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CYP enzymes ◦ enzyme induction  liver produces extra enzyme to break down drug
with continued exposure
Genetics
Pharmacokinetics
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Estimates that there is a 10-year gap between
medically relevant bio-technological
advances and appropriate application, or
translation into routine medical practice
Pharmacokinetics
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Enzyme Inhibition
◦
◦
Some drugs inhibit CYP enzymes and
increase their own levels, as well as levels
of any other drug metabolized by that
enzyme. Can produce toxicities.
Example: Inhibition of antipsychotic
medication by SSRIs.
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CYP enzymes -
◦ enzyme induction  liver produces extra enzyme to break
down drug with continued exposure
 Genetics
 Liver
disease
cirrhotic liver
In some cases, biotransformation can be to
another psychoactive compound
ex. benzodiazepenes
diazepam
nordiazepam
oxazepam
Pharmacokinetics
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Excretion
◦ Primarily accomplished by kidneys.
 2 organs (about the size of a fist)
located on either side of the spine in the
back.
 Keep the right balance of water and salt
in the body
 Filter everything out of blood and then
selectively reabsorb what is required.
 Can be useful for eliminating certain
drugs in overdose.
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all drugs not in gaseous state need to use
fluid routes of excretion
◦ fluid routes include -sweat, tears, saliva, mucous,
urine, bile, human milk
◦ amount of drug excreted in each of these fluids is
in direct proportion to amount of fluid excreted
SO…….
Pharmacokinetics
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Sometimes drugs are not metabolized and
are excreted intact.
◦ Lithium
◦ Mushroom amanita muscaria
 In large doses it is toxic and lethal; small amounts are
hallucinogenic.
 Hallucinogenic ingredients are not greatly metabolized
and are passed to the urine. Siberian tribespeople
discovered this and recycled the drug by drinking their
urine.
Pharmacokinetics
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Sometimes drugs are not metabolized and
are excreted intact.
◦ Lithium
◦ Mushroom amanita muscaria
 In large doses it is toxic and lethal; small amounts are
hallucinogenic.
 Hallucinogenic ingredients are not greatly metabolized
and are passed to the urine. Siberian tribespeople
discovered this and recycled the drug by drinking their
urine.
absorption, distribution and excretion do
not occur independently
1.
Body weight - smaller size
•
concentration of drug based on body fluid
2.
Sex differences
3.
Age
4.
Interspecies differences
rabbits – belladonna (deadly nightshade)
5.
Intraspieces differences
6.
Disease states
7.
Nutrition
8.
Biorhythm - chronopharmacology
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half-life - time takes for the blood
concentration to fall to half its initial value
after a single dose
½ life tells us critical information about how
long the action of a drug will last
Table 1.4
Julien: A Primer of Drug
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How long would it take for a drug to reach
12.5% remaining in blood if its ½ life is 2
hours?
How long would it take for a drug to reach
12.5% remaining in blood if its ½ life is 100
hours?
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Provides a good indication of the time
necessary to reach steady state after a dosage
regime has been initiated (6X)
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drug elimination = drug availability
usually try and maintain steady state
concentration in therapeutic window
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So if a drug had a 3 hour ½ life – how long
would it take to reach steady state?
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Therapeutic drug monitoring - branch of
clinical chemistry that specializes in the
measurement of medication levels in blood.
Its main focus is on drugs with a narrow
therapeutic range,
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- need to reach threshold plasma
concentration at the receptor site to initiate
and maintain a pharmacological response.
◦ assume that plasma represents good indicator of
local site
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TDM is actually indirect
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How is TDM determined?
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What happens if?
◦ Plasma levels are too high –
◦ Plasma levels are too low –
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Focus on levels rather than dose
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Determine if patient is taking drug as
prescribed
Avoid toxicity
Enhance therapeutic process
Reduction in cost of therapy
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Definition:
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Types of tolerance:
◦ Metabolic tolerance:
 Type of pharmacological tolerance
◦ Pharmacological Tolerance
◦ Behavioral conditioning
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Physical dependence:
◦ Entirely different than tolerance
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Pharmacodynamics
◦ drugs produce their effects by binding to and
interacting with receptors
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What is a receptor?
◦ usually a protein on the surface or in the cell

each NT binds to its own receptors
◦ there can be multiple receptor subtypes
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each NT binds to its own receptors
◦ there can be multiple receptor subtypes
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useful for understanding drugs that work on
the specific neurotransmitters

Given drug may be more specific for a given
set of receptors than is the endogenous nt
◦ 5HT – (serotonin) – attaches to more than 15 nt
receptors –
◦ Buspirone (BuSpar) attaches to 5HT 1A but no
affinity for other 5HT receptors.
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Bind to the receptor site that nt normally
binds to; acts just like nt
◦ Agonist
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Can facilitate endogenous nt;
◦ Agonist
◦ Allosteric action
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Bind to the receptor site but do not initiate
transmitter-like activity
◦ Antagonistic effect
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Drugs exert effects by forming reversible
bonds w specific receptor
100s of different types of receptors w ability
to recognize 1 nt characterizes each of these
Drugs do not create any unique effects –
modulate normal neuronal functioning
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Several configurations of proteins
Ion channel receptors
◦ ionotropic
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1. ionotropic postsynaptic receptors
quick action and over quickly
◦ “ion channel receptors”
Ion channel - close
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Ion channel - open
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Ligand-gated channels
Neurotransmitter
receptor
Ca2+ -activated
K+ channel
Cyclic nucleotide
gated channel
Na+
Na+
Glu
cAMP
Ca2+
K+
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cAMP
K+
cGMP
K+
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2. G-protein coupled receptors
◦ (metabotropic)
◦ 2nd messenger systems
◦ more than 50 G protein coupled receptors have
been identified (large and diverse family)
◦ control many cellular processes
◦ Involved in synaptic effects of many nt
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3. carrier proteins (transporter)
◦ presynaptic transporters – transport NT back into
presyn ending
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4. enzymes –
◦ what is an enzyme?
◦ breakdown NT -
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receptors exhibit high specificity for specific
nt (and certain drugs)
Minor modification in structure of drug can
have major impact
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info on a range of doses of drug
dose usually presented on horizontal axis
(log concentration)
size of effect or percentage affected usually
on vertical axis
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the intensity or magnitude of the response
in a single person
the % of people who exhibit a characteristic
effect at a given dosage
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potency - amount of drug required to elicit
a response
slope of the line tells you about how much
difference in drug is needed for small
effects relative to larger effect
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Efficacy - maximum effect obtainable
- peak of the DRC indicates the maximum effect
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Variability and slope –
individual differences in drug response
A. As dose increases; effect increases
B and C - maximal effect that dose can reach (differ in effic
D. Inverted U function - works better at intermediate dose
higher or lower doses
Different DRC depending upon measure of
interest
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ED 50 - The dose of a drug that produces
the desired effect in 50% of the population
LD 50 –
TI = Therapeutic Index – measure of safety
LD 50/ED 50
hypothetical drug that can be used as a sedative –
this is tested in mice –
** dose cannot guarantee 100% sleeping and no deaths
Caution in interpreting DRC
Often see a bell-shaped curve in response to drug