Download Dr. Begay`s Notes from Pharm I

PSYCHOPHARMACOLOGY I
The Brain, Body, and Drug
Relationship
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.
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:
– 12:00 take 100 mg
– 04:00 50 mg left; take 100 mg
– 08:00 25 mg left; 50 mg left; take 100 mg
– 12:00 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
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 Alzheimer’s 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.
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 benzodiazepines;anxiety
effects;found in cortex, hippocampus;
ion channel receptor type.
• GABA9b): found in amygdala;Gprotein-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
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