• Normal clotting requires sufficient levels of vitamin K in the body because it is essential as a cofactor for the synthesis of the active forms of: factor II, VII, IX, X.
• Warfarin is a vitamin k antagonist. it opposes the action of vitamin k and as aresult disrupts the activation of clotting factors ii, vii, ix, and x.
• Warfarin inhibits 2 of the enzymes in the vitamin k cycle: vitamin K epoxide reductasse and vitamin K reductase.  As a result, the conversion of vitamin K epoxide to vitamin KH2 is blocked. Without vitamin KH2 activation of factors II, VII, IX, and X does not occur and clotting is prevented.

• Pharmacodynamics

• anti coagulation effect takes place within 24 hours after admin
• peak anticoagulant effect ay be delayed 72 to 96 hours

• absorption - completely absorbed after oral admin with peak concentration with in 4 hours
• distribution - approximately 99% of the drug is bound to plasma proteins
• metabolism - primarily cytochrome p 450 enzymes in the liver to inactive metabolites, cyp450 enzymes involved in metabolism of warf include 2c9, 2c19, 2c8, 2c18, 1a2 and 3a4, patients with one or more variant alleles have decreased s warfarin clearance
• excretion - principally excreted in urine and to a lesser extent into bile
• terminal half life after a single dose is approximately 1 week.
• elderly patients - patients 60 years or older appear to exhibit greater than expected INR response to the anti coagulant effect of warf.
• as patient age increases, a lower dose of warf is usu required
• the cause of increased sensitivity in elderly is unknown but may be due to a combination of pk and pd factors

what is the isoenzyme primarily responsible for metabolism of warfain?

and what is the normal allele (that is the allele that provides a standard rate of warfarin metabolism)?

cyp450 2c9

CYP2C9*1

• prophylaxis and treatment of the thromboembolic complications associated with AF and/or cardiac vallve replacement
• prophylaxis and treatment of venous thrombosis and its extension, and pulmonary embolism (PE)
• reduction in the risk of death, recurrent mycocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after MI

in order for warfarin to exert its anticlotting effects factor II and factor X have to be blocked and deactivated. These clotting factors however have long half lives  

• factor II half life 72 hours
• factor x has half life of 24 hours

• daily inr after the initial dose of warf and until it stabilizes in the threapeutic range
• frequency after stabilization depends on patient but, generally 1 to 4 weeks.
• additional inr tests should be perfored when other warfarin products are interchanged with warfarin.

• patients with nonvalvular af, anticoagulate with warfarin to inr of 2.5 range 2 - 3
• patients with persistent or paraxysmal af and at high risk of stroke (ischemic stroke, tia or sestemic embolism or 2 of the following risk factors: age > 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus) Long term anticoagulation therapy with warfarin is recommended
• Persistent or paroxysmal af and intermediate risk ie having 1 of the following risk factors: age > 75, moderatel or severely impaired left ventricular systolic funciton and/or heart failure, history of hypertension, or diabetes mellitus:) long term anticoagulation with warfarin is recommended.
• AF and mitral stenosis: long term anticoagulation with warfarin is recommended
• AF and prosthetic heart valves: long term anticoagulation with warfarin is recommended; the target INR may be increased and asa added depending on valve type and position, and on patient factors.

• category D for women with mechanical heart valves
• pregnancy X for otehr pregnant populations

• Pediatric USE?

• adequate studies not conducted
• dosing varies by patient age, with infants generally having the highest and adolescents having the lowest millligram per kilogram dose requirements to maintain inrs
• difficulty maintaining therapeutic inr in ped's has been reported

• because clotting factors are produced and warfarin is metabolized in the liver, hepatic dysfunction can potentiate (INCREASE) the response  to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

• based on published data in 15 nursing mothers, warfarin was not detected in human milk
• monitor breast-feeding infants for bruising or bleeding
• effects in premature infants have not been evaluated
• exercise caution

• warfarin exposure during pregnancy can cause spontaneous abortion birth defects or fetal death.
• females should be counseled regarding risks and benefits
• discuss pregnancy planning with females of reproductive potential who are on warfarin therapy
• if patient becomes pregnant while taking warfarin, she should be apprised of the potential risks to the fetus

• warfarin can cause major or fatal bleeding
• perform regular monitoring of INR in all treated patients
• drugs, dietary changes, and other factors affect INR levels achieved with warfarin therapy
• instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding

• pregnancy
• hemorrhagic tendencies or blood dyscrasias (an imbalance of the constituents of the blood)
• recent or contemplated surgery of central nervous system or the eye or traumatic surgery resulting in large open surfaces
• bleeding tendencies
• threatened abortion, eclampsia, and preeclampsia
• unsupervised patients with conditions associated with potential high level of noncompliance
• spinal puncture and other diagnostic or therapeutic precedures with potential high level of noncompliance
• spinal puncture
• hypersensitivity to warfarin
• major regional lumbar block anesthesia
• malignant hypertension

• hemorrhage - warf can cause major or fatal bleeding. bleeding is more likely to occur in the first month.
• risk factors for bleeding include:
• high intensity of anticoagulation
• age > or equal to 65
• history of variable INRs
• history of gi bleeding
• hypertension
• cvd
• anemia
• malignancy
• trauma
• renal impairment
• genetic factors
• concommitant drugs
• long duration of warfarin therapy

• diarrhea
• hepatic disorders
• poor nutritional state
• steatorrhea (excess fat in stools) usu due to pancreatic disease 
• vitamin k deficiency

factors which may cause decreased INR response?

• increased vitamin k intake
• hereditary warfarin resistance

• hemorrhage
• necrosis of skin and other tissues
• systemic atheroemboli and cholesterol microemboli

• immune system disorders: hypersensitivity/allergic reactions
• vascular disorders; vasculitis
• hepatobiliary disorders; hepatitis, elevated liver enzymes
• gi disorders; nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating
• skin disorders: rash, dermatitis, pruritus, alopecia
• respiratory disorders: tracheal or tracheobronchial calcification 
• general disorders; chills

drug interactions:

2 main ways drugs may interact with warfarin?

3 pharmacokinetic mechanisms for drug interactions with warfarin are?

• enzyme induction (increasing the action of the enzyme)
• enzyme inhibitioon (depressing or arresting its function)
• reduced plasma protein binding (more drug is unbound and active)

• synergism (combined action of the drugs is greater than the sum of each acting separately)
• competitive antagonism (drug blocks the site of action of the other drug)
• altered physiologic control loop for vitamin K metabolism (this is seen in hereditary resistance)

• its peak anticoagulant effect may be delayed 72 to 96 hours
• narrow therapeutic window
• INR must be carefully monitored
• genetic factors can affect its action
• many drugs, certain foods, and herbal supplements can increase or decrease its anticoagulant effects.

clinical trial data ?

risk reduction range?

incidence of major bleeding?

5 trials with 3711 patients with nonrheumatic af, were

• AFASAK
• BATAAF
• SPAFI
• CAFA
• SPINAF
• RR RANGE 60-86% in all except cafa (45%) which was stopped early
• incidence of major bleeding ranged from 0.6% to 2.7%