Feb 1 Thursday

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Feb 1 Thursday Drug Entry into the Body and
Pharmacokinetic Principles (chapter 1)
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Psychopharmacology study of how drugs affect
brain, behavior, and mental processes Pharmacokin
etics basic principles of drug absorption into
the blood, distribution through the body (to the
brain), metabolism, and excretion Pharmacodynamic
s study of how the drug interacts with tissues
(brain cells) to produce its effects
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Administered Dose the amount of a drug that is
taken/given Target Dose the amount that
reaches the tissues (brain) Determination of
administered doses based on average person
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Pharmacokinetics ADME (or LADME) Liberation
separation form the vehicle in which it was
administered Absorption the drug travels from
the point of entry into the body into the
bloodstream path and speed depend on the route
of administration Distribution throughout the
circulation and to the brain Metabolism
breakdown of the drug into by-products for
excretion and into components that no longer
produce the desired effects Elimination of
metabolic waste products
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Routes of Administration Oral swallowed (not
dissolved in mouth) Parenteral injected as
liquid Subcutaneous injection just under
skin Intramuscular injection into
muscle Intravenous into vein Inhalation into
lungs via smoke or aerosol Transdermal through
the skin (topical cream or patch) Transmucosal
through nose or mouth or under tonque (not
swallowed) Rectal suppository into rectum
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• Depending on route, path to bloodstream (B)
  differs.
• Oral route absorbed in small intestine ? B
• Subcutaneous muscle ? B
• Intramuscular muscle ? B
• Intravenous directly ? B
• Inhalation lungs ? B
• Transdermal through skin to muscle ? B
• Transmucosal mucous membranes ? B

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• Circulatory Path
• From tissues ? capillaries ? veins
• Back to heart in right atrium ? right ventricle
  ? lungs for reoxygenation ? left atrium of heart
  ? left ventricle ? pumped out via aorta ?arteries
  ? capillaries ? tissues of body
• Blood-Brain Barrier ?brain cells

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• Feb 5

V

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• Membranes that must be crossed for a drug in
  bloodstream to be distributed to body tissues
• Cell membranes
• Walls of the Capillaries
• Blood brain barrier
• Placental Barrier
• Next time

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• Influences on the Integrity of the Drug Molecule
  During Distribution
• Binding to blood proteins
• Major blood protein albumin
• 2. Dilution in blood and fluids blood, liver,
  kidneys, lungs, muscle
• 3. Sequestration in body fat
• 4. Metabolism along the way
• oral route stomach, small intestine, liver
• all routes blood enzymes, and on second pass,
  kidneys and liver
• Liver most important organ for drug metabolism

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• Metabolism of psychoactive drugs
• mostly in liver by cytochrome P450 enzyme
  family (several hundred members)

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• Liver Metabolism
• liver uses enzymes to break down substances into
  forms that can be used (nutrients) or eliminated
  (foreign substances like drugs depleted
  substances)
• Cytochrome P450 family of enzymes metabolizes
  most drugs
• Break down into ionized compounds that kidneys
  metabolize and excrete

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• Active metabolites breakdown products that are
  active at the drugs site of action prolong
  action of parent compound
• Inactive metabolites have no action at the
  drugs site of action
• Toxic metabolites are harmful to the body and
  produce immediate or longterm side effects
  (tobacco smoke charcoal broiled foods)

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• Metabolism of psychoactive drugs cytochrome
  P450 enzyme family (several hundred members)
• Important terms
• 1st pass metabolism liver is on the route
  between the site of administration (oral route)
  and the site of action in brain. Passes thru
  liver first before going to brain.
• 2nd pass metabolism after first time
  circulating thru the brain, the blood (containing
  drug) then goes thru the liver and kidneys

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• Half-life amount of time it takes for blood
  levels to drop to half of initial values
• 100 mg x ½ 50 mg 50
• 50 mg x ½ 25 mg
• 25 x ½ 12.5
• 12.5 x ½ 6.25 93.75
• 6.25 x ½ 3.12
• 3.12 x ½ 1.56 98.5
• 6 half-lives for most to be cleared.

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• Issues
• 1. Metabolic competence and variation
• 2. Genetic variations
• 3. Individual differences
• 4. Enzyme induction use increases production
• 5. Enzyme competition and drug interactions

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• Metabolic competence
• 40 fold variation across individuals
• 2. Genetics individual variations
• Individual characteristics diet fat/muscle
  ratio drug use history

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• 4. Enzyme induction
• Use of certain P450 enzymes induces increased
  production of the enzyme.
• Then, same dose on repeated administration is
  metabolized faster.
• Metabolic tolerance reduced effect of same dose
  on repeated administration due to changes in
  metabolism
• Ex alcoholics and anesthesia occupational
  chemicals (industrial solvents used to clean
  heavy machinery) Munich autoworkers and weekend
  alcohol tolerance

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• 5. Enzyme competition multiple things in diet,
  hormones, drugs may use the same P450 pathway for
  metabolism
• Drug interactions competition for breakdown by
  the available enzymes.
• Drug may not be metabolized as expected builds
  up to toxic levels, or at least to level of
  increased side effects.
• Ex grapefruit juice and valium alcohol and
  certain drugs drug-drug interactions

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• Important Terms/Concepts
• 1. Dose-response relationship
• 2. Efficacy
• 3. Effective Dose
• 4. Lethal dose
• 5. Therapeutic Index
• 6. Potency
• 7. Side Effects

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• 1. Dose-Response Relationship
• relationship between the amount of the drug and
  the magnitude of the specific effect measured
• Usually refers to amount of drug administered and
  the therapeutic effect (or desired effect)
• May be used more precisely for amount of drug in
  blood and the effect measured
• Different effects will have different
  dose-response relationships

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• Variables that influence the dose-response
  relationship
• all pharmacokinetic factors abs., dist.,
  biotransformation, excretion
• But when designed for a particular route and dose
  range for use, body weight is an important
  variable.
• Same amount gets different response in a 95 vs
  350 pound person
• - so doses are expressed as mg drug/ kg bodyweight

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• Variables that influence the dose-response
  relationship
• all pharmacokinetic factors
• Body weight - so doses are expressed as mg drug/
  kg bodyweight
• Diet, genetics, metabolism, general health status
• Given these individual differences, a group
  dose-response curve is used based on large
  sample.
• Effect may be selected then plot affected as a
  function of dose.

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• Dose-response curve for each effect
• Ex amphetamine, a stimulant drug
• Curve for appetite suppression effect curve for
  effect on sleep curve for euphoria curve for
  blood pressure effects (stroke)
• Alcohol different dose-response curves for
  disinhibition motor effects sedation
  anesthesia
• (NEJM case report)

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• Want to know the dose at which most people get
  the desired effect with minimal side effects.
• Actual prescription amounts and dosage repetition
  intervals are based on the average person the
  dose at which most people experience the desired
  effect.
• In reality, a 40 fold difference across adult
  individuals genetics and culture and experience
  (enzyme induction, expectation)