Lecture 9 - Pharmacokinetics Flashcards
define pharmacokinetics
what the body does to a drug
how can the ways of getting a drug to a patient be changed?
formulation
site of administration
how does formulation change how the drug gets to the patient?
solid (rate of action depends on dissolution)
liquid
patient compliance is important (less frequent is easier)
how does site of administration change how the drug gets to the patient?
local
systemic - enteral or parenteral
define oral bioavailability
proportion of the dose given orally that reaches the systemic circulation in an unchanged form
how can bioavailability be expressed?
amount or rate
how is bioavailability expressed as amount?
measured by area under curve of blood drug level vs time
how is bioavailability expressed as rate?
measured by peak height and rate of rise of drug level in blood
what is the therapeutic ratio?
maximum tolerated dose/minimum effective dose OR ld50 (lethal dose to 50% of people)/ed50 (effective dose in 50% of people)
what is the first pass effect?
substances absorbed from the lumen of the ileum enter venous blood, the hepatic portal vein and pass through the liver where it may be extensively metabolised
how much of an oral dose of paracetamol is usually metabolised by the first pass effect?
90%
define drug distribution
the theoretical volume into which a drug has distributed assuming that this is occurring instantaenously
how is drug distribution calculated?
amount given/plasma concentration at time 0
what level of the drug exerts an effect?
free level NOT the total
when is the free level of the drug important?
if the drug is highly bound to albumin
if the drug has a small volume of distributionif the drug has a low therapeutic index
what is an object drug?
class 1 drug used at a dose much lower than the number of albumin binding sites
what is a precipitant drug?
class 2 drug used at a dose greater than the available albumin binding sites
what happens when class 1 and class 2 drugs are administered simultaneously?
class 1 are displaced by class 2, raising free levels of the object drug higher risk of toxicity
what are the precipitant drugs for the object drug warfarin?
sulphonamides
aspirin
phenytoin
what are the precipitant drugs for the object drug tolbutamide?
sulphonamides
aspirin
what is the precipitant drug for the object drug phenytoin?
valproate
how is rate of drug metabolism calculated?
vmax[C]/km+[C]
when is a drug metabolised by first order kinetics?
when a drug is used at a concentration lower than km
what is the rate of metabolism with first order kinetics?
vmax[C]/km
what does first order kinetics mean?
metabolism is proportional to drug concentration
what is the graph of first order kinetics?
straight line when a log scale on the y axis vs time
when is a drug metabolised by zero order kinetics?
when a drug is used at a concentration much higher than km
what is the rate of metabolism with zero order kinetics?
vmax[C]/[C]
what does zero order kinetics mean?
the enzyme is saturated so the rate of decline of plasma drug level is constant, regardless of concentration
what is the graph of zero order kinetics?
straight line when normal (not log) plasma concentration is plotted against time
when will a steady state be reached with zero order kinetics?
within 5 half lives of the drug
if an immediate effect is needed with zero order kinetics, what is done?
loading dose
what does first order kinetics give?
predictable therapeutic response from dose increases
what does zero order kinetics give?
therapeutic response that can suddenly escalate as elimination mechanisms saturate
what is phase 1 of drug metabolism?
a reactive group is exposed on the parent molecule or added to the molecule
generates a reactive intermediate that can be conjugated with a water soluble molecule to form a water soluble complex
what are the most common chemical reactions in phase 1?
oxidation
reduction
hydrolysis
what does phase 1 require?
cytochrome p450 and nadphenzymes are inducible and inhibitable
what drugs does phenobarbitone induce?
warfarin
phenytoin
what drug does rifampicin induce?
oral contraceptive
what drug do cigarettes induce?
theophylline
what drugs does cimetidine inhibit?
warfarin
diazepam
how can drugs bypass phase 1?
already have a reactive group on their molecule
what is phase 2 of drug metabolism?
reactive intermediate from phase 1 is conjugated with a polar molecule to form a water soluble complex
what is the most common conjugate?
glucoronic acid
what is glucoronic acid?
available by product of cell metabolism
what can drugs be conjugated with?
glucoronic acid
sulphate ions
glutathione
what does phase 2 require?
specific enzymes
uridine diphosphate glucoronic acid (udpga) - high energy cofactor
how does the kidney control drug excretion?
only free unbound drug is filtered through glomerulus
drugs can be actively secreted by the tubule
urine pH can determine how much of the drug is excreted
how will urine pH affect drug excretion?
for weak acids - alkaline urine will make the drug ionised so there will be less tubular absorption - increase excretion
for weak bases - acidic urine will increase excretion as the base will be ionised so the drug stays in the lumen
