Review of Pharmacology - 9E (2015)

Review of Pharmacology
Hematology
444
Unfractionated heparin provides
this scaffolding and thus inhibits
both factor IIa and Xa whereas
LMW heparins and fondaparinux
only cause conformational
change in ATIII and thus inhibit
only factor Xa.
INR = (PT of patient/PT of reference) ISI
Where ISI is international sensitivity index that depends on the sensitivity of reference
thromboplastin to WHO standard thromboplastin.
• Management of warfarin overdose is done as follows:
*INR < 5 but above therapeutic range –
*INR 5-9 –
*INR > 9 but no bleeding –
*INR > 20 or bleeding –
Discontinue warfarin temporarily and restart at
low dose.
Vitamin K 1
(1 mg oral)
Vitamin K 1
(2 – 3 mg oral)
Fresh frozen plasma.
• Warfarin shows a number of drug interactions, therefore requires dose adjustment
with several medications.
• Drugs increasing the effect of warfarin, thus requiring dose reduction include
broad spectrum antibiotics, cephalosporins like cefamandole, cefoperazone and
moxalactam (cause hypoprothrombinemia), aspirin, phenylbutazone and various
microsomal enzyme inhibitors (erythromycin, cimetidine etc.).
• On the other hand, enzyme inducers (like rifampicin, griseofulvin etc) and oral
contraceptives (increase clotting factors) decrease the effect and thus require
increase in dose of warfarin.
• New oral anticoagulants include dabigatran etexilate, rivaroxaban and apixaban.
These do not require monitoring. Dabigatran etexilate is a prodrug and its active
metabolite is a direct thrombin inhibitor whereas rivaroxaban and apixaban are factor
Xa inhibitors. Rivaroxaban has maximum (80%) whereas dabigatran etexilate has
minimum (6%) oral bioavailability.
2. Indirect Thrombin Inhibitors
• This group includes unfractionated heparin, low molecular weight heparin
(enoxaparin, dalteparin, tinzaparin, ardeparin, nadroparin and raviparin) and fondaparinux
and idraparinux.
• Heparin is the strongest organic acid present in the body (in mast cells).
• Heparin is not physiologically active anticoagulant. Commercially it is produced
from ox lung and pig intestine.
• This group of drugs act by activating antithrombin III (AT III) in plasma. Normally
AT III inactivates several clotting factors, most importantly factor Xa and IIa
(thrombin) but the reaction is very slow. Heparin accelerates this inactivation
process by binding to ATIII and inducing the conformational change in it to expose
the binding sites. Only conformational change is required for inactivation of factor
Xa whereas inactivation of thrombin is also dependent on formation of scaffolding
by heparin (that binds both ATIII and IIa). Unfractionated heparin provides this
scaffolding and thus inhibits both factor IIa and Xa whereas LMW heparins and
fondaparinux only cause conformational change in ATIII and thus inhibit only
factor Xa.
• Heparin also increases the relase of tissue factor pathway inhibitor (TFPI) from the
endothelium that may contribute to its anticoagulant activity.
• As heparin is inhibiting already activated factors, so there is no time lag between
the administration and action of this drug, therefore it can be used for initiation of
anticoagulant therapy.
• Heparin is not absorbed by oral route, therefore should be given either by s.c. or i.v.
routes (i.m. route is contra-indicated due to more chances of hematoma formation).
• Unfractionated heparin is metabolized by non-renal routes whereas LMW heparin
and fondaparinux are excreted by kidney and are contra-indicated in renal failure.
• It does not cross the placenta and is thus anticoagulant of choice during pregnancy.
• At higher doses, heparin also exerts antiplatelet action.
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