lecture 20 - pharmacokinetics Flashcards
what is mode of action of lithium
Mode of action: unknown - enhances serotonin, norepinephrine, glutamatergic, protein kinase C activity, influences second messenger systems, may stimulate neurogenesis
what is monitoring for lithium ?
Measure Li+ concentration weekly till stable then every 3 months for 1 year then 6 monthly, 3 monthly if high risk (BNF)
Monitor baseline renal, cardiac and thyroid function then 6 monthly
what are side effects of lithium
Hypothyroidism, rarely hyperthyroidism
Weight gain
Hypercholesterolaemia
Hyperparathyroidism (overactive parathyroid gland) and hypercalcaemia
Nephrogenic diabetes insipidus (lithium competes with ADH receptors in the kidney) and dehydration
Permanent kidney damage (rare)
what is the lithium overdose and to city levels?
> 1 – 1.2 mmol/L, particularly in the elderly
Tremor, nausea, diarrhoea, drowsiness, confusion, apathy, restlessness, diabetes insipidus (kidneys are unable to converse water)
> 1.5 mmol/L GIT, CNS, kidney, endocrine, cardiovascular, haematological, muscle, dermatological, ophthalmological
> 2 mmol/L potentially life-threatening toxicity
Muscle twitching, convulsions, renal failure, dehydration, electrolyte imbalance, coma, death
what are drug interactions with lithium?
Diuretics
Thiazides: inhibit Na+ reabsorption in distal tubule, compensatory reabsorption of Li+ in proximal tubule - decreased Li Clearance by 20-25%
Loop: conflicting data, case reports of major toxicity, esp. in elderly
Non-steroidal anti-inflammatories (NSAIDs)
Inhibit prostaglandin synthesis by blocking COX 1 and COX 2, reduce renal blood flow, increase reabsorption of Na+ and Li+
Li+ CL by a mean of 10-25%; wide variation, concentrations may increase by >100%
ACE inhibitors and ARBs
Na+ reabsorption, reduce GFR - compensatory in Li+ reabsorption in proximal tubule. Multiple case reports, effect may be delayed for 3-5 weeks
Antidepressants, antipsychotics and antiepileptics
Often administered in combination with Li+
Case reports of severe neurotoxicity with antidepressants and antipsychotics but no convincing evidence of interactions
Some cases may result from increased Li+ concentrations in patients with dehydration, electrolyte abnormalities
Other drugs
Large doses of sodium bicarbonate antacids reduce Li+ concentrations
Alcohol: avoid if possible but may use may be linked with condition so difficult to control
what is lithium pharmacokinetics - absorption
Administered as a salt of lithium carbonate (tablets) or lithium citrate (liquid)
Absorbed by passive diffusion as lithium ion
Bioavailability 60 - 90% with modified release formulations
Peak concentrations 5-6 hours after modified release, 1 – 2 hour after immediate release formulation
what is lithium distribution?
V = 0.7 - 0.8 L/kg (8 – 10 hours to distribute to tissues)
lithium elimination?
Elimination
Filtered by the glomerulus, 75% reabsorbed in the proximal renal tubule (kidneys recognise lithium as sodium)
Reduced by sodium depletion and dehydration, e.g. infection - increased reabsorption
Elimination half-life 24 – 48 h according to renal function
what is average steady state concentration mean?
the average concentration across the whole dosage interval, not at a specific time after the dose
describe phenytoin pharmacokinetics
Unlike most drugs, there is NO direct proportional relationship between dose rate and steady state concentrations of phenytoin
Cannot use standard kinetic equations
From basic enzyme kinetic theory
Rate of metabolism increases as concentration increases
Rate of increase gets smaller as concentration increases
At infinitely high concentrations, the maximum rate of metabolism (Vmax) is achieved
describe the units for phenytoin at steady state equation.
units of dosing rate and vmax must be the same - mg/day or mg/kg/day
dosing rate and vmax must be in the same form ie phenytoin or phenytoin sodium
units of Cssav and Km must be the same: mg/L
what happens when concentration is less then Km?
Elimination rate is roughly proportional to dose rate – steady state concentration increases in proportion to dose rate - “linear” kinetics
what happens when concentration is more than Km?
Nonlinear increase in steady state concentration with increasing dose rate – “nonlinear” kinetics
what is the elimination half life of phenytoin trend like?
Phenytoin elimination half-life increases as phenytoin concentration increases
how calculate loading dose if no phenytoin given before?
Cmax= s x D / V
