Pharmacokinetics 2 Flashcards
where does metabolism most commonly occur ?
in the gut or lungs but most commonly in the liver
roughly how many T0.5 lives of a drug need to be gone through to cause complete removal of a drug from the body ?
about 5x
what does liver metabolism mean ?
it means that orally administered drugs may be metabolised before reaching the systemic circulation = 1st pass metabolism
what are the 2 sequential steps that often occur in the metabolism of a drug ?
phase 1= oxidation, reduction, hydrolysis- this is difficult to predict and renders the drug more liable to attack/more active - products may be more reactive and toxic than the parent compound
phase 2= conjugation - this makes it more excretable
what happens in phase 1 metabolism ?
a reactive group such as a hydroxyl group is added to the drug and this acts as an attack point for conjugation system which adds larger substituents to it e.g glucuronyl, sulphate or acetyl group
- drugs are modified to change their characteristics
what can oxidases do?
they can unmask polar groups on drugs
what is an example when the metabolised drug is the active one ?
aspirin or isoniazid - have to be taken orally to produce the active form
what enzymes carry out phase 1 metabolism ?
cytochrome p-450 family - there are many different subtypes
what happens in p-450 inhibition ?
reduce drug degradation leading to….
increase in drug plasma concentration leading to….
risk of severe adverse side effects
what happens with p450 induction ?
increased drug degradation leading to…
decreased drug plasma concentration leading to…
loss of pharmacological effect leading to….
risk of secondary effects
what happens in phase 2 metabolism ?
this stage involves attaching larger substituent groups to phase 1 metabolites or drugs - attach onto hydroxyl, thiol or amino groups
propose of the conjugation is to render the drug inactive and allow it to be excreted in the urine or plasma
how is aspirin metabolised ?
it is hydrolysed to produce salicyclic acid
then phase 2 metabolism results in conjugates with glycine or glucuronic acid to make several ionised metabolites that can be excreted in the urine
the glycine conjugate contains many groups that can accept hydrogen bonds making it more water soluble and more excretable
what is excretion ?
it is the irreversible removal of drugs from the body -NOT MOVEMENT FROM ONE COMPARTMENT TO ANOTHER
what are some examples of avenues of excretion ?
bile/faeces, lungs, saliva, sweat, tears and milk
what is the main route of excretion ?
renal excretion- within the urine via the kidney
what must be considered with renal excretion ?
reabsorption must be considered
renal excretion= (filtration + secretion)- reabsorption
- if the rate of reabsorption is changed the rate of excretion can be changed
how can you increase the excretion of aspirin ?
to increase excretion you want to make a basic environment for example using sodium bicarbonate - this makes aspirin more ionised to stop reabsorption
what is clearance ?
it is a measure of drug elimination from plasma and has units of a virtual flow
what does a low volume of distribution mean ?
it means the majority of the drug is in the systemic circulation so its easier to remove
what must be taken into account with drug dosing ?
must take into account kidney function as this effects clearance rates
how is renal clearance calculated ?
=CU * VU / CP
CU- urine drug concentration
VU- urine production rate
CP- plasma drug concentration
how is clearance calculated ?
= F * dose / AUC
F- fraction absorbed after administration
= K * Vd
K- elimination rate
Vd- volume of distribution
what is an elimination rate ?
it is the fraction of drug eliminated per unit time
what is a 1st order elimination rate ?
the speed of drug excretion drops with a lowering of plasma concentration. the T0.5 remains constant therefore elimination speed of this drug is easy to predict
what is a zero order elimination rate ?
if the drug must first be metabolised by enzyme x its profile may change if the enzyme is limited relative to the drug concentration
- bottleneck is produced when enzyme is saturated as more drug can not be excreted
e. g. alcohol- saturation of the system means the drug can no longer be turned over
how are most drugs metabolised?
through 1st order kinetics
how is C(t) calculated ?
C(0)exp(-total clearance/Vd)*t
then if logs is taken into this equation the slope produced is linear
a steeper slope indicates faster clearance rates
what is the plasma half life ?
it is the time to equilibriate between plasma and target compartments
what is the duration of action dependent upon ?
it is related to the t0.5 life and therapeutic range of a drug - the length of time it is effective is dependent on the time present within th therapeutic window
How is the initial concentration of drug calculated ?
c(0)= Q/Vd
Q- quantity of drug
Vd= volume of distribution
when administering a drug on repeat doses why are elimination rates so important ?
they are important to avoid overdose/toxicity
what happens in continuous infusion?
it is an extreme case where plasma concentration will increase untila steady state concentration is reached where the rate of infusion equals the rate of elimination
c(steady state)= rate of infusion/rate of elimination
for most drugs when is the steady state achieved ?
after 5 t0.5
why is chloroquine taken weeks before visiting an area with malaria risk ?
because it has a steady state of 5 weeks therefore it needs to be taken before, however this causes compliance problems
how do clearance and volume of distribution affect the T half life ?
- reduced clearance = slower elimination and increased T0.5
- more a drug is sequestered away in tissue such as adipose tissue, the more difficult it is for the the drug to be eliminated
- volume of distribution shows the amount of free drug in the plasma and a high volume of distribution means it will be more difficult to eliminate it from the body
- patients health must be taken into account, fat content, circulation issues, kidney disease, liver disease - these can all affect clearance
what is the aim when taking a drug ?
the aim is to achieve a steady state dose in the body
what is pharmacokinetics essential for ?
for working out the route of delivery and dose regime of a drug
- all elements of drug disposition must be considered
what are the varying degrees of compliance ?
high to low
- treatment alleviates symptom
- treatment but no symptoms
- prophylaxis
