Definitions

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Definitions

• Pharmacokinetics
• The process by which a drug is administered,
  absorbed, distributed, bound, inactivated,
  metabolized and eliminated by the body
• Pharmacodynamics
• The interactions of a drug and the receptors
  responsible for its action in the body and CNS

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Drug Administration

• Orally (swallowed)

• through Mucus Membranes
• Oral Mucosa (e.g. sublingual)
• Nasal Mucosa (e.g. insufflated)

• Rectally (suppository)

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Drug Administration (cont.)

• Parenterally (injection)
• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous (SC)
• Intraperitoneal (IP)

• Inhaled (through lungs)

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Drug Administration (cont.)

• Topical/Transdermal (through skin)

• Directly into CNS
• Intracranial or intracerebral (into brain tissue)
• Intracerebroventricular (into brain ventricles)

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Drug Administration Summary

• Pharmacokinetics relates to bioavailability
• The fraction of an administered dose of a drug
  that reaches the blood stream
• How quickly a drug reaches its site of action
  relates to addictiveness.

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Distribution Solubility

• Water-soluble
• Ionized (have electrical charge)
• Crosses through pores in capillaries, but not
  cell membranes
• The extent of ionization of a drug is expresses
  as the pKa of the drug
• Lipid(fat)-soluble
• Non-ionized (no electrical charge)
• Crosses pores, cell membranes, blood-brain-barrier

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Distribution Blood Brain Barrier
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Depot Binding

• Drugs bind to depot sites or silent receptors
• Deposits slow elimination, can increase drug
  detection window

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Metabolism Elimination

• Liver
• Enzymes transform drugs into more water-soluble
  metabolites

• Kidneys
• Traps water-soluble compounds for elimination via
  urine

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Metabolism and Elimination (cont.)

• Half-lives and Kinetics
• Half-life
• Plasma half-life Time it takes for plasma
  concentration of a drug to drop by 50.
• Whole body half-life Time it takes to eliminate
  half of the body content of a drug.
• Factors affecting half-life
• age
• renal excretion
• liver metabolism
• protein binding

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First order kinetics A constant fraction of drug
is eliminated per unit of time. When drug
concentration is high, rate of disappearance is
high.
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Zero order kinetics Rate of elimination is
constant. Rate of elimination is independent of
drug concentration. Constant amount eliminated
per unit of time. Example Alcohol
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The Dose-Response Curve

• X-axis Dose
• Y-axis Response, measured as either
• magnitude of response in individual
• number/percentage of individuals responding at a
  given level

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Therapeutic Index

• ED50 dose at which 50 population shows
  response
• LD50 dose at which 50 population dies
• TI LD50/ED50, an indication of safety of a drug
  (higher is better)

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Potency

• Relative strength of response for a given dose
• accessability, affinity, and efficacy
• D-R curve shifts left with greater potency

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Efficacy( of maximal change elicited)

• Maximum possible effect
• Indicated by peak of D-R curve

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Tolerance(desensitization)

• Decreased response to same dose with repeated
  exposure
• or more drug needed to achieve same effect
• Right-ward shift of D-R curve
• Sometimes occurs in an acute dose (e.g. alcohol)
• Can develop across drugs (cross-tolerance)
• Caused by compensatory mechanisms that oppose the
  effects of the drug

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Tolerance

• Physical
• User requires more of the drug to achieve the
  same effect, and the same amount will produce a
  lesser effect.
• Psychological
• As the user becomes familiar with the drugs
  effects, s/he learns tricks to hide or counteract
  the effects.
• Metabolic
• The user is able to break down and/or excrete the
  drug more quickly due to repeated exposure.

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Sensitization

• Increased response to same dose with repeated
  exposure
• or less drug needed to achieve same effect
• Left-ward shift in D-R curve
• Sometimes occurs in an acute dose (e.g.
  amphetamine)
• Can develop across drugs (cross-sensitization)

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Mechanisms of Tolerance and Sensitization

• Pharmacokinetic
• changes in drug availability at site of action
  metabolic changes
• Pharmacodynamic
• changes in drug-receptor interaction (G-protein
  uncoupling down regulation)
• Conditioning
• automatic physiological change in response to
  cues
• Motivational
• change in organisms behavior to
  attenuate/increase effect

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Pharmacodynamics

• Receptor
• target/site of drug action (e.g.
  genetically-coded proteins embedded in neural
  membrane, cytoplasm, nucleus)
• Lock and key model
• Drug acts as key, receptor as lock, combination
  yields response

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Pharmacodynamics continued

• Affinity
• propensity of a drug to bind with a receptor
• Selectivity
• specific affinity for certain receptors (vs.
  others)

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Agonism and Antagonism

• Agonists facilitate receptor response
• Antagonists inhibit receptor response

(direct ant/agonists)
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Agonists

• Full Agonist
• Partial Agonist
• Direct/Competitive Agonist
• Indirect/Noncompetitive Agonist

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Antagonists

• Direct/Competitive Antagonist
• Indirect/Noncompetitive Antagonist
• Inverse Agonist

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Important implications ofdrug-receptor
interaction

• drugs can potentially alter rate of any
  bodily/brain function
• drugs cannot impart entirely new functions to
  cells
• drugs do not create effects, only modify ongoing
  ones
• drugs can allow for effects outside of normal
  physiological range