PHAR 300 Lecture Notes - Cytochrome P450, Drug Metabolism, Cyp1A2
7 Jun 2018
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PHAR300
Drug responses in different age groups
Drugs are tested in «!small!» numbers of
people
-usually young healthy adults
-we thus need to make sure the drugs that are
on the market can be used by everyone
-different responses depending on the age
group -> pharmacokinetics (how the drug
is handled by the body)
-we always try to stay in the therapeutic
window
Age related changes
-total body water, fraction of lipophilic drug
in fatty tissues, liver metabolism of drug,
renal drug elimination
-change in clearance (rate at which the drug
is removed from blood)
-low when we were born, then goes up
and then down
Prenatal pharmacology
-most pregnant women (90%) take at least 1 medication
during pregnancy, 70% take at least one predication
medication
-number of women who take 4 or more is increasing
-physiological changes
-cardiovascular (increases in CO, HR…)
-serum albumin
-coagulation factors
-kidneys : changes in renal blood flow and GFR -> could
affect elimination of the drug
-liver : some of the cytochromes P450
-lungs : tidal volume increases => inhale/exhale more of a
potential drug
-stomach and intestines : nausea, vomiting…
-distribution : some of the common drugs have big
changes in the apparent volume of distribution (virtual
space that the drug is distributed in) => increases during
gestation
-might affect how much drug we need to give
-metabolism : some P450 are increased, others are
decreased (rate of metabolism thus changes), and changes in
GI function (where we have some metabolising enzymes)
=> could affect the half-life
-e.g. CYP1A2 demethylates caffeine (caffeine is used to
1
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treat newborn respiratory disorders) => gives rise to theophyline or theobromine
-caffeine half-life : depends on the demethylation reaction -> way higher in pregnant women
than normal people because CYP182 is decreased during pregnancy
-other targets if drugs in pregnancy -> effects of the conceptus (developing embryo)
-placental transport : same type of transport as
in other membranes => only difference
compared to any membrane is that the placenta
also has drug metabolising enzymes -> can
control what gets through and in what form
-the drug is thus going to get to the conceptus
-time of distribution : rapid and slow diffusing
drugs exist (reverse on the graph : solid line is
maternal) -> if it is a rapidely diffusion drug,
the fetus will get it right away ; if slowly
diffusing drug, we give it IV and the amount
will decrease with time ; the fetus slowly gets
the drug but at some stages it is in higher
concentration than in the mum because it gets
out slowly -> we may accumulate higher
concentrations of drugs in the fetus than in the
mother (probably due to a difference in pH)
-fetal livers don’t do much (have not all the
metabolising enzymes)
-drug goes back to the mother so that it can be eliminated
-how do drugs affect the fetus
-no effect
-transient effect e.g. decrease in fetal breathing movements
-irreversible structural malformations
-delayed effects on behavior or reproductive function
2
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Document Summary
Drugs are tested in small numbers of people. We thus need to make sure the drugs that are on the market can be used by everyone. Different responses depending on the age group -> pharmacokinetics (how the drug is handled by the body) We always try to stay in the therapeutic window. Total body water, fraction of lipophilic drug in fatty tissues, liver metabolism of drug, renal drug elimination. Change in clearance (rate at which the drug is removed from blood) Low when we were born, then goes up and then down. Most pregnant women (90%) take at least 1 medication during pregnancy, 70% take at least one predication medication. Number of women who take 4 or more is increasing. Kidneys : changes in renal blood ow and gfr -> could affect elimination of the drug. Lungs : tidal volume increases => inhale/exhale more of a potential drug.
