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Pharmacology > Anticoagulants > Flashcards

Anticoagulants Flashcards

1
Q

Coagulation factors are present in blood as…because…

A

Zymogens
Serine proteases
Cofactors

Gives tight regulation of the cascade to prevent solidification of all blood

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2
Q

Where are heparins naturally produced?

A

Mast cells

Vascular endothelium

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3
Q

Where are heparins extracted from for pharmaceutical use?

A

Porcine intestinal mucosa

Bovine lung

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4
Q

How do heparins work?

A

Inhibits coagulation in vitro and vivo - enhance antithrombin III activity by 1000 fold.

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5
Q

Unfractionated heparin has a onset time of ?

A

T1/2 30 mins AT LOW DOSE

T1/2 2hrs AT HIGH DOSE (mixed elimination)

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6
Q

How does unfractionated heparin work?

A

Binds to antithrombin and causes conformational change, increasing activity of ATIII.

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7
Q

What is the aim of giving anticoagulants ?

A

Prevent thrombus formation and growth

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8
Q

For unfractionated heparin to inhibit IIa what must it do?

A

Heparin must bind simultaneously antithrombin (ATIII) and IIa

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9
Q

For unfractionated heparin to inhibit Xa what must happen?

A

Unfractionated heparin must bind antithrombin (ATIII)

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10
Q

Name a low molecular weight heparin

A

Dalteparim

Enoxaparin

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11
Q

What is the difference in administration between unfractionated and LMW heparin?

A

Unfractionated- typically IV bolus/infusion, subcutaneous for prophylaxis with lower bioavailability.

LMW- almost always subcutaneous, enoxaparin given IV for ACS

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12
Q

What is the bioavailability and half life like for LMWH?

A

> 90%

T1/2 - 2 hours or more independent of dose

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13
Q

Why does LMWH have a more predictable dose response?

A

It doesn’t bind to endothelial cells, plasma proteins and macrophages as it is too short/

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14
Q

what is the main difference between inhibition of the cascade between unfractionated and LMW heparin?

A

LMWH only able to inhibit Xa, through enhancing antithrombin activity.

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15
Q

What is the difference between fondaparinux and other LMWH?

A

Fondaparinux - selectively inhibits Xa by binding to ATIII, with a half life of 18hrs

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16
Q

What is the difference in dose response between the two types of heparins?

A

Unfractionated - non-linear

LMWH- predictable

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17
Q

What is the metabolism difference between the two types of heparins?

A

Unfractionated - dose dependant; protein binding, depolymerisation, desulfation (first and zero order).

LMWH- rapid liver or slower renal excretion

18
Q

What is the difference in monitoring heparins?

A

Unfractionated- unpredictable, monitor activated partial thrombi plastic time

LMWH- generally no monitoring, since dose response is predictable

19
Q

What is the difference in action time between the heparins?

A

Unfractionated- IV infusion fast

LMWH- slow subcut

20
Q

When would you choose to use unfractionated heparin over LMWH?

A

When there is severe renal impairment and fine control is required.

21
Q

What are some of the uses of heparin?

A

Prevent VTE- perioperative prophylaxis
Pregnancy- unable to cross placenta
VTE- initial treatment prior to oral agents
Acute coronary syndromes- short term to reduce recurrence / extension of coronary artery thrombosis post MI.

22
Q

What is the antidote to heparin and how does it work?

A

Protamine sulphate - forms inactive complex with heparin. Dissociates heparin from ATIII, irreversible binding amount guided by heparin dose.
Greater effect with unfractionated. No effect on fondaparinux.

23
Q

What are some of the ADR to heparin?

A

Bruising & bleeding - site of injections, intracranial, GI, epistaxis. Hepatic/renal impaired, elderly or those with carcinomas at higher risk

Herparin induced thrombocytopenia

Hyperkalaemia - inhibition of aldosterone secretion

Osteoporosis - long term use, higher risk with unfractionated and more prevalent in pregnancy.

24
Q

What is a vitamin K antagonist and its mechanism of action?

A

Warfarin - competitive inhibition if VKOR preventing activation of vitamin k to active reduced form. This inhibits factors II,VII,IX,X as they require vitamin K as a cofactor to become action.

25
Q

what is the half life of warfarin and why does it have a delayed onset of action?

A

Half life 36-48hrs

Delay due to circulating active factors lasting for several delays before they are metabolised and replaced.

26
Q

What are the conditions warfarin is used for?

A 
VTE and superficial vein thrombosis 
Heart valve replacement - biological prosthetic and mechanical 
Used generally in long term management 
AF with high stroke risk 
Cardioversion
27
Q

What are the pharmacokinetics of warfarin?

A

Good GI absorption, 95% bioavailability
Plasma concentration doesn’t correlate directly with clinical effect
Is a racemic mixture of two enantiomers- R and S which have different potency and metabolisms.

Crosses placenta in the 1st (teragonenic) and 3rd (haemorrhagic) trimesters.

Response affected by CYP2C9 - functionally polymorphisms contribute to individual variables.
Also affected by vitamin K intake.

28
Q

What is meant by the term ‘bridging’ therapy?

A

Using both a LMWH and warfarin when starting or stopping warfarin, so that there is still some level of anticoagulation.

29
Q

What is the most effective antidote for warfarin?

A

Vitamin K1 is prothrombin complex concentrate I.V

30
Q

What is the principle ADR of warfarin?

A

Bleeding

Epistaxis and spontaneous retroperitoneal bleeding.

31
Q

Cephalosporins may interfere with warfarin how?

A

Cephalosporin antibiotics eliminate gut bacteria, which have a role in producing vitamin K

32
Q

Which drugs increase INR due to displacement of warfarin from albumin?

A

NSAIDs and drugs decrease GI absorption of vitamin K.

33
Q

What drugs increase warfarin metabolism and decrease INR?

A

Barbiturates
Phenytoin
Rifampicin
St. John’s wart

34
Q

Which drugs affect warfarin due to their effects of inhibiting CYP2C9?

A 
Amiodarone
Clopidogrel
Alcohol at intoxication levels 
Quinolone 
Metronidazole
35
Q

What is an INR and what is the rough guide?

A

International normalised ratio: prothrombin time measured using factor VII (most sensitive to vitamin K depletion) and standardised against control plasma.

INR 2.5:
-DVT, PE & AF (risk

36
Q

What are DOACs and how do they work?

A

Direct acting oral anticoagulants:
Apixaban,edoxaban, rivaroxaban

Inhibit both free Xa and Xa bound to antithrombin. Do not directly affect IIa.

37
Q

What is different about dabigatran in comparison to other DOACs?

A

Selective direct competitive thrombin inhibitor, both circulating and thrombus bound IIa.
Half life 9hrs

38
Q

Why are DOACs sometimes preferable to warfarin?

A

Standard dosing and little/no direct monitoring required.

39
Q

Why might other DOACs be prescribed instead of dabigatran?

A

Dabigatran is contraindicated in low creatinine clearance and other DOACs at very low (<15ml/min).

40
Q

DOACs are also affected by CYP inhibitors and inducers, name these?

A

Inducers- reduce plasma concentration; carbamazepine, phenytoin and barbiturates.

Inhibitors- increase plasma concentration; macrolides.

41
Q

What antidotes are available for DOACs?

A

Andexanet and idarucizumab; not often used, very expensive.

Pharmacology (22 decks)

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