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CYP enzymes -◦ enzyme induction -
liver produces extra enzyme to break down drug with continued exposure
Genetics
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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
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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.
Pharmacokinetics
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CYP enzymes -◦enzyme induction - liver produces extra enzyme to break
down drug with continued exposureGenetics
Liver disease
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cirrhotic liver
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In some cases, biotransformation can be to another psychoactive compound
ex. benzodiazepenes
diazepam nordiazepam oxazepam
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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.
Pharmacokinetics
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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…….
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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.
Pharmacokinetics
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absorption, distribution and excretion do not occur independently
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1. Body weight - smaller size • concentration of drug based on body fluid
2. Sex differences
3. Age
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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
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Table 1.4Julien: A Primer of Drug Action, Eleventh EditionCopyright © 2008 by Worth Publishers
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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
TDM is actually indirect
How is TDM determined?
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What happens if?
◦ Plasma levels are too high –
◦ Plasma levels are too low –
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:
Types of tolerance:◦ Metabolic tolerance:
Type of pharmacological tolerance◦ Pharmacological Tolerance◦ Behavioral conditioning
Physical dependence:◦ Entirely different than tolerance
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Pharmacodynamics◦ drugs produce their effects by binding to and
interacting with receptors
What is a receptor?◦ usually a protein on the surface or in the cell
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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
useful for understanding drugs that work on the specific neurotransmitters
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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
Can facilitate endogenous nt; ◦ Agonist◦ Allosteric action
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”
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Ion channel - close
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Ion channel - open
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Copyright © motifolio.com
Ligand-gated channels
Neurotransmitterreceptor
Ca2+ -activatedK+ channel
Cyclic nucleotidegated channel
Na+
K+
Glu
K+
Ca2+
Na+
K+
cAMP
cAMP
cGMP
7111158
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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
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
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A. As dose increases; effect increasesB and C - maximal effect that dose can reach (differ in efficacy)D. Inverted U function - works better at intermediate doses than higher or lower doses
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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
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hypothetical drug that can be used as a sedative – this is tested in mice –
** dose cannot guarantee 100% sleeping and no deaths
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Caution in interpreting DRCOften see a bell-shaped curve in response to drug