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TDM Final

PHAR143 final

MOA of warfarin Inhibits VKORC1, slowing the rate of synthesis of functional clotting factor (no effect on circulating factors or formed thrombus)
Onset of warfarin Delayed anticoagulant effect (dependent on half-life of circulating clotting factors). Initial prothrombotic state due to inhibition of protein C & S (body's natural anticoagulants)
What does INR measure? Activity of VII, X, and II
At what INR is there no additional clinical benefit? INRs >4.0
Isomers of warfarin Racemic mixture of R and S. S is 5x more potent than R
Metabolism of warfarin isomers S metabolized by 2C9, R by 3A4 and 1A2
Half-life of warfarin ~40 hours (mostly dependent on genetics)
VKORC1 genotypes Explains ~25% of variation. AA: very sensitive. GG: more resistant
2C9 genotypes (in terms of warfarin) *2 and *3 associated with increased risk of overanticoagulation and bleeding
Use of genetic testing for warfarin treatment CHEST AT9 currently recommends AGAINST routine use: cost, lab availability, long term utility
Initiation warfarin therapy CHEST AT9: 10 mg for first 2 doses recommend for patients healthy enough to be treated as outpatients
Age as factor in warfarin dosing Requirements tend to decrease with age. 4mg common starting dose in elderly (vs 5-10mg)
Sex as factor in warfarin dosing Men require more than women
Ethnicity as factor in warfarin dosing Blacks>whites>hispanics & asians
Weight as factor in warfarin dosing Heavier patients need higher doses
Liver disease as factor in warfarin dosing Tend to have lower requirements (reliant on baseline INR)
When to draw INR for inpatient? Baseline prior to initiation of therapy, then daily.
Smoking status as factor in warfarin dosing Tend to have higher requirements due to 1A2 induction. Decreases INR over time. Cessation may increase INR.
"Rule of 7s" If patient is therapeutic (in goal INR range) before steady state, consider the 7 day equivalent dose: total up dose received thus far, divide by 7
How to think of warfarin dosing for calculation purposes mg/week
How often to draw INR for outpatient warfarin initiation? Minimum of 2-3 INRs per week
When should you NOT adjust warfarin for patient with INR out of range? INRs +/- 0.5 often return to normal in 1-2 weeks without intervention. If patient miss doses, do not adjust dose.
When and how to make adjustments of maintenance warfarin doses? Adjustments should be in range of 5-20% if patient is at steady state. Add up weekly dose,ask "what is smallest % change I can make given patient's tablet supply?"
When to consider holding warfarin doses INRs 4.5 and higher
Vitamin K (phytonadione) administration Give if patient is actively bleeding. If not bleeding, only give if INR >10
Route and dose of phytonadione administration PO>IV>SubQ>IM. 2.5-5mg usually adequate
Why should you not administer phytonadione subq or IM? VitK is a fat-soluble vitamin and would stay in the muscles, acting like a depot. Patient would have acute resistance to warfarin.
Maximum time between INR follow-ups Follow-ups should never be beyond 12 weeks (or every 4 weeks for most patients)
When to follow up on any warfarin dose changes Within 7-10 days (will see ~75% of the change)
Which enzyme more likely to have drug interaction with warfarin 2C9>3A4>1A2
What source to use for warfarin drug interactions? Micromedex's DrugDex
The 8 A's of warfarin Antibiotics, amiodarone, antifungals, antidepressants, alternative therapies, antiplatelets, anti-inflammatories, acetaminophen (high dose)
What drug interactions may require a preemptive dose reduction of warfarin? Amiodarone, TMP/SMX, metronidazole
Drugs that induce metabolism (of warfarin) and may decrease INR phenytoin, rifampin, phenobarbital, carbamazepine, nafcillin, dicloxicillin, St. John's Wort
Pharmacodynamic interactions of warfarin NSAIDs, celecoxib, aspirin, clopidogrel. does NOT affect the INR, but increases bleeding risk
Adding levothyroxine to patient stabilized on warfarin INR will INCREASE by decreasing available clotting factors relative to warfarin
Adding antithyroid drug to patient stabilized on warfarin INR will DECREASE by increasing available clotting factors relative to warfarin
Dietary interaction of green, leafy veggies and warfarin Vitamin K in diet will decrease INR by increasing amount of available clotting factor. Consistency is key, not avoidance
Alcohol and warfarin 2 servings/day unlikely to affect INR. Acute binges increase INR and fall risk
When to increase MD of warfarin INR <1.5, increase by 10-25%/week, recheck INR in 1-2 weeks.
Abbreviated New Drug Application (ANDA) Does not require new safety & efficacy studies. Requires bioequivalency (BE) studies. Not required for all strengths of a drug-if composition is same for different strengths, just need to test one.
In-vivo standards of immediate release vs delayed release and ER products In-vivo standards are the same. the difference comes with dissolution testing
Biopharmaceutical Classification System: Class I High solubility, high permeability
Biopharmaceutical Classification System: Class II Low solubility, high permeability
Biopharmaceutical Classification System: Class III High solubility, low permeability
Biopharmaceutical Classification System: Class IV Low solubility, low permeability
At what volume (mL) is a drug considered to have high vs low solubility? <250 mL is high solubility. >250 mL is low solubility
At what permeability (1 x 10^-6 cm per s)is a drug considered to have high vs low permeability? <5 is low permeability. >5 is high permeability (>90% drug absorbed)
Solubility testing criterion Highest dosage strength, pH range 1-7.5. Highly soluble when highest dosage strength soluble in <250mL of aqueous media in pH range
Permeability testing criterion Methods: mass balance, absolute bioavailability, intestinal permeability. High permeability is when >90% of drug is absorbed
Biowavers Do not apply to NTI drugs. Available for BCS Class I drugs. No need for BE testing
Key elements of bioavailability Active ingredient is focus, look at process by which drug is released from oral dosage form (disintegration, dissolution). Relative fraction of drug absorbed systemically vs IV form. Delivery to SOA
Key measures of bioavailability used for bioequivalency comparison Cmax and AUC
Key elements of BE Absence of significant difference. Rate of absorption, extent of absorption. Active ingredient, same molar dose, similar conditions (most do both fasted and fed state)
A-rated FDA BE category Considered to be therapeutic equivalent of another product
B-rated FDA BE category Actual or potential BE differences identified and the drug is not therapeutically equivalent
AA rating no BE problems
AB rating Meet BE requirements through in-vivo and/or in-vitro testing
"Two one-sided test procedure" 1. Is generic, when subbed for innovator, significantly less bioavailable? 2. Is brand name, when subbed for generic, significantly less bioavailable? Methods assure no more than 5% chance that generic not equivalent to innovator will be approved.
Variability allowed for bioequivalence studies Geometric mean of AUC and Cmax must fall within 80-125% range around reference product mean. 90% CI must fall within 80-125% range around reference product mean.
NTI BE limits Changes as fxn of intra-patient variability of reference product. If reference variability <10%, BE limits are narrower than 90-111.11%. If reference variability >10%, BE limits are wider capped at 80-125% Do double crossover study
Characteristics of BE studies Single dose, normal adult volunteers, no concomitant medications, fed and fasting states, usually in 30-50 individuals, usually crossover study design
Sensitivity "if a person or sample has something, how often will the test be positive?"
Specificity "If a person or sample does not have something, how often will the test be negative?"
Key measure of precision in a drug assay technique? Measured as coefficient of variability (standard deviation/mean x 100)
What determines if an assay has good standards of precision? <15% is acceptable, <10% is optimal, <5% is excellent
Measurement of accuracy of an assay Correlation coefficient-measures goodness of fit, should be >0.95. Determines upper and lower limits of an assay.
Equation that measures GFR Modified Modification of Diet in Renal Disease (MDRD)
Cockroft-Gault Equation assumptions Adult with stable renal function
Adustments for Cockroft-Gault equation >30% above ideal BW for obese. Minimum SCr 1mg/dL
When to use IBW, TBW, ABW?!? Calculate IBW to determine if patient's TBW is >30% above IBW. If so, use ABW. If not, use TBW. NEVER USE IBW IN COCKRAUFT-GAULT EQUATION
Aminoglycoside (AG) overview IV antibiotics, concentration-dependent (want high Cmax), post-antibiotic effect (PAE)
AGs MOA bind to 30S ribosome to inhibit protein synthesis
AGs bacterial coverage -cidal for gram - bacteria. synergistic with beta-lactam ABs for selected gram + bacteria (Enterococcus, S. aureas)
AGs AE nephrotoxicity (reversible, non-oliguric). Ototoxicity (irreversible, less frequent)
Drug levels for AGs Penetration good to most tissues of body, poor to lungs, CSF, bone, and prostate. Peak determines efficacy (1 hr after infusion start). Trough utilized for toxicity (measure trough 30 mn before dose)
Vanco bacterial coverage Narrow coverage of gram + bacteria, including MRSA ("gold standard"), slow bactericidal activity
Vanco PD time-dependent killing (AUC/MIC correlates w/ efficacy)-frequency of dosing vs high peaks
Vd of vancomycin Average 0.7 L/kg (0.4-1 L/kg) Not greatly affected by fluid status
AE of vanco Overstated: nephrotoxicity, "Redneck syndrome", otoxocitiy
Most practical marker for vanco efficacy Trough concentariton at Css, drawn w/in 30 mn before next infusion (before 4th dose, per guidelines)
Goal trough for most vaco indications 10-20 mc/mL
Goal trough for severe infection w/ vanco 15-20 mcg/mL, used for pneumonia, bacteremia, endocarditis, osteomyelitis, meningitis
Determine initial loading dose of vanco 15-20 mg/kg using ABW (round to nearest 250mg increment)
Making adjustments to vanco dosing Make sure at steady state: estimate Cl, calculate kel, calculate t1/2, at 3-5t1/2? If necessary modify dosing interval or dose (rearrange to see if rounding provides appropriate trough)
Salt factor of aminophylline S=0.8 (80% theophylline)
Distribution of theophylline distributes well into CSF, not well into fatty tissue. Use IBW for calculations.
Vd of theophylline Average 0.5 L/kg
Metabolism of theophylline 1A2 (major) 2E1 (minor)
Elimination of theophylline Average clearance for adult, nonsmoker= 0.04L/kg/h
Goal serum concentrations of theophylline 5-15 mg/L (safe and effective). No advantage >15 mg/L, just increase risk of ADRs
Adverse effects of theopylline <20 mg/L tachycardia, nervousness, restlessness, N/V
Toxicity effects of theophylline >20 mg/L N/V/D, HA, insomnia, agitation, muscle cramps, tremor
Toxicity effects of theophylline 25-35 mg/L tachycardia, occasional PVC
Toxicity effects of theophylline >35 mg/L hyperglycemia, hypotension, cardiac arrythmias, seizures, death
Time to sample aminohylline concentrations 24 hours after starting infusion, then at steady-stage (48 hours)
Loading dose of aminophylline 5 mg/kg or equation
MD of aminophylline 0.5 mg/kg/hr of equation
Half-life of theophylline in most patients 8h
What order is theo/aminophylline first-order at steady state
Azithromycin and theophylline Minimal interaction, not as much as other macrolides. not a clinically significant reaction
Vd of phenytoin 0.7 L/kg
serum concentration of phenytoin 10-20 mg/L (~10% unbound)
infusion rate of phenytoin <50 mg/min (fosphenytoin <150mg/min)
Strengths available of sodium phenytoin extended 30, 100, 200, 300
phenytoin loading dose 18 mg/kg or Dose= (vd x tbw) (change in cp). Divide dose over 12-24 hours, not giving more than 600 mg in a single dose
Determining phenytoin initial MD Adults: 5-7 mg/kg/day. Children: 6-15 mg/kg/day
Earliest a phenytoin concentration can be measured to determine if right MD? 14 days (half life range 7-42 hrs)
Monitoring phenytoin post-loading dose IV: >2 hours after end of infusion. Oral: 12-24 hr minimum after last dose
Privitera Method of adjustming phenytoin dose <7 mg/L: increase 100 mg/day. 7-12 mg/L: increase 50 mg/day. >12 mg/L: incrase 30mg/day or less
Phenytoin metabolism Capacity-limited, increases risk of causing dose-related side effects
Patient types with altered protein binding renal failure, hypoalbuminemia, neonates, pregnant women, multiple highly protein bound drugs, critical care patients
Child-Pugh Score Class A Score 5-6: mild to no hepatic impairment
Child-Pugh Score Class B 7-9: moderate hepatic impairment
Child-Pugh Score Class C 10-15: severe hepatic impairment
Which CYP450 Isoenzyme function decreases first as hepatic function declines 2C19, then 1A2, 2D6, 2E1/3A4
Normal albumin range 3.4-5.4 g/dL
1A2 inhibitor Cimetidine
2C9/19 inhibitor omeprazole
3A4 inhibitors Clarithromycin, erythromycin, grapefruit juice, cimetidine
Strong inhibitor affect on AUC/Cl Increases AUC >5-fold or decreases Cl >80%
Moderate inhibitor affect on AUC/Cl Increases AUC >2-fold or decreases Cl 50-80%
Weak inhibitor affect on AUC/Cl Increases AUC >1.25-fold or decreases Cl 20-50%
Jelliffe Nomogram Tells digoxin time to steady-state: start at CrCl 100 ml/min with 7 days to steady-state. 90 ml/min has 8 days, so on.
Valproate dosing for adults 15-45 mg/kg/day in 2-4 doses
Valproate dosing for children 5-60 mg/kg/day in 2-4 doses
Created by: steponmegrace