CYP enzymes -◦ enzyme induction -

liver produces extra enzyme to break down drug with continued exposure

Genetics

Pharmacokinetics

Estimates that there is a 10-year gap between medically relevant bio-technological advances and appropriate application, or translation into routine medical practice

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

CYP enzymes -◦enzyme induction - liver produces extra enzyme to break

down drug with continued exposureGenetics

Liver disease

cirrhotic liver

In some cases, biotransformation can be to another psychoactive compound

ex. benzodiazepenes

diazepam nordiazepam oxazepam

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

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…….

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

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

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

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 1.4Julien: A Primer of Drug Action, Eleventh EditionCopyright © 2008 by Worth Publishers

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?

Provides a good indication of the time necessary to reach steady state after a dosage regime has been initiated (6X)

drug elimination = drug availability

usually try and maintain steady state concentration in therapeutic window

So if a drug had a 3 hour ½ life – how long would it take to reach steady state?

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,

- 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?

What happens if?

◦ Plasma levels are too high –

◦ Plasma levels are too low –

Focus on levels rather than dose

Determine if patient is taking drug as prescribed

Avoid toxicity Enhance therapeutic process Reduction in cost of therapy

Definition:

Types of tolerance:◦ Metabolic tolerance:

Type of pharmacological tolerance◦ Pharmacological Tolerance◦ Behavioral conditioning

Physical dependence:◦ Entirely different than tolerance

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

each NT binds to its own receptors◦ there can be multiple receptor subtypes

each NT binds to its own receptors◦ there can be multiple receptor subtypes

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.

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

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

Several configurations of proteins Ion channel receptors

◦ ionotropic

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

Neurotransmitterreceptor

Ca2+ -activatedK+ channel

Cyclic nucleotidegated channel

Na+

K+

Glu

K+

Ca2+

Na+

K+

cAMP

cAMP

cGMP

7111158

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

3. carrier proteins (transporter)

◦ presynaptic transporters – transport NT back into presyn ending

4. enzymes –◦ what is an enzyme?◦ breakdown NT -

receptors exhibit high specificity for specific nt (and certain drugs)

Minor modification in structure of drug can have major impact

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

the intensity or magnitude of the response in a single person

the % of people who exhibit a characteristic effect at a given dosage

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

Efficacy - maximum effect obtainable - peak of the DRC indicates the maximum effect

Variability and slope –individual differences in drug response

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

Different DRC depending upon measure of interest

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 DRCOften see a bell-shaped curve in response to drug