFP),
Prothrombin complex concentrate (PCC),
Activated prothrombin complex concentrate (aPCC, FEIBA),
Recombinant activated F VII (rFVIIa, NovoSeven),
Tranexamic acid (Exacyl)
Factor inhibitors
ndirect (as part of an inactivationg complex):
Heparin, Dalteparin, Fondaparinux
Direct factor inhibitors:
- Direct thrombin inhibitors: e.g. Dabigatran-etexilate
- Direct Xa inhibitors: Rivaroxaban
Factor synthesis inhibitors
Vitamin K antagonists: Warfarin
Heparin
MOA: inhibits blood coagulation by accelerating the action of AT-III increasing its inactivation mainly of factors IIa (thrombin) & Xa.
It also affects IXa, XIa and XIIa;
Kinetics: s.c., i.v. injection (b/c the drug doesn’t cross membranes readily), T1/2: 60-90min,
metabolized by macrophages and monocytes and excretion not fully known but largely by kidney, CANNOT cross the placenta;
IND: Treatment of DVT, acute PE, arterial embolisation. Prophylaxis of postoperative venous thrombosis and recurrent thromboembolism, treatment of MI and unstable angina, Anticoagulant safe during pregnancy; Dose:
-Prophylactic (→2-3X5000-7500 IU s.c or 5-7 IU/kg/h i.v infusion),
-Acute therapy (usually 5000 IU initial bolus i.v. followed by 1000-1500 IU/h i.v infusion);
SEs: bleeding, hypersensitivity, thrombocytopenia (HIT), alopecia, mild elevation of transaminase, decreased aldosterone synthesis at high doses, osteoporosis (in prolonged - 3-6months treatment);
Contra-IND: HST to heparin, bleeding disorders, alcoholism, recent surgery of the brain/eye/spinal cord; Extra: Due to unreliable pharmacokinetics the effect should be monitored by measuring aPTT (should be 1.5-2.5 the control), overdose is treated with protamine sulfate
Warfarin
MOA: Inhibits the reduction of Vit. K
(by Vit. K-epoxide reductase) and thus prevents the γ-carboxylation of the glutamate residues in factors II, VII, IX, X;
Kinetics: p.o adm. (100%BA), ↑plasma protein binding, can cross the placenta, T1/2- 40h (but shows considerable individual variability),
Hepatic metabolism by CYP450 system, excreted by urine/feces;
IND: continuation of heparin therapy, prophylaxis of thromboembolic events, prevention and treatment of DVT and PE, stroke prevention, stroke prevention in the setting of A.fib / prosthetic heart valves, protein C and S deficiency, antiphospholipid syndrome;
SEs: bleeding
(minor bleedings can be prevented by p.o Vit. K1, severe bleeding i.v Vit K1/fresh frozen plasma/factor concentrates),
teratogenic (developmental defects, death of fetus), skin lesions & necrosis (rarely), purple toe syndrome (rare), Allergy, GI symptoms, Hair loss, necrosis of subcutaneous tissue;
Dose: 2-10mg, monitor effect by INR determination; Contra-IND: pregnancy, lactation, active bleeding, underlying disease with bleeding;
Drug interactions:
-absorption (antacids, cholestyramine inhibit abs. of coumarins),
-drugs affecting metabolism (Enzyme inhibitors (e.g. Metronidazole, Fluconazole, Phenylbutazonem sulfonamides) and
-Enzyme inducres: (Barbiturates, Rifampin, Phenytoin)),
-Potentiation of coagulation (→Aspirin, heparin, Amiodarone, Fluconazole, Metronidazole, TMP-SMX).
-Attenuation of coagulation (→Hypothyroidism, strong diuretic therapy, Barbiturates)
Extra: Delayed anticoagulant effect (8-12h), long T1/2. Hepatic metabolism (CYP450).
monitored with INR-> 2-3 (therapeutic range)
ROA: oral-good absorption
Dalteparin
MOA: LMWH, accelerates the action of AT III, increasing its inactivation of Factor Xa;
Kinetics: s.c, T1/2- 2-4h, renal excretion, CANNOT cross the placenta;
IND: same as heparin, prefered in pregnancy;
Dose:
-Prophylactic (→ 2500-5000 IUx1/day),
-Acute treatment (→170-250 IU/kg/h s.c X1-2/day);
SEs: bleeding, HIT, osteoporosis;
Contra-IND: HST reactions to heparin, bleeding disorders, alcoholism, recent brain/eye/spinal cord surgery
ROA: Subcutaneous injection
Extra: not prolonged aPTT, renal metabolism, less likely to cause HIT.
Antidote: Protamin Sulfate
Fondaparinux
MOA: The “smallest LMWH”, Synthetic pentasaccharide, analog of AT III (→inactivates only F Xa);
IND: Primarily DVT, also treats PE, prophylaxis of venous thromboembolism (in the setting of orthopedic &abdominal surgery);
Kinetics: s.c adm. (100% BAs.c.), eliminated mostly by urine, T1/2- 15-17h;
Contra-IND: severe renal impairement;
SEs: bleeding (there is NO available agent for the reversal of bleeding associated with Fondaparinux), HIT (rarely)
Antidote: Protamine sulfate, Ciraparantag
Dabigatran-etexilate
MOA: prodrug of dabigatran which is a direct thrombin inhibitor (both clot bound and free thrombin);
IND: Prevention of venous thromboembolism in orthopedic surgery (hip/knee replacement), prevent stroke and systemic embolism (in patient with non-valvular A.fib), DVT and PE treatment and prophylaxis; Contra-IND: mechanical and prosthetic heart valves, not recommended to patients with bioprosthetic heart valves;
Kinetics: p.o adm. (1-2X/day), activated by non-specific esterases, eliminated renally;
SEs: bleeding (antidote→Idarucizumab inj./inf.→ it’s a specific anti-dabigatran Ab), GI disturbances (dyspepsia, abdominal pain, esophagitis, GI bleeding); Extra: abrupt discontinuation can increase the risk of thrombotic events
Antitode: Idarucizumab
Rivaroxaban
MOA: Direct inhibitor of FXa (→ reduces the production of thrombin from prothrombin);
IND: Prophylaxis of thrombotic events following acute coronary syndrome, prevention of stroke (in non-valvular A.fib), treatment and prophylaxis of DVT and PE;
Kinetics: p.o adm., Hepatic metabolism by CYP3A4/5 and CYP2J2, some is excreted by urine and some by feces (dose adjustment in decreased renal function); Drug-interaction: should be avoided together with CYP3A4 inducers (e.g. Phenytoim, carbamazepine, rifampin) due to the potential for reduced efficacy of F Xa inhibitors;
SEs: bleeding (no antidote)
Antidote: andexanet alpha
Mechanisms of anti-coagulants
- Binding and inactivation of clotting factors
- Inhibition of factor synthesis(resulting in synthesis of functionally inactive factor)
What cells produce Heparin?
Mast cells
