Pharmacokinetics 2

Question 0

where does metabolism most commonly occur ?

Answer 0

in the gut or lungs but most commonly in the liver

Question 1

roughly how many T0.5 lives of a drug need to be gone through to cause complete removal of a drug from the body ?

Answer 1

about 5x

Question 2

what does liver metabolism mean ?

Answer 2

it means that orally administered drugs may be metabolised before reaching the systemic circulation = 1st pass metabolism

Question 3

what are the 2 sequential steps that often occur in the metabolism of a drug ?

Answer 3

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

Question 4

what happens in phase 1 metabolism ?

Answer 4

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

Question 5

what can oxidases do?

Answer 5

they can unmask polar groups on drugs

Question 6

what is an example when the metabolised drug is the active one ?

Answer 6

aspirin or isoniazid - have to be taken orally to produce the active form

Question 7

what enzymes carry out phase 1 metabolism ?

Answer 7

cytochrome p-450 family - there are many different subtypes

Question 8

what happens in p-450 inhibition ?

Answer 8

reduce drug degradation leading to….
increase in drug plasma concentration leading to….
risk of severe adverse side effects

Question 9

what happens with p450 induction ?

Answer 9

increased drug degradation leading to…
decreased drug plasma concentration leading to…
loss of pharmacological effect leading to….
risk of secondary effects

Question 10

what happens in phase 2 metabolism ?

Answer 10

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

Question 11

how is aspirin metabolised ?

Answer 11

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

Question 12

what is excretion ?

Answer 12

it is the irreversible removal of drugs from the body -NOT MOVEMENT FROM ONE COMPARTMENT TO ANOTHER

Question 13

what are some examples of avenues of excretion ?

Answer 13

bile/faeces, lungs, saliva, sweat, tears and milk

Question 14

what is the main route of excretion ?

Answer 14

renal excretion- within the urine via the kidney

Question 15

what must be considered with renal excretion ?

Answer 15

reabsorption must be considered
renal excretion= (filtration + secretion)- reabsorption
- if the rate of reabsorption is changed the rate of excretion can be changed

Question 16

how can you increase the excretion of aspirin ?

Answer 16

to increase excretion you want to make a basic environment for example using sodium bicarbonate - this makes aspirin more ionised to stop reabsorption

Question 17

what is clearance ?

Answer 17

it is a measure of drug elimination from plasma and has units of a virtual flow

Question 18

what does a low volume of distribution mean ?

Answer 18

it means the majority of the drug is in the systemic circulation so its easier to remove

Question 19

what must be taken into account with drug dosing ?

Answer 19

must take into account kidney function as this effects clearance rates

Question 20

how is renal clearance calculated ?

Answer 20

=CU * VU / CP
CU- urine drug concentration
VU- urine production rate
CP- plasma drug concentration

Question 21

how is clearance calculated ?

Answer 21

= F * dose / AUC
F- fraction absorbed after administration

= K * Vd
K- elimination rate
Vd- volume of distribution

Question 22

what is an elimination rate ?

Answer 22

it is the fraction of drug eliminated per unit time

Question 23

what is a 1st order elimination rate ?

Answer 23

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

Question 24

what is a zero order elimination rate ?

Answer 24

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

Question 25

how are most drugs metabolised?

Answer 25

through 1st order kinetics

Question 26

how is C(t) calculated ?

Answer 26

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

Question 27

what is the plasma half life ?

Answer 27

it is the time to equilibriate between plasma and target compartments

Question 28

what is the duration of action dependent upon ?

Answer 28

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

Question 29

How is the initial concentration of drug calculated ?

Answer 29

c(0)= Q/Vd
Q- quantity of drug
Vd= volume of distribution

Question 30

when administering a drug on repeat doses why are elimination rates so important ?

Answer 30

they are important to avoid overdose/toxicity

Question 31

what happens in continuous infusion?

Answer 31

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

Question 32

for most drugs when is the steady state achieved ?

Answer 32

after 5 t0.5

Question 33

why is chloroquine taken weeks before visiting an area with malaria risk ?

Answer 33

because it has a steady state of 5 weeks therefore it needs to be taken before, however this causes compliance problems

Question 34

how do clearance and volume of distribution affect the T half life ?

Answer 34

• 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

Question 35

what is the aim when taking a drug ?

Answer 35

the aim is to achieve a steady state dose in the body

Question 36

what is pharmacokinetics essential for ?

Answer 36

for working out the route of delivery and dose regime of a drug
- all elements of drug disposition must be considered

Question 37

what are the varying degrees of compliance ?

Answer 37

high to low

• treatment alleviates symptom
• treatment but no symptoms
• prophylaxis