Pharmacokinetics
Psychopharmacology
• Psychopharmacology is the study of the effects
of drugs on the nervous system and on behavior
• The term drug has many meanings:
– Medication to treat a disease
– A chemical that is likely to be abused
– An “exogenous” chemical that significantly alters the
function of certain bodily cells when taken in
relatively low doses (chemical is not required for
normal cellular functioning)
Drug Effects
All drugs produce harmful as well as beneficial
effects.
• Main effects are related to desired therapeutic
effect.
• Side effects are unrelated to the desired effect.
• Placebo Effects are based upon an inert
substance's ability to elicit a significant therapeutic
response, independent of any chemical property.
Drug Effectiveness
• Dose-response (DR) curve:
Depicts the relation between
drug dose and magnitude of
drug effect
• Drugs can have more than one
effect
• Drugs vary in effectiveness
– Different sites of action
– Different affinities for receptors
• The effectiveness of a drug is
considered relative to its safety
(therapeutic index)
Dose-Effect Curves
Therapeutic Index
This is a figure of two different
dose response curves. You can
obtain a different dose response
curve for any system that the drug
effects. When you vary the drug,
this is the Independent variable,
what you are measuring is the % of
individuals responding to the drug.
Here we see the drugs effects on
hypnosis and death. Notice that the
effective dose for 50 % of the
people is 100 mg and if you double
the dose to 200 mg then 1 % of
your subjects die. Thus, if you
want to use this drug to hypnotize
99 % of your subjects, in the
process you will kill 2-3 % of your
subjects.
Drug Safety and Effectiveness
• Not all people respond to a similar dose of a drug
in the exact same manner, this variability is based
upon individual differences and is associated with
toxicity. This variability is thought to be caused
by:
– Pharmacokinetic factors contribute to differing
concentrations of the drug at the target area.
– Pharmacodynamic factors contribute to differing
physiological responses to the same drug concentration.
– Unusual, idiosyncratic, genetically determined or
allergic, immunologically sensitized responses.
Pharmacokinetics
• Drug molecules interact with target sites to effect the
nervous system
– The drug must be absorbed into the bloodstream and then
carried to the target site(s)
• Pharmacokinetics is the study of drug absorption,
distribution within body, and drug elimination
– Absorption depends on the route of administration
– Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the
extent to which the drug binds to blood proteins (albumin)
– Drug elimination is accomplished by excretion into urine
and/or by inactivation by enzymes in the liver
Overview
Pharmacokinetics
Routes of Administration
• Routes of Administration:Orally:
• Rectally:
• Inhalation: Absorption through mucous
membranes:
• Topical:
• Parenterally:
– Intravenous:
– Intramuscular:
– Subcutaneous:
Routes of Administration
Drug Delivery Systems
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Tablets
Injections (Syringe)
Cigarettes
Beverages
Patches
Suppositories
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Candy
Gum
Implants
Gas
Creams
Others?
– Stamps
– Bandana
Membranes
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Types of Membranes:
Cell Membranes: This barrier is permeable to many drug molecules but not to
others, depending on their lipid solubility. Small pores, 8 angstroms, permit
small molecules such as alcohol and water to pass through.
Walls of Capillaries: Pores between the cells are larger than most drug
molecules, allowing them to pass freely, without lipid solubility being a factor.
Blood/Brain Barrier: This barrier provides a protective environment for the
brain. Speed of transport across this barrier is limited by the lipid solubility of
the psychoactive molecule.
Placental Barrier: This barrier separates two distinct human beings but is
very permeable to lipid soluble drugs.
Drug Distribution
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Dependent upon its route of administration and target area, every drug has to
be absorbed, by diffusion, through a variety of bodily tissue.
Tissue is composed of cells which are encompassed within membranes,
consisting of 3 layers, 2 layers of water-soluble complex lipid molecules
(phospholipid) and a layer of liquid lipid, sandwiched within these layers.
Suspended within the layers are large proteins, with some, such as receptors,
transversing all 3 layers.
The permeability of a cell membrane, for a specific drug, depends on a ratio of
its water to lipid solubility. Within the body, drugs may exist as a mixture of
two interchangeable forms, either water (ionized-charged) or lipid (nonionized) soluble. The concentration of two forms depends on characteristics of
the drug molecule (pKa, pH at which 50% of the drug is ionized) and the pH
of fluid in which it is dissolved.
In water soluble form, drugs cannot pass through lipid membranes, but to
reach their target area, they must permeate a variety of types of membranes.
Acute vs Steady State
Drug Half-Life
Liver P450 systems
• Liver enzymes inactivate some drug molecules
– First pass effect (induces enzyme activity)
• P450 activity is genetically determined:
– Some persons lack such activity  leads to higher drug
plasma levels (adverse actions)
– Some persons have high levels  leads to lower
plasma levels (and reduced drug action)
• Other drugs can interact with the P450 systems
– Either induce activity (apparent tolerance)
– Inactivate an enzyme system
Drug Metabolism and PK
P450 Interactions
• Substrate: Is the drug metabolized via a specific
hepatic isoenzyme?
• Inhibitor: does a specific drug inhibit a specific
hepatic isoenzyme?
– Would expect this to interfere with drug inactivation
• Inducer: does a specific drug enhance a specific
hepatic isoenzyme?
– Would expect this to speed up drug inactivation
–http://www.georgetown.edu/departments/pharmacology/clinlist.html
Drug-Hepatic Interactions
Enzyme
Substrate
Inhibitor
Inducer
–1A2
Clozapine, haloperidol
Cimetidine
Tobacco smoke
–2B6
Bupropion
Thiotepa
Phenobarbital
–2C19
Citalopram
Fluoxetine
Prednisone
–2C9
Fluoxetine
Paroxetine
Secobarbital
–2D6
Most ADs, APs
CPZ, ranitidine
Dexamethasone
–2E1
Gas anesthetics
Disulfiram
Ethanol
– 3A4,5,7
Alprazolam
Grapefruit juice
Glucocorticoid
–http://www.georgetown.edu/departments/pharmacology/clinlist.html
Drug Enantioners
• A drug molecule may be organized in such a way
that the same atoms are mirror images
– Enantioners represent drug molecules that are
structurally different (spatial configutation)
• Different physical properties
– Light rotation (levo = left; dextro = right)
– Melting points
• Different biological activities (typically: dextro > levo)
– Fenfluramine = racemic mix of
• dextro-fenfluramine
• levo-fenfluramine
• Enantiomers often have different affinity for
receptors
Supra-additive:
The Case of Fen-Phen
BODY WEIGHT (g)
440
DEX 0 - 0 PHEN
DEX 0 - 5 PHEN
DEX 1 - 0 PHEN
DEX 1 - 5 PHEN
RESIDUAL
400
360
320
40
0
1
3
5
7
9
11
13
15
17
19
21
DAYS
Wellman et al., 2003