PSYCHOPHARMACOLOGY I The Brain, Body, and Drug Relationship

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PSYCHOPHARMACOLOGY I

• The Brain, Body, and Drug Relationship

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DEFINITIONS

• Psychoactive drugs those drugs that alter
  cognition, behavior, and emotions by changing the
  functioning of the brain.
• Psychopharmacology the study of the use,
  mechanisms, and effects of drugs that act on the
  brain and subsequently alter behavior.

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PHARMACOKINETICS

• Is the study of how drugs move through the body.
  
• Absorption
• Distribution
• Metabolism
• Elimination

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DRUG ABSORPTION

• Oral
• Rectal
• Injection
• Inhalation
• Skin
• Mucous Membranes

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DRUG DISTRIBUTION

• Factors that influence distribution
• Solubility
• Reversible binding to plasma proteins
• Body Membranes

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Solubility

• Water-soluble molecules do not readily cross cell
  membranes
• Lipid-soluble molecules do cross cell membranes
• MOST PSYCHOACTIVE DRUGS ARE LIPID-SOLUBLE
  MOLECULES

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Cellular Membranes

• Typical Cell Membranes
• Walls of Capillary Vessels
• Blood-brain Barrier
• Placental Barrier

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DRUG METABOLISM

• Hepatic Cytochrome P450 enzyme system
• Drugs are enzymatically biotransformed into
  metabolites that are less fat soluble and
  therefore less capable of being reabsorbed from
  renal distal tubules.

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ELIMINATION OF DRUG

• Kidneys
• Lungs
• Bile

• Skin
• Saliva
• Breast milk

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DRUG HALF-LIFE

• Drug half-life the time required for the drug
  concentration in blood to fall by one-half
  determines the length of time necessary to reach
  a steady state concentration.

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DOSE-RESPONSE RELATIONSHIP

• There is a relationship between drug level in the
  blood and the level of drug at the receptor
  site.
• Steady state amount of drug entering blood
  stream is equal to the amount of drug being
  eliminated from blood.

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Half-Life Calculations

• Drug with a 4 hour half-life
• 1200 take 100 mg
• 0400 50 mg left take 100 mg
• 0800 25 mg left 50 mg left take 100 mg
• 1200 12.5 mg 25 mg 50 mg take 100 mg
• After 6 half-lives, drug concentration is at
  steady state about 98.4.

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DRUG TOLERANCE

• A state of progressively decreasing
  responsiveness to a drug.
• Metabolic tolerance
• Cellular-adaptive tolerance

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PHARMACODYNAMICS

• The study of the biochemical and physiological
  effects of drugs and their mechanism of action

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DRUG-RECEPTOR INTERACTIONS

• Receptors are located on surface of cell membrane
• Attachment of transmitter to receptor activates
  the receptor, allowing for a signal to be
  transmitted to inside of cell
• Intensity of signal is determined either by
  percentage of receptors occupied or by rate of
  reversible transmitter binding

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Drug-Receptor Interactions

• A drug can either enhance or diminish the signal
  by binding to the receptor site
• Note a drug cannot import new functions to a
  cell
• Note a drug does not create effects but merely
  modulates ongoing functions

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Definitions

• AGONIST A drug that is capable of mimicking
  the action of a neurotransmitter.
• ANTAGONIST A drug that is capable of blocking
  the action of a neurotransmitter

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DOSE-RESPONSE RELATIONSHIPS

• Potency the absolute amount of drug needed to
  produce a defined effect.
• Efficacy the maximum effect obtainable by a
  given drug.

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Drug Responsiveness

• ED50 Effective dose for 50 of the subjects
• LD50 Lethal dose for 50 of the subjects
• Therapeutic Index LD50/ED50
• The higher the therapeutic index, the safer the
  drug!

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The Nervous System

• Central Nervous System
• Brain
• Spinal Cord
• Peripheral Nervous System
• Somatic nervous system
• Autonomic nervous system
• Parasympathetic nervous system
• Sympathetic nervous system

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The Brain

• Brain Stem
• Medulla decussation of motor cortex vomit
  reflex
• Pons reticular activating system locus
  coeruleus, raphe nucleus
• Midbrain auditory information, muscle movement
  eye movement.
• Cerebellum coordinating and smoothing out motor
  movements.

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Diencephalon

• Subthalamus functions with basil ganglia to
  from the extrapyramidal system
• Hypothalamus involved with autonomic nervous
  system eating, drinking, sleeping, body
  temperature, sexual behavior, emotion controls
  hormone output of the pituitary gland.

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Limbic System

• Amygdala fear and aggression
• Hippocampus consolidation of memory
• Exerts primitive types of behavioral control
  integrates emotion, reward, and behavior with
  motor autonomic function. Includes septum,
  nucleus accumbens, and cingulate gyrus.

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The Brain

• Thalamus sensory input, projections to the
  sensory area of the cortex
• Basil ganglia motor functioning extrapyramidal
  motor system. Includes the putamen, globus
  pallidus, and caudate nucleus
• Cerebrum occipital, temporal, frontal, and
  parietal lobes of cortex

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THE NEURON

• Structure
• Dendrites, cell body, axon
• Function
• Receptor/dendrite electrical current cell body,
  action potential axon/synapse neurotransmitter,
  receptor/dendrite

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Action Potential

• Resting membrane potential
• Threshold all or none response
• Influx of Na ions or Cl- ions
• Depolarization of cell membrane, or
• Hyperpolarization of cell membrane
• Return to the resting potential

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Transmission of Information

• Transmitter released from presynaptic vesicles
• Diffusion across the cleft
• Receptor interaction on postsynaptic membrane
• Transmitter removed from the cleft
• Metabolic inactivation, or
• Active reuptake by a transporter protein/storage

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Receptors

• Neurotransmitter must have an affinity for all
  three different receptors
• Postsynaptic receptor
• Presynaptic receptor
• Storage granule receptor

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Receptor Affinity

• Presynaptic receptor Cocaine binds to and
  blocks (dopamine/norepinephrine site)
• Storage granule transporter receptor reserpine
  binds to and blocks (norepinephrine site)
• Postsynaptic receptor Haldol binds to and
  blocks (Dopamine site)

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Drug Interactions

• Additive effect when 2 2 4
• Synergistic effect when 2 2 6
• Antagonistic effect when 2 2 1 or 0

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Classes of Receptors

• Fast receptors linked directly to an ion
  channel (GABA (a) receptors)
• G-protein-coupled receptors linked to modulary
  receptors that are linked to intracellular second
  messengers
• Transporter protein receptors presynaptic
  receptors that function in uptake

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NEUROTRANSMITTERS

• Acetylcholine
• CNS 2 separate areas (1) septal nuclei and
  the nucleus basalis (2) midbrain nuclei
• PNS neuromuscular junctions and within the
  autonomic nervous system, especially the
  parasympathetic system

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Acetycholine

• Synthesis Acetyl coenzyme A Choline yields
  Acetycholine (Ach)
• Action Binds reversibly to postsynaptic
  receptors. Terminated by acetylcholine esterase
  (AChE), degraded into acetate and choline that
  are taken back into the presynaptic axon terminal

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Acetylcholine

• Function Ach plays a role in learning and
  memory. May also be involved in circuits that
  modulate pain, sensory reception, arousal,
  attention, mood, and REM sleep.
• Destruction of Ach neurons within the septal
  nuclei/nucleus basalis gives rise to Alzheimers
  disease.

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CATECHOLAMINES

• Dopamine and Norepinephrine
• Location
• Dopamine Three major dopamine systems
• Local circuits in hypothalamus
• Substantia nigra to the basal ganglia
• Ventral tegmentum to the medial forebrain bundle

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Catecholamines

• Location
• Norepinephrine
• CNS cell bodies in the locus ceruleus and
  project to the limbic system, hypothalamus, and
  cortex
• PNS adrenergic neurons play a major role in the
  sympathetic nervous system

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Catecholamines

• Synthesis
• Tyrosine, an amino acid, is converted to dopa,
  then into dopamine, and then into norepinephrine,
  and then into epinephrine within the adrenal
  glands

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Catecholamines

• Mechanism of action Postsynaptic binding of DA
  or NE trigger a sequence of chemical events
  within the postsynaptic cell membrane affecting
  ion channels and intracelluar metabolic activity.
  Termination of transmitter action by presynapse
  reuptake mechanism and MAO enzyme degradation
  within axon terminal.

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Catcholamines

• Function
• Dopamine regulation of certain body hormones,
  regulation of movement, and a major player in
  reward center.
• Norepinephrine produces alerting, focusing,
  positive feelings of reward, and analgesia. Also
  involved in hunger, thirst, emotion, sex
  behavior modulation

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Serotonin

• Location CNS
• Projections stemming from raphe nuclei (pons and
  medulla) and terminating in cerebral cortex,
  hippocampus, hypothalamus, and limbic system.
  Network parallels those of NE but not as
  widespread

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Serotonin

• Synthesis Manufactured in neurons from
  tryptophan, an essential amino acid, and then
  stored in vesicles within the axon terminal.
• Action 5-HT activates postsynaptic cell
  membrane receptors. Action terminated by
  reuptake mechanisms.

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Serotonin

• Function
• Seems to have the opposite effect of NE and is
  generally inhibitory in action. Plays a role in
  regulation of anger, mood, sleep. Regulates
  release of hormonal factors from the hypothalamus.

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Gamma-Amino-Butyric Acid

• Found in high concentrations in the brain and
  spinal cord.
• GABA(a) bind benzodiazepinesanxiety
  effectsfound in cortex, hippocampus ion channel
  receptor type.
• GABA9b) found in amygdalaG-protein-coupled
  receptor type

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Opioid Peptides

• Greatest concentration of receptors in the
  amygdala, effects emotional behavior
• Four types of receptors mu, kappa, sigma, and
  delta.
• Transmitter types include met-enkephalin, and
  leu-enkephalin (endorphins)
• A role in stress response, mental illness, drug
  craving, pain perception