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Q7 Assignment: Warfarin (Coumadin) (Topic 1 (Pharmacokinetics (Special…
Q7 Assignment:
Warfarin (Coumadin)
Topic 1
Pharmacokinetics
General Definition
journey taken by a drug from site of administration, into plasma, distribution by random process, metabolism, and elimination
Onset of Action
Initial effect on INR seen in 24-72 hours
Full therapeutic effect 5-7 days
Dependent on reduction in vitamin K-dependent coagulation factors
Half life of prothrombin (factor II) is 60-72 hours
Administered Orally
Absorption
Rapid, complete
Distribution
0.14 L/kg
Protein binding
99%
Metabolism
Hepatic
Hepatic function impairment can potentiate response to warfarin via impaired synthesis of clotting factors & decreased metabolism of warfarin
Primarily CYP2C9
Minor Pathways
CYP2C8, 2C18, 2C19, 1A2, 3A4
Time to peak plasma
~4 hours
Half-life Elimination
20-60 hours
Mean 40 hours
Highly variable
Excretion
Urine
92% as metabolites
Minimal as unchanged drug
Special Considerations
Renal Cl is a minor determinant of anticoagulant response to warfarin
Geriatric patients (60yr+) exhibit greater than expected INR response to warfarin
Asian patients may require lower initiation & maintenance doses
VKORC1 & CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements
Dosing Requirements
Molecular Pharmacodynamics
General Definition:
what drugs do to the body & how they do it
(drug targets, cell receptors, etc)
Vitamin K required for hepatic synthesis of:
Coagulation factors II, VII, IX, and X
Proteins C & S
(endogenous anticoagulants)
Normal formation of coagulation factors
biologically activated by addition of carboxyl groups to certain glutamic acid residues w/in protein structure
an "active" vitamin K is oxidized to an "inactive" form
"inactive" form is reactivated by vitamin K epoxide reductase complex 1 (VKORC1)
Mechanism of Warfarin Action
Warfarin
competitively
inhibits subunit 1 of VKORC1
depletes functional vitamin K reserves
reduces synthesis of active clotting factors
Tolar, Mirek. “Hematology Drugs 2.” Q7 Pharmacology . 21 Feb. 2019, San Francisco, CA.
Duration
2-5 days
Topic 2
Dental Applications
& Considerations
No Local Anesthetic/Vasoconstrictor Precautions
Medical Consult
Recent INR reading
(within a few days)
INR is normal for a healthy patient
INR of 2.0-3.0
Surgery acceptable for patients with....
Prophylaxis or tx of venous thrombosis
Tx of pulmonary embolus
Prevention of systemic embolism
Tissue heart valves
Atrial fibrillaton
Acute MI
Usage
Signs of Warfarin overdose may be first indicated by bleeding from gingival tissue
For stroke patients undergoing dental procedures
consult w/ prescribing physiciaon prior to any surgery to determine if temporary dose reduction or avoidance of medication is needed
stroke patients should remain on warfarin during dental procedures because it is unlikely to increase bleeding risk in these patients
Effects on Dental Treatment
Dental Pain
Patients who require acetaminophen tx of dental pain for multiple days
Increased INR results
NSAIDS
Do not affect INR, but increases bleeding risk
Increased risk of bleeding
relevant to dental surgeries
tooth extraction
2011 study found no significant difference in patient bleeding with or without discontinuing warfarin
hemostasis successfully established by packing extraction sockets with oxidized cellulose and suturing
Increased risk of mouth ulcers
Taste disturbance
Concurrent antibiotic use
associated with 2-fold increased risk of bleeding requiring hospitalization
all 5 antibiotic drug classes associated w/ increased bleeding risk
macrolides
quinolones
cotrimoxazole
penicillins
cephalosporins
Azole antifungal use
4-fold increased risk of bleeding
Antibiotic & Antifungal Considerations Common for Dental Tx
Topic 3
General Clinical Considerations
Indications
Prophylaxis
Prevention of Unwanted Blood Clotting
Deep venous thrombosis (DVT)
Pulmonary embolism
Atrial fibrillation
Myocardial infarction
Mechanical prosthetic heart valves
Recurrent systemic embolism
Limitations
NO direct effect on an established thrombus
role is to prevent further extension of formed thrombus & secondary complications
does NOT reverse ischemic tissue damage
Toxicities
Signs of Warfarin Overdose
Unusual Bleeding
Blood in stools or urine
Excessive menstrual bleeding
Bruising
Excessive nose bleeds/bleeding gums
Persistent oozing from superficial injuries
Bleeding form tumor, ulcer, or other lesion
General Dosages
Average dose:
5.2mg/d
Dosing is individualized
hepatic function
cardiac function
age
nutritional status
concomitant medications
bleeding risk
Oral dosing regemin
Starting Doses
for healthy individuals: 10mg once daily for 2 days, then reduce dose
in general: start 2-5mg once daily
recommended for patients w/ confirmed HIT once platelet recovery has occurred
Lower Starting Doses for....
Pts w/ hepatic impairment, poor nutrition, heart failure elderly, high risk of bleeding, reduced genomic variants of catabolic enzymes
Higher Starting Doses for....
Pts receiving enzyme-induced agents with low risk of bleeding,
Continued Maintenance
adjust dose according to INR results
usually 2-10mg daily
dose adjustments during maintenance phase
dose administered 2-3 days prior will have most prominent effect on current INR reading
JON D. HORTON, PHARM.D., and BRUCE M. BUSHWICK, M.D., York Hospital, York, Pennsylvania. Am Fam Physician. 1999 Feb 1;59(3):635-646.
Contraindications
hemorrhagic tendencies
Co-morbidities That May Contribute to Increased Bleeding
Kidney disease
Tumor
Bone marrow failure
Chemotherapy
Autoimmune diseases
Liver disease
active GI ulceration, GI bleeds
cerebral aneurysm, CNS hemorrhage
dissecting aortic aneurysm
spinal puncture
Hypersensitivity to warfarin
recent surgery of the eye or CNS
blood dyscrasias
pregnancy
Warfarin crosses placenta
teratogenic effects reported following 1st trimester exposure
adverse CNS events to fetus following exposure in any trimester
spontaneous abortion, fatal hemorrhage
eclampsia
UNLESS pregnant woman has high-risk mechanical heart valves, high risk for thromboembolism
Drug Interactions
Increased anticoagulant effect when combined with...
Antibiotics
(
Metronidazole
)
NSAIDS
(
Aspirin
)
Antifungals
Tricyclic antidepressants
Certain herbals
(
gingko, ginseng, ginger, garlic
)
Acetaminophen
with daily doses exceeding 1.3-2 g/day for multiple consecutive days
Risk of Bleeding
frequently in competition for CYP2C9
