Warfarin Pharmacology

Indications of Warfarin
Prophylaxis and treatment of:
-Venous thrombosis
-Pulmonary Embolism
-Thromboembolism disorders
-Atrial Fibrillation with risk of embolism
-Prophylaxis of systemic embolism post MI (LV thrombus)

Which form of Warfarin is more important to us
S-Warfarin is more important than R-Warfarin

S form is 5x more active than R

Which CYP enzymes metabolize R-Warfarin
CYP1A2
CYP3A4
CYP2C19

Which CYP enzymes metabolize S-Warfarin
CYP2C9

Metabolism is 3x faster than R

Warfarin MOA
Extrinsic Pathway

Warfarin blocks Vitamin K Epoxide Reductase.
Vitamin K is required to activate II, VII, IX, and X cofactors

How do Polymorphisms affect warfarin metabolism?
Polymorphisms of CYP2C9 DECREASE metabolism of warfarin

We see the polymorphisms at the promotor region which decreases the synthesis of Vitamin K Epoxide Reductase Complex 1 = decreased Vitamin K regeneration

Important SNPs

CYP2C9*2

Displayed 8-13%
430 C > T
Arg144Cys
17% decrease in activity

Important SNPs

CYP2C9*6

Displayed <0.5% 818A > del
Truncation
0% activity

Important SNPs

CYP2C9*3

Displayed 6-10%
1075A > C
Ile359Leu
37% decrease in activity

CYP2C9 dosing adjustments to remember
*1/*1: Rapid metabolism-↑ dose
*1/*2: Rapid Metabolism- same dose
*1/*3: Reduced Metabolism- ↓ dose
*2/*2: Poor Metabolism- ↓↓ dose
*2/*3: Very Poor Meta.- ↓↓↓ dose

VKORC1 (VK) dosing adjustments to remember
GG – More protein- ↑ dose
AG – Less Protein- Usual dose
AA – Even less protein- ↓ dose

Typical Warfarin sensitivity genotype found in African American Populations
CYP2C9*1*1 VK GA – 29%

Warfarin Adverse Effects
Bleeding (GI)
Contraindicated in pregnancy (would give LMWH)
Warfarin induced skin necrosis – increased in patients with protein C or S deficiency
“Purple toes syndrome”
Hepatic dysfunction

Important points of Warfarin
-Blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting
-Also inhibits Proteins C & S
-7-15 day delay in action because of T1/2 of clotting factors in plamsa
-Recovery needs synthesis of new clotting factors
-Action reversed with vitamin K
-Highly plasma protein bound (95%)
-Warfarin for long-term, Heparin for short-term

Drugs that affect warfarin MOA
Food rich in Vitamin K

Drugs that are substrates of CYP2C9
NSAIDs, Ketoprofen, Ibuprofen, Diclofenac, Antidiabetics (Glipizide)

Drugs that are CYP2C9 inhibitors
Antifungals (Fluconazole, Miconazole)
Antibacterials (Sulphaphenazole)
Anticonvulsants (Valproic acid)

Coumadin (warfarin) Class Anticoagulant Coumadin (warfarin) Action Inhibits the clotting of blood WE WILL WRITE A CUSTOM ESSAY SAMPLE ON ANY TOPIC SPECIFICALLY FOR YOU FOR ONLY $13.90/PAGE Write my sample Coumadin (warfarin) Indications Treatment of venous thrombosis, pulmonary embolism, …

Dose response curve shows the relationship between the drug response and the dose Free drug compared to drugs that are protein bound, molecules that can produce a pharmacologic effect WE WILL WRITE A CUSTOM ESSAY SAMPLE ON ANY TOPIC SPECIFICALLY …

Absorption Process by which a drug enters the circulatory system (blood). Intravenous (IV) & Intra-Arterial Administration/Dosage routs that do not require absorption. WE WILL WRITE A CUSTOM ESSAY SAMPLE ON ANY TOPIC SPECIFICALLY FOR YOU FOR ONLY $13.90/PAGE Write my …

MOA: PCN cell wall biosynthesis MOA: cephalosporins cell wall biosynthesis WE WILL WRITE A CUSTOM ESSAY SAMPLE ON ANY TOPIC SPECIFICALLY FOR YOU FOR ONLY $13.90/PAGE Write my sample MOA: carbapenems cell wall biosynthesis MOA: vancomycin cell wall biosynthesis MOA: …

What marked the beginning of modern pharmacology? During the 1800s chemists were able to isolate the pure chemicals from plants. When did mass production of medicine begin? In the World War II era (1939-1945) WE WILL WRITE A CUSTOM ESSAY …

Pharmacology The scientific study of the action of drugs on a living system. A medication interacts with receptors and produces a biological response Pharmacokinetics Involves the absoption, distribution, metabolism, and elimination (excretion) of the drug in a living system WE …

David from Healtheappointments:

Hi there, would you like to get such a paper? How about receiving a customized one? Check it out https://goo.gl/chNgQy