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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
what are unfractioned heparins
→ 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
what are some examples of low molecular weight heparins
dalte**parin** enoxa**parin**
27
low molecular weight heparins
→ 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
what is fondaparinux an example of and its role
→ low molecular weight heparin → synthetic pentasaccharide selectively inhibiting Xa by enhancing ATIII
29
comparison of unfractioned heparins and low molecular weight heparins
30
Briefly, describe the pharmacokinetics of heparin
- Rapid onset of action (heparin cover) - Rapid offset of action
31
Describe the uses of heparin
- **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
Identify some adverse drug reactions of heparin
- 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
Describe the reversal therapy for heparin (what is used, how?)
**Protamine sulphate:** - Dissociates heparin from anti-thrombin III - Irreversible binding to heparin - Used for major bleeding, allergy / anaphylaxis
34
Identify some anti-platelet drugs and their mechanism of action
- **Aspirin** – COX-1 (cyclo-oxegenase) inhibition - **Dipyridamole** – Phosphodiesterase Inhibitors - **Clopidogrel** – Inhibit ADP dependent aggregation - **Glycoprotein IIb / IIIa Inhibitors** – decreases platelet crosslinking by fibrinogen
35
Vitamin K antagonist
Warfarin
36
what is prostacyclin (PGI2)
→ 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
how does aspirin work
→ 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
who to avoid giving aspirin to
→ 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
which drugs should you avoid giving aspirin with
* other anti-platelet and anticoagulants
40
why does the anti-platelet effect last the lifespan of a platelet
because after 7-10 days the platelet function will recover
41
what are some other reasons to prescribe aspirin
→ 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
how do ADP receptor antagonists work and what are some examples?
→ inhibit binding of ADP→P2y12 receptors so inhibit activation of GPIIb/IIIa receptors → Clopido**grel** → prasu**grel** → tica**grelor**
43
how do ADP receptor antagonists drugs slightly different from each other
* **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
what are some side effects of ADP receptor antagonists
* bleeding especially with hepatic or renal failure * GI upset and rarely thrombocytopenia
45
drug interactions with ADP receptor antagonists
* 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
what are some other uses of ADP receptor antagonists
* ischemic stroke (TIA) * N/STEMI
47
phospodiesterase inhibitors
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
glycoprotein IIb/IIIa inhibitors
* **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
50
what is PCI (**percutaneous coronary intervention)**
→ 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
treatment if someone has an ACS
1. PCI 2. when heamodynamically stable: 3. ACEi, B blockers, dual anti-platelet therapy 4. statin
52
what is tranexamic acid used for
→ treats excessive blood loss after major trauma → inhibits fibrinolysis by inhibiting plasmin
53
according to the nice guidelines what is the medication that should be used as secondary prevention if someone has just had a TIA
**Clopidogrel** inhibits ADP binding to platelet receptors
54
DOACs examples
Direct acting oral anticoagulants: → api**xa**ban → edo**xa**ban → rivaro**xa**ban
55
how do DOACs work
→ 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
adverse effects of DOACs, warnings and drug interactions
→ 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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