Pharmacokinetics

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Pharmacokinetics
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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)

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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.

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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)

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Dose-Effect Curves
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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.
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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.

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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

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Overview
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Pharmacokinetics
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Routes of Administration

• Routes of AdministrationOrally
• Rectally
• Inhalation Absorption through mucous membranes
• Topical
• Parenterally
• Intravenous
• Intramuscular
• Subcutaneous

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Routes of Administration
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Drug Delivery Systems

• Tablets
• Injections (Syringe)
• Cigarettes
• Beverages
• Patches
• Suppositories

• Candy
• Gum
• Implants
• Gas
• Creams
• Others?
• Stamps
• Bandana

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Membranes

• 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.

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Drug Distribution

• 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
  (non-ionized) 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.

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Acute vs Steady State
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Drug Half-Life
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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

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Drug Metabolism and PK
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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

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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

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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 gt levo)
• Fenfluramine racemic mix of
• dextro-fenfluramine
• levo-fenfluramine
• Enantiomers often have different affinity for
  receptors

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Supra-additiveThe Case of Fen-Phen
Wellman et al., 2003