PK calculations Flashcards
Digoxin mechanism of action and therapeutic range?
Increase CF, Decrease AV conduction (POSITIVE INOTROPE). Increases amount of calcium in cardiomyocytes.
target = 0.8-2microgram/L
toxicity > 2.5microgram/L
Theophylline Target
Clearance increased in?
10-20mg/L
Smoking
Theophylline Target neonates
50% metabolised to caffeine. 5-10microgram/L
Gentamicin info, side effects, therapeutic ranges
aminoglycoside. Low therapeutic index causing nephro + ototoxicity
Target peak = 5-8mg/L multiple or 20mg/L for once daily
Target trough < 1mg/L
PEAK =/ measured 1 hour post IV/IM should not exceed 12mg/L
TROUGH = immediately before dose should not exceed 2mg/L
If trough too high - increase dose interval
Lithium, how it works, target concentrations. Signs of toxicity
Substitute for sodium or potassium in the CNS
0.4-1mmol/L optimum prophylaxis
0.8-1.2mmol/L for acute mania
TOXICITY > 1.5mmol/L = N+D+V, CNS deficits, tremor
Lithium model , concentration measurements and drug interactions
2-compartment model. Before morning dose and ideally 12 hours after last evening dose. Steady state in 3-5 days.
ACE increase Lithium levels, thiazide increase levels through impact on sodium levels. Theophylline and caffeine decreases
Designing a Lithium dose regimen
- Estimate CrCL (ml/min)
- Estimate Lithium Clearance (L/h)
- Choose Lithium concentration within the range (e.g. 5mmol/L)
- DR (mg/h) = CL x Cssav / F.s.m
- Daily dose (mg) = CL x 0.5 (target conc) x 24 / F.s.m
s and m convert dose of lithium salt from mg to dose of Li in mmol
Checking a Lithium dose regimen
- Estimate CrCL (ml/min)
- Estimate Lithium Clearance (L/h)
- Predict average SS conc and compare with target
Predicted = DR/CL = F.s.m.Dose (mg)/Lithium Clearance x 24
Factors to consider when interpreting serum concentration
Poor control, toxicity
Is the time the sample is taken a valid comparison with target range?
Is the sample likely to represent steady state?
Has the patient adhered to regimen?
Beware of on admission samples
Is the result consistent with prescribed/reported dosage regimens
Designing a gentamicin dose regimen
- Target peak>12mg/L
trough < 0.5mg/L - How often?
dosage interval must be 4-5 intervals, choose practical 24, 36, 48 hourly - Dose (mg) = Target C (mg/L) x V (L)
- Confirm safety. Predict SS peak and trough then check these are within the target range.
Designing a vancomycin dose regimen
1. Loading dose Target Cpeak = 20mg/L Dose = Ctarget x V (round to nearest 250mg) 2. Maintenance Dose Css target = 20mg/L DR (mg/L) = Ctarget x CL (L/h) Daily dose (mg/day) = Ctarget x CL (L/h) x 24
vancomycin how to administer:
- Continuous infusion
- Intermittent infusion
- daily dose then either continuous or 2x 12hr infusions
- Daily dose into 1,2 or 3. Aim to maintain trough >10mg/L.
* EACH DOSE INFUSED AT 500mg/hr and NO FASTER*
vancomycin toxicity
> 20mg/L
7 days duration
rate >500mg/hr - red man syndrome caused by histamine release. Occurs 4-10mins after start of infusion
2 compartment model
e.g. digoxin/lithium
Compartment 1 - drug first diffuses into blood, liver, kidney
Compartment 2 - poorly perfused tissues
Distribution into 2nd compartment continues until the free conc in the 2nd compartment is equal to the free conc in the peripheral compartment.
diffuses back into compartment 1 for elimination
considerations for 2 compartment model when measuring concentrations
High C before distribution misleading (not actually dangerous). After IV digoxin, clinicians wait 4-6 hours before taking serum concentration.
Plasma samples obtained less than 6 hours after oral digoxin or 12 hours after oral IR lithium are of questionable value
Phenytoin - target range and main characteristic
5-20mg/L
Non-linear elimination. Rate of metabolism increases as concentration increases. At high conc Vmax is reached (max rate of metabolism)
Rate of metabolism = Vmax.C/Km+C (Km=conc at half Vmax)
Concentration
linear pharmacokinetic elimination.
Conc>Km - nonlinear
Loading dose Phenytoin (no drug present)
LD = Target C x V/F.s.m
target C top of range = 20-25 mg/L
Loading dose Phenytoin (drug present)
LD = (Target C- Measured C) x V/F.s.m
Maintenance Dose
MD = Target C (lower 8-12mg/L) x V/F.s.m
When should lithium conc be measured
days 4-7 then weekly till stable for 4 weeks (increases serotonin, NE, glutamate)
Digoxin Toxicity, causes, symptoms, range
GI - N+V+D, Visual Disturbances, headache, fatigue
Cardiac - AV block. >2.5um/L
Causes. Potentiated by hypokalaemia (diuretics), hypothyroidism. PGP substrate - quinidine inhibits PGP increasing digoxin conc
Interactions - CYP3A4 Inhibitors increase digoxin conc (amiodarone, verapamil, macrolides, spironolactone)
Inducers decrease dig conc (rifampicin, St John’s Wort)
Digoxin V of distribution
Use actual up to 20% above ideal body weight in obesity. Reduced in renal impairment
Designing a digoxin dosage regimen
Oral LD = Dose (ug) = Ctarget (ug/L) x V/F.s
Oral MD = Cav target x CL x dosage interval(h)/F.s
When is steady state achieved?
After 5 half lives (t1/2 = 0.693/k)
Michaelis-Menten given in exam
DR=Vmax.C/Km+C
Phenytoin (DR=Vmax.C/Km+C) rearranged for Css av
Css av = Km.DR/Vmax - DR
t1/2 Phenytoin
t1/2 = 0.693 x V (Km+Css) /Vmax
what happens to Fu of phenytoin if albumin is low?
Fu increases. Bound and total decreases. This leads to misinterpretation of phenytoin calculations
C phenytoin corrected
Ccorrected = Cmeasured / ((0.9xalbumin/42) +0.1)
Phenytoin Cl
CL=Vmax/Km+Css
