Nonlinearities
13 important questions on Nonlinearities
What are other possibilities of non-linear pharmacokinetics?
- Shortened infusion results in an increased AUC: e.g. fluorouracil, taxol or cisplatin.
- saturable absorption in GI tract results in a decreased proportional AUC at higher doses. (e.g. methotrexate)
- Saturable plasma protein binding results in a decreased proportional AUC at higher doses. e.g. valproic acid.
- Saturable active secretion in the kidney results in an increased proportional AUC at higher doses. e.g. penicillins
- Saturable reabsorption in the kidney results in a decreased proportional AUC at higher doses. e.g. cisplatin.
What is the value of Vm?
What is a result of the enzyme activity characterized by the michaelis menten kinetics?
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What is the case if the concentration is much lower than the Km?
There will be an proportionality constant = intrinsic clearance = Vmax/Km.
Most drugs are at therapeutic concentrations in these conditions..
What is the case if the concentration is much higher than Km?
The rate of metabolism approaches (asymptomatically) Vmax (nonlinear kinetics or saturation kinetics)
e.g.: phenytoin, ethanol, salicylate (at high concentrations), and many drugs at toxic concentrations.
What is the difference between administering the drug between meals and during or after a meal?
- During or after a meal: This can be done to avoid gastro-intenstinal side-effets or to improve the absorption by administration with a fat meal, but the absorption can also be lower.
Sometimes you have to take a drug before the meal because of a risk of vomiting. HIV-drugs have a very narrow therapeutic range. The effect on food is very important. It can care 50% difference in absorption.
What is the right to time to take hypnotics or diuretics?
diuretics: in the morning
What is a charateristic of carbamazepine with respect to the chronopharmacokinetics?
What kind of drugs can induce renal function loss?
So what kind of influence does the circadian rhythm have in pharmacokinetics?
- distribution: like plasma protein binding
- metabolism: enzyme activity (e.g. CYP 450 isoenzymes
- excretion: GFR
What is the mycophenolic acid circadian rhythm in PK?
- The dose is about 1000 mg every 12 hours
- The plasma concentration is monitored over 24 hours
- The AUC is related to efficacy and side effects: A too low AUC may lead to an acute rejection.
- There is a difference in time of absorption between patients.
What is the difference between linearities and nonlinearities?
What are examples of saturability?
- saturable (active) transport
- saturable binding to plasma proteins.
- saturable solubility.
- saturable first pass metabolism
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