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SA Clinical Pharmacology & Therapeutics > S10) Anti-Coagulant and Anti-Platelet Therapy > Flashcards

S10) Anti-Coagulant and Anti-Platelet Therapy Flashcards

1
Q

What is warfarin’s mechanism of action?

A

Warfarin inhibits the production of Vitamin K dependent clotting factors by stopping the conversion of Vit K to active reduced form

→ half life is 26-48 hours

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2
Q

Warfarin is the preferred drug choice for long term anti-coagulation.

How is warfarin administered?

A

Orally – due to good GI absorption

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3
Q

Briefly, describe the pharmacokinetics of warfarin

A
  • Slow onset of action (needs Heparin initially)
  • Slow offset (t1/2 48 hrs)
  • Heavily protein bound
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4
Q

How is warfarin metabolised and what is the clinical significance of this?

A

Mixed function Oxidase cytochrome p450 system:

  • Caution with liver disease
  • Caution if used with drugs that affect p450 system
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5
Q

what is INR

A

→ international normalised ratio - clotting time against a standard = comparable

normally 2.5

if 3-3.5 = recurrent DVT, PE in patients recieving anti-coagulants

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6
Q

Warfarin crosses the placenta.

What is the clinical signicance of this?

A
  • Do not give in 1st Trimester → Teratogenic
  • Do not give in 3rd Trimester → Brain Haem
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7
Q

How can one monitor the effects of warfarin?

A
  • Extrinsic Pathway Factors
  • Prothrombin Time
  • INR (International Normalised Ratio)
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8
Q

Provide some examples of drugs which potentiate the actions of warfarin

A
  • Amiodarone, quinolone, metronidazole – inhibit hepatic metabolism and CYP2C9
  • Aspirin – inhibit platelet function
  • Cephalosporin antibiotics – reduce Vitamin K from gut bacteria
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9
Q

Provide some examples of drugs which inhibit the actions of warfarin

A

Inducing hepatic enzymes, thus increasing metabolism of warfarin:

  • Anti-epileptics (except Na+ valproate)
  • Rifampicin
  • St Johns Wort
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10
Q

What are the usual indications for warfarin?

A
  • DVT (3-6 months)
  • PE (6 Months)
  • Atrial fibrillation (Until risk > benefit)

– venous thromboembolism

– superficial vein thrombosis

– longer term use over heparins

–

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11
Q

What are the adverse drug reactions of warfarin?

A
  • Teratogenic
  • Bleeding/bruising (intracranial, epistaxis, injection, GI loss)
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12
Q

warfarin drug-drug interactions

A

→ reduce vit K by eliminating gut bacteria (Cephalosporin antibiotics)

→ displacement of warfarin from albumin , NSAIDS and drugs that decrease GI absorbing K = increase INR (more anti-coagulated)

→ acceleration of warfarin metabolism, Barbiturates, phenytoin, rifampicin = decrease INR (less anticoagulated)

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13
Q

In seven steps, describe the clinical approach one takes before prescribing warfarin

A

⇒ Indication

⇒ PMH e.g PUD, SAH, bleeding disorder

⇒ Medications (interactions)

⇒ Age, Mobility (blood tests and clinics)

⇒ Review blood tests (LFTs, Plt, INR),

⇒ Consider loading dose and heparin cover

⇒ Prescribe

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14
Q

How does one manage a patient on warfarin with increasing INR levels of 3.0 < INR < 6.0 (no bleeding)?

A
  • Reduce warfarin dose and stop
  • Restart warfarin when INR < 5.0
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15
Q

How does one manage a patient on warfarin with increasing INR levels of 6.0 < INR < 8.0 (no bleeding / minor bleeding)?

A
  • Stop warfarin
  • Restart warfarin when INR < 5.0
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16
Q

How does one manage a patient on warfarin with increasing INR levels of INR > 8.0 (no bleeding / minor bleeding)?

A
  • Stop warfarin
  • Restart warfarin when INR < 5.0
  • If other risk factors for bleeding, give patient oral Vitamin K
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17
Q

How does one manage a patient on warfarin who experiences major bleeding?

A
  • Stop warfarin
  • Give prothrombin complex
  • Give oral Vitamin K
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18
Q

Describe the mechanism of action of heparin

A
  • Activate Anti-Thrombin III (ATIII) via unique pentasaccharide sequence
  • Deactivates thrombin, Factor Xa, IIa, IXa, (probably VIIa, XIa, XIIa)
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19
Q

Identify and describe the two different types of heparin molecules

A
  • Unfractionated Heparin (intravenous for continuous or subcutaneous for prophylaxis) 20 kDa
  • Low molecular weight Heparins (subcutaneous) 3-4 kDa
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20
Q

Compare and contrast the varying effects of LMW heparin and Unfractionated heparin on Factor Xa and thrombin

A
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21
Q

Compare and contrast UFH and LMWH based on the following factors:

  • Dose-response
  • Bio-availability
  • Action
  • Administration
  • Initiation
A
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22
Q

pharmacokinetic of warfarin

A

→ good GI absorption, taken orally = 95% bioavailability

→ CYP2C9 polymorphism = significant inter-individual variability

→ mixture of two enantiomers - R and S which have different potencies and so are metabolised differently

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23
Q

How is heparin administered?

A

Parenterally – due to poor GI absorption

24
Q

what produces heparins

A

mast cells and vascular endothelium

25
Q

what are unfractioned heparins

A

→ fast onset of action,

→ IV bolus and infusion (low bioavailability)
→ binding to antithrombin III = confrontational change and increased activity of antithrombin III

→ binds to ATIII and IIA to catalyse inhibition of thrombin IIa

→ Xa inhibition only needs ATIII binding

26
Q

what are some examples of low molecular weight heparins

A

dalteparin

enoxaparin

27
Q

low molecular weight heparins

A

→ given s.c

→ long half life and bioavailability

→ predictable response as it doesn’t bind to endothelial cells, plasma proteins, macrophages

→ don’t activate thrombin IIa

→ inhibition of Xa

28
Q

what is fondaparinux an example of and its role

A

→ low molecular weight heparin

→ synthetic pentasaccharide selectively inhibiting Xa by enhancing ATIII

29
Q

comparison of unfractioned heparins and low molecular weight heparins

A
30
Q

Briefly, describe the pharmacokinetics of heparin

A
  • Rapid onset of action (heparin cover)
  • Rapid offset of action
31
Q

Describe the uses of heparin

A
  • Prevention of thrombo-embolism during operation in those normally on warfarin (stopped for surgery)
  • Heparin cover for DVT/PE and AF
  • Pregnancy in place of warfarin
  • Reduces recurrence/extension of acute coronary syndromes
32
Q

Identify some adverse drug reactions of heparin

A
  • Bruising/bleeding sites (intracranial, GI loss, epistaxis, injection sites)
  • Osteoporosis
  • Thrombocytopenia

→ hyperkalemia (inhibition of aldosterone secretion)

→ avoid giving to people with clotting disorders and renal impairment

33
Q

Describe the reversal therapy for heparin (what is used, how?)

A

Protamine sulphate:

  • Dissociates heparin from anti-thrombin III
  • Irreversible binding to heparin
  • Used for major bleeding, allergy / anaphylaxis
34
Q

Identify some anti-platelet drugs and their mechanism of action

A
  • Aspirin – COX-1 (cyclo-oxegenase) inhibition
  • Dipyridamole – Phosphodiesterase Inhibitors
  • Clopidogrel – Inhibit ADP dependent aggregation
  • Glycoprotein IIb / IIIa Inhibitors – decreases platelet crosslinking by fibrinogen
35
Q

Vitamin K antagonist

A

Warfarin

36
Q

what is prostacyclin (PGI2)

A

→ produced by endothelial cells that inhibit platelet aggregation

→ bind to platelet receptors and reduce levels of cAMP

→ this reduces calcium levels

→ reduction in platelet aggregation

37
Q

how does aspirin work

A

→ COX-1 inhibitor

(COX-1 produces arachidonic acid that forms thromboxane)

→ irreversible / high doses can also inhibit PGI2

however, will not completely inhibit platelet aggregation as there are other aggregating agents

38
Q

who to avoid giving aspirin to

A

→ reyers syndrome (increase of pressure in brain → aspirin can worsen this)

→ hypersensitivity

→ 3rd trimester of pregnancy can cause premature closing of ductus arteriosus (shunt between pulmonary artery and the aorta)

39
Q

which drugs should you avoid giving aspirin with

A
  • other anti-platelet and anticoagulants
40
Q

why does the anti-platelet effect last the lifespan of a platelet

A

because after 7-10 days the platelet function will recover

41
Q

what are some other reasons to prescribe aspirin

A

→ AF patients past stroke

→ secondary prevention of Transient ischemic attacks (mini stroke)

→ secondary prevention Acute coronary syndromes

-< NSTEMI/STEMI → chewable is the best because It increases absorption

42
Q

how do ADP receptor antagonists work and what are some examples?

A

→ inhibit binding of ADP→P2y12 receptors so inhibit activation of GPIIb/IIIa receptors

→ Clopidogrel

→ prasugrel

→ ticagrelor

43
Q

how do ADP receptor antagonists drugs slightly different from each other

A
  • Clopidogrel and prasugrel are irreversible inhibitors of P2Y12 they are prodrug
  • clopidogrel has a slow onset of action without loading dose
  • ticagrelor and prasugrel have longer acting
44
Q

what are some side effects of ADP receptor antagonists

A
  • bleeding especially with hepatic or renal failure
  • GI upset and rarely thrombocytopenia
45
Q

drug interactions with ADP receptor antagonists

A
  • clopidogrel requires CYPs (cytochrome p450)for activation as it is a pro drug. This is produced in the liver
  • SO must avoid CYP inhibitors (erythromycin) or if someone has hepatic failure
46
Q

what are some other uses of ADP receptor antagonists

A
  • ischemic stroke (TIA)
  • N/STEMI
47
Q

phospodiesterase inhibitors

A

eg: Dipyridamole

→ inhibits cellular uptake of adenosine so increased adenosine → inhibit platelet aggregation via A2 receptor

→ Also prevent cAMP degradation so inhibit GP11b/IIIa

must avoid giving with adenosine

48
Q

glycoprotein IIb/IIIa inhibitors

A
  • abciximab (IV)
  • blocks binding of fibrinogen and and vonWillebrand factor
  • terminates the final step of platelet formation
  • can cause bleeding and should be careful to use =with other anti-paletelt and anti-coagulating agents
49
Q
A
50
Q

what is PCI (percutaneous coronary intervention)

A

→ using stent to remove plaque

→ normally go for this method if they have a STEMI

but it can cause repercussion injury where there a damaging oxidative and calcium species can come in

51
Q

treatment if someone has an ACS

A
  1. PCI
  2. when heamodynamically stable:
  3. ACEi, B blockers, dual anti-platelet therapy
  4. statin
52
Q

what is tranexamic acid used for

A

→ treats excessive blood loss after major trauma

→ inhibits fibrinolysis by inhibiting plasmin

53
Q

according to the nice guidelines what is the medication that should be used as secondary prevention if someone has just had a TIA

A

Clopidogrel inhibits ADP binding to platelet receptors

54
Q

DOACs examples

A

Direct acting oral anticoagulants:
→ apixaban

→ edoxaban

→ rivaroxaban

55
Q

how do DOACs work

A

→ Direct Xa: inhibit free Xa bound with ATIII (dint directly effect thrombin IIa

→ Direct IIa: dabigatran → selective direct competitive thrombin inhibitor

→ need more monitoring over warfarin

56
Q

adverse effects of DOACs, warnings and drug interactions

A

→ bleeding, skin reactions

→ avoid in pregnancy and breastfeeding: contradicted in low creatinine clearance. Avoid in people with severe hepatic disease

→ has less frequent interactions that warfarin but affect CYP inhibitors and inducers:

– reduced by carbamazepine, phenytoin

– increased by macrolides

SA Clinical Pharmacology & Therapeutics (36 decks)

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