FRS 5. PHARMACOKINETICS WORKSHOP Flashcards
Describe phase I of drug metabolism in the liver
Phase I metabolism is mainly dependent on the cytochrome P450 enzyme system
o produces a more polar metabolite by the processes of oxidation, reduction and hydrolysis
Describe phase II of drug metabolism in the liver
Phase II metabolism (conjugation) converts the parent drug (or metabolite) into a more polar form by
combining it with an endogenous compound such as glycine, glutamine, sulphate or glucuronic acid, or by adding an acetyl or a methyl group
How do drugs enter the systemic circulation?
o directly (e.g. by intravenous injection) o indirectly following absorption from the site of administration (typically from the small intestine following oral administration)
Describe absorption of water soluble drugs
are often poorly absorbed following oral administration
o usually eliminated from the body through excretion by the kidneys into the urine
Describe absorption of lipid soluble drugs
also filtered at the glomerulus, but readily cross cell membranes => reabsorption in
the proximal tubule
What is the Therapeutic index
difference between concentration that achieves a therapeutic response, and the concentration that achieves a toxic response
Why does therapeutic index vary between patients?
o concentration-time profile achieved with a standard dose regimen
o pharmacokinetic variability between patients
absorption, distribution, metabolism and elimination of drugs can vary between patients
o pharmacodynamic variability
actual response to drugs can differ between patients (e.g. target molecule may be found
in different quantities due to polymorphisms etc.)
What is a loading dose?
large initial dose => can put patients straight into therapeutic range
loading dose (mg) = target concentration (mg/L) x volume of distribution (L)
What is the apparent volume of distribution?
theoretical volume throughout which the drug would be evenly distributed to obtain the measured
serum concentration
(the volume of distribution is the volume of plasma that would be necessary to account for the total amount of drug in the patient’s body, if that drug were present throughout the body at the
same concentration as found in the plasma.)
Why is the apparent volume of distribution important in calculating a loading dose?
decides target level
What is the calculation for volume of distribution
dose (mg) / concentration (mgL-1) = volume of distribution (L)
How does a drug being bound to plasma proteins affect volume of distribution?
the plasma concentration will be relatively high, and volume of distribution low
How does a drug being bound to tissue proteins affect the volume of distribution
plasma concentration would be low but volume of
distribution high
Which drugs generally have low volumes of distribution?
water soluble drugs that do not easily cross cell membranes generally
Which drugs generally have high volumes of distribution?
lipid soluble drugs
How is the input rate/infusion rate calculated?
input rate = drug dosing rate (mg/h) = steady state concentration (mg/L) x clearance (L/h)
How is the output rate/clearance calculated?
output rate = steady state concentration (mg/L) x clearance (L/h) / bioavailability (F)
What is bioavailability?
proportion that reaches circulation from oral dose
How is the steady state concentration determined?
average steady state concentration determined by dividing infusion rate
by clearance
What is clearance?
- defined as the volume of serum (or plasma, blood, etc.) cleared of drug per unit time
- therefore has the units of ml/min-1 or L/h-1
- depends on
o rate of drug delivery (i.e. blood flow) to the liver (or kidney for some drugs)
o efficiency, or “extraction ratio” of drug removal by the liver (or kidney)
What can affect clearance?
can be altered by patient characteristics e.g. age, weight, pregnancy, renal disease, hepatic disease, cardiac disease, drug interactions etc.
What is the significance of altered clearance rates?
o this means that “sick” patients often require lower doses of drugs than patients who are not so
seriously ill
o also the case for many drugs in renal and hepatic failure where the ability to clear drugs is
impaired
What is the elimination half life?
time for concentration to fall to half
- half-life is directly proportional to volume of distribution and inversely proportional to
the clearance
What is elimination half-life
governs the time it takes to eliminate a drug from the body and time to accumulate
to steady state on multiple dosing or during constant infusion
o takes about 4-5 half lives
Bioavailability
(proportion of a drug reaching systemic circulation) depends on
- water and lipid solubility i.e. absorption from the GI tract
- first pass metabolism in the liver (passing through portal system)
