anticoagulant drugs

Question 0

give examples of injectable anticoagulants and oral anticoagulants

Answer 0

injectable anticoagulants

• unfractionated heparin UFH
• low molecular weight heparin LMWH
• hidurin

oral anticoagulants
- warfarin

Question 1

go through the process of coagulation cascade after platelet activation

talk about anti-thrombin III

Answer 1

activated platelets provide a phospholipid surface for coagulation cascade to activate thrombin

• thrombin will cleave fibrinogen–> firbin which will stabilise the platelet plug to a permanent plug
• intrinsic: requires contact activation of F12 to the exposed collagen.
• 12a converts 11->11a, convert 9->9a convert 10->10a
• 10a convert prothrombin->thrombin
• 8->8a catalysed by thrombin where 8a serves as cofactor for 9a to activate 10 ->10a
• thrombin activates 9->9a, 8->8a, and 5->5a
• 5a serves as cofactor for 10a to convert prothrombin ->thrombin

extrinsic
- exposure to tissue factor + subendothelial cells -> activate 7->7a which catalyse 10->10a, also helps 9->9a that helps through intrinsic pathway.

ATIII – endogenous INHIBITOR of the coagulation cascade - inhibits thrombin and clotting factors (8->8a serve as cofactor for 9a) hene reduce coagulation formation

Question 2

unfractionated heparin UFH 
- nature 
MOA
consequences 
limitations 
uses
pharmacokinetics
S/Es

Answer 2

accelerate the action of antithrombin III

• inhibits thrombin and clotting factors
• specifically, pentasaccharide H5 binds to ATIII and alters active site
• this complex binds to thormbin and inhibit 10a, 7a, 11a and 9a - hence an indirect inhibitor of coagulation by acting on plasma factors

limitations

• heparin bind to man proteins and not just plasma proteins – hence demolishes any clot found
• PF4 platelet factor 4 binds to heparin - body recognises this as foreign and 1) generate autoantibodies causing further activation of platelets to increase thrombus 2) destroy platelets

uses:

• venous thrombosis
• pulmonary embolism
• MI
• unstable angina
• cardiac and vasular surgery
• angioplasty

pharmacokinetics

• IV(imm) or subcutaneous – delay up to 1hr
• absorption not from gut due to size and charge
• short half life at low conc and longer at high conc
• elimination about 40-90mins
• resistance hence about 35% need larger dose for therapeutic effects

SEs

• risk of bleeding increased if given w warfarin or antiplatlet or thombolytics
• heparin induced thrombocytopenia (loss of platelet)

Question 3

low molecular weight heparin LMWH
examples
MOA
pharmacokinetics

Answer 3

enoxaparin, nadroparin

MOA:

• inhibits factor 10a but minimally affects thrombin – aka F2a
• increases action of ATIII (inhibit thrombin) on factor 10a but not its action on thrombin – molecule too small to bind to both enzyme and inhibitor

admin:SC
half life- longer than UFH and is independent of dose - effect more predictable and dosing less frequent
-monitoring not required unlike UFH
more convenient to use – self-inject

Question 4

hidurin - give an example of a type of drug under this class 
nature
MOA
consequence/effects
uses
pharmacokinetics
SEs

Answer 4

lepirudin used clinically
direct thrombin inhibitors (inhibit thrombin cleavage of fibrinogen->fibrin )
binds irreversibly to both fibrin-binding and catalytic sites on thrombin
- inhibits thrombin from catalyzing fibrinogen-> fibrin to stabilise platelet ->permanent clot

uses: thromboembolic disease in patients w HIT (heparin-induced thrombocytopenia)

IV, dose adjusted accordin to APTT, clearance renal, half life 80 mins

SEs
- hypersensitivity issues and bleeding

Question 5

oral anticoagulants explain the general reason + give an example, nature, MOA, uses, PK and SEs

Answer 5

inhibit synthesis of clotting factors
clotting factors 2(thrombin), 9,7, 10 has to be modified into glutamate residues to finalise the synthesis and this is mediated by vitK
carboxylation of residues is dependent on ACTIVE VIT K.
oral anticoagulant are hence vitK antagonist - inhibit enzymatic reduction of vitK to active form hence unable to finalise the synthesis of clotting factors for coagulation cascade.

eg warfarin
competitive inhibitor of vitK reductase
- replace heparin where LT therapy is required
prevent thrombosis in high risk patients - bedridden, history of DVP/PE, AF, unstable angina and prosthetic heart valves

PK:

• po administration
• rapid and complete absorption from the gut
• distribution: small due to strongly bound to albumin
• slow onset of action - consumption of existing y-carboxylated factors before it can inhibit the rest hence requires 12-16hours for it to work
• warfarin crosses placenta hence dont give during 1st month pregnancy - teratogenic or in later stages esp during delivery - intracranial hemorrhage
• metabolism: p450

complications:

• liver disease - interfere w synthesis of clotting factors
• hyperthyroidism - high MR increases effects of anticoagulants by increasing degradation of clotting factors
• drugs interaction

effects lessen in
– hypothyroidism, pregnancy, drugs that induce hepatic p450