pharmacokinetics 4/4 Flashcards
Anti-epileptics
use
examples
‘Seizure’: covers a whole range of conditions
Range of drugs available for treatment
‘old style’ e.g.
phenytoin
carbamazepine
sodium valproate / valproic acid
‘new style’ e.g.
gabapentin
But lots of patient considerations too
Phenytoin
Does not obey linear pharmacokinetics
Cannot use the CpSS equation we have used previously
Therapeutic range 10-20 mg/L
Below 10 mg/L, no effect
Above 20 mg/L, blurred vision, drowsiness, coma
Liver enzyme inducer – so lots of drug interactions
Heavily metabolised by liver
Highly protein bound
Rise in phenytoin Cp as a function of dose is related to the dropping off of the rate at which it is metabolised
Michaelis-Menten for phenytoin equation
dont need to memorise
daily dose = vmax * cpss / Km+ cpss
Vmax comes from population data = 7 mg/kg/day
KM comes from population data = 5.7 mg/L
can be rearranged into cpss = daily dose * KM/ vmax- dailydose
lithium
Effective in acute mania, prophylaxis of manic depression
Very narrow therapeutic window (0.4-1.2 mmol/L)
Important to determine effective levels for individuals, as these vary markedly from person to person
Toxic, dose-dependent side effects
blurred vision, drowsiness, confusion, palpitations
Some dose-independent side effects
poorly tolerated in about a third of patients
Known teratogen (in early weeks of pregnancy)
Clear requirement for TDM
Decreased by
diuretics, esp. thiazides
decreased renal function
most NSAIDs
Increased by
Aminophylline
OTC antacids
ADME of lithium
Absorption
Administered orally as tablet or liquid. 100% bioavailable for normal release
NO
Distribution
Two compartment model with distribution complete in ~12 hours
Vd around 0.7L/kg
NO
Metabolism
None
YES
Excretion
Follows 1st order kinetics. Clearance approximates to 25% of creatinine clearance
YES
Half life
12 to 24 hours, variable
NO
what is the formulation of lithium
Oral solids e.g.
Lithium carbonate Li2CO3
e.g. Camcolit 250mg immediate release
Oral liquids
Lithium citrate Li3C6H5O7
Absorbed more quickly
Formulations not necessarily bioequivalentTherefore be careful if switching formulations/brands
Lithium level conversion
0.4 – 1.2 mmol/L therapeutic range
Lithium has MWt = 7 1 mmol of Lithium = 7 mg
So therapeutic range of Lithium is 2.8 – 8.4 mg/L
Remember the salt factor e.g. for Li2CO3
MWt of Li2CO3 is 74
MWt of two lithium ions is 14
Salt factor for lithium carbonate is 14/74 = 0.19
I’d give you the necessary values to work out ‘S’ in an exam
Theophylline
Narrow therapeutic range
Serious toxicity at > 20 mg/L
arrhythmias / seizures, no warning signs!
Significant inter-patient variability in p/kinetics
Less used now for COPD, as longer-acting inhaled -agonists are available
Often formulated as sustained release
Therapeutic range 5-15 mg/L
ADMDE of theophylline
Need to know?
Absorption
Oral bioavailability ~100%
Variable in EC / SR tabs and suppositories
Remember salt factor too (e.g. aminophylline)
NO
NO
YES - not values!
Distribution
Two compartment model with distribution phase complete in less than 1 hour
Vd averages 0.5L/kg
NO
Metabolism
Significant metabolism by liver; wide inter-patient variability;
YES: Overall, elimination is first order
Excretion
<10% excreted unchanged,
No need to adjust dose in renal problems
yes - overall elimination in first order
Half life
~ 8 hrs in healthy non-smoking adults
NO
Theophylline – variation in clearance
Significant changes with age
Significant changes with disease state, for example:
Decreased by liver cirrhosis
BG: Increased by cystic fibrosis
Significant changes with co-medication, for example:
BG: Decreased by oral contraceptives
Increased by phenytoin
Absorption / administration
No appreciable oral bioavailability
Very large
Broken down by proteases in the GIT
Administered mostly IV, but also SC and IM
SC admin leads to lymphatic system and hence to systemic circulation
Distribution
Distribution is mainly due to convection of fluids from vascular space via interstitial tissue space to lymphatic system
Volume of distribution tends to be in the range 8 – 20 L
Metabolism and Elimination
By excretion or catabolism
Too large to be filtered by kidneys
Fragments might be filtered, but usually reabsorbed
Very small amount of biliary excretion
Mostly eliminated through intracellular catabolism
Broken down to constituent amino acids
Pharmacokinetic consequences
Typically very long half lives, measured in days (e.g. 20 days) rather than hours
Dosing intervals are therefore very long
P/kinetic behaviour varies from Mab to Mab ; some linear, some non-linear (some Michaelis-Menten, some showing different behaviour)
