Pharmacology: The Science of Drug Action

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Pharmacology The Science of Drug Action

• Chapters 4 and 5

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Pharmacology

• Pharmacokinetics
• Explains the processes involved in
  administration, absorption, distribution,
  transformation, and elimination a drug
• Pharmacodynamics
• Explains the nature of physiological and
  biochemical interactions between a drug and the
  target tissue responsible for the drug effect

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Pharmacokinetics

• Administration
• Absorption
• Distribution
• Biotransformation
• Excretion

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Routes of Administration

• Oral
• Intramuscular (IM)
• Intraperitoneal (IP)
• Intravenous (IV)
• Inhalation
• Intracranial (IC)
• Intracerebroventricular
• Topical

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Absorption

• Moving from the site of administration to the
  bloodstream
• Drugs exert effects by first traveling into the
  bloodstream
• How fast do drugs leave the site of
  administration?
• Route
• Acidity/Alkalinity
• Absorption relates to bioavailability
• The amount of the drug that reaches the
  bloodstream and/or site of action

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Distribution

• Refers to a drugs ability to reach a wide range
  of tissues
• Solubility Lipid solubility. Highly lipid
  soluble greater distribution and effect.
• Blood Brain Barrier
• Depot binding Drug binding to inactive sites
• Fat, Protein, Muscle
• THC testing

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Blood-brain barrier limits drug access to brain
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Biotransformation

• Drug Metabolization Mainly in LIVER
• Many drugs are broken down into other compounds.
  Some are not transformed at all
• Enzymes break down drugs into metabolites
• Drugs that use the same enzyme interact
• Metabolites can be active or inactive
• Metabolization occurs in an ordered manner
• Half-life The amount of time it takes for drug
  plasma level to be reduced by half
• THC 20 hours 9 days
• Cocaine 45 minutes
• Zoloft 2-3 days Prozac 7-9 days

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Drug Elimination

• Drugs are excreted in a variety of ways
• Urine
• Breath
• Feces
• Sweat
• Can be excreted changed or unchanged (alcohol vs.
  psylocibin)

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Target - Receptor
Depot Bone Fat
Blood Plasma
Excretion Intestines, Kidneys, Lungs, etc.
Absorption Distribution
Plasma Protein Binding
Metabolites
Administration Oral, IV, IM, IP, SC, Inhalation,
TC
Feces, Urine, Sweat, Saliva
Liver
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Pharmacodynamics

• Interaction between the drug and the target
  tissue
• For psychoactive drugs target tissues are
  receptors in CNS
• General Terms
• Receptor
• Site of initial interaction
• Ligand
• Any molecule that binds to a receptor
• Agonists
• Increases NT for a transmitter system
• Antagonists
• Decreases NT for a transmitter system

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Receptors

• METABOTROPIC
• Slower, longer lasting
• Work through a second messenger

• IONOTROPIC
• Work rapidly. Involved in fast NT
• Ion channels open when NT occupies
• Sodium
• Calcium
• Chloride

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Agonist/Antagonist

• Agonist
• Drug binds and induces full pharmacological
  effect
• Partial Agonist
• Drug binds and exerts only a partial effect
• Competitive Antagonist
• Binds to same receptor as agonist
• Reduces the effect
• Effect can be overcome by sufficient dose
• Noncompetitive Antagonist
• Binds in other ways, but disrupts agonist binding
  
• Reduces the effect
• Effect can not be overcome by sufficient dose

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Forms of Drug Action at the Synapse

• Ways to agonize
• Stimulate release
• Receptor binding
• Inhibition of reuptake
• Inhibition of deactivation
• Promote synthesis
• Ways antagonize
• Block release
• Receptor blocker
• Prevent synthesis

8. Autoreceptors
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Acetylcholine
Agonists
Nicotine Physostigmine
Antagonists
Muscarinic receptor - Atropine Nicotinic
receptor - Curare
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GABA

• Valium, Xanax, Ativan
• Act as GABA agonists
• GHB, Rohypnol
• GABA agonist

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Dopamine

• Cocaine
• dopamine reuptake inhibitor
• Amphetamine
• increases DA release
• Antipsychotics
• block post-synaptic dopamine receptor

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Serotonin

• Selective-serotonin reuptake inhibitors (SSRIs)
  used to treat depression

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Dose Issues
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General Drug Effects

• Main Effect The reason why the drug is taken
• This may be therapeutic or recreational
• Side Effects All effects other than the main
  effect
• One persons side-effect is another persons main
  effect.
• Ultimately drugs have an effect, we label it base
  on need or context.

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Dose Response Curve

• Dose-Response Curve
• Plots the relation between the dose of the drug
  and the size of the effect
• Specific to the behavior you are measuring
• Drugs have multiple effects and curves

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DRC Characteristics

• Slope
• gradual versus steep
• Potency
• amount required to produce effect
• Maximum efficacy
• upper end where response levels out

of Maximal Effect
Drug Dose
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Effective vs. Lethal Dose

• Effective Dose (ED)
• Dose level for chosen effect in of population
• ED50, dose in which drug is effective for 50 of
  population
• Lethal Dose (LD)
• Dose level for death in of population
• LD50 lethal dose for 50 of the population
• Therapeutic Index
• LD50/ED50 - Serves as margin of drugs safety
• Higher ratio ? more safe/less toxic
• 20 or more relatively safe, 100 preferred

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Drug Interactions

• Using multiple drugs increases the complexity of
  the experience
• Antagonism One drug inhibits the effect of
  another drug
• Cocaine and alcohol (Pharmacodynamic)
• St. Johns Wort and Birth Control Pills
  (Pharmacokinetic)
• Potentiation The two drugs together produced
  and enhanced effect
• Alcohol and nicotine

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Street dynamics

• Reality is that with illicit drugs,
  pharmacodynamics is ignored
• Most drugs are diluted
• Changes ED
• Most are cut with dangerous compounds
• Changes LD
• Sometimes dose is too high, leading to acute
  toxicity
• Potentiation and Antagonism work here

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Issues of Repeated Use

• Tolerance Sensitization Dependence and Withdrawal

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Tolerance

• Decreased response to drug with repeated use
• Shifting DRC to the right
• 3 types
• Metabolic
• Liver enzymes
• Cellular
• Receptor down-regulation
• Learned
• Context/cues
• Acute vs. Protracted
• Acute is within a single administration
• Cross-tolerance
• Tolerance to one drug leads to tolerance of other
  drugs in the same class.

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Sensitization

• Increased response to a drug with repeated use
• Shifting DRC to the left
• Cocaine-induced, movement, cataplexy and seizures
• Cocaine is a good example of a drug induces
  tolerance (euphoria) and sensitization (movement)

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Repeated Self-Administration

• Mesolimbic dopamine system
• Abused drugs all tend to activate this system
• 3 stages
• Pleasure
• Associative learning through classical
  conditioning
• Incentive salience
• Craving (wanting)
• Get DA release by cues/context alone

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Dependence/Withdrawal

• Physiological Dependence
• Body adapts to presence of drug. Needs drug on
  board to maintain homeostasis
• Indicated by the display of withdrawal symptoms
  upon cessation of drug use
• Withdrawal symptoms
• Behaviors displayed by a user when drug use ends
• Typically the opposite of the drug effect

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Behavioral Pharmacology
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Behavioral Pharmacology

• Study of the relationship between the
  physiological actions of drugs and their effects
  on behavior and psychological function
• Drugs do not create behaviors outside the normal
  species-typical repertoire
• They alter the probability or form of behaviors
• Uses the principles of operant and classical
  conditioning to examine the effects of drugs as
  well as the differences and similarities between
  drugs
• Self-administration studies
• Discrimination studies
• Conditioned place preference studies
• Conflict paradigm studies

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Self-administration

• Train animal to press lever for drug
  administration
• All drugs shown to be SA by animals are SA by
  humans
• Alcohol
• Cocaine
• THC

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Drug Discrimination

• Drugs can serve as discriminative stimuli
• Animals learn to respond in certain ways in the
  presence of a drug
• Discrimination is related to interoceptive cue
• Using these techniques, it appears that animals
  classify drugs just like humans
• Amphetamine and cocaine alike, but different from
  morphine, while morphine is like heroin and other
  opiates

• Method to ask animals about the interoceptive
  cues associated with different drugs
• Press left lever if on morphine gt get food
  Right lever if given saline gt get food
• Give new drug - is it like morphine?
• Left lever - Yes
• Right lever - No

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Conditioned Place Preference

• Pair drug administration with a place in the
  environment
• Give animal a choice of where to hang out.
• Measure where animal spends time

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Conflict Paradigm

• Train animal to associate both reinforcement and
  punishment with a certain behavior
• Food and shock w/lever press
• Administer a drug to test effects
• Xanax