Exam 4 Mechem 3.docx - Exam 4 MECHCHEM III ABUSE & OVERDOSE...

Exam 4 MECHCHEM III
ABUSE & OVERDOSE – 1 hr
Terminology
 Tolerance : decreased effect with continued use
o larger doses are required to produce same response
o opposite of sensitization
 Dependence : biological adaptation caused by chronic use
o withdrawal generally reverse of normal effect
o examples: sedation, sedation, vasoconstriction
 Note: these are results of chronic therapy that are not predictors of addiction
 Addiction : chronic neurobiological disease
o genetic, psychosocial, and environmental factors affect development and
manifestation
o drug seeking behavior
 Pseudoaddiction : also show drug seeking behavior
o preoccupation with getting the medication due to:
 inadequate disease state management
 fear or anxiety associated with condition/past experiences
 act of seeking the drug in the presence or absence of addiction
o “self-fulfilling prophecy?” Need for mutual exclusivity?
Addiction & the Brain
 Key projections: mesocorticolimbic
o dopamine transmission from ventral tegmental area (VTA) to prefrontal
cortex and nucleus accumbens
o this connects executive functioning to the experiences of reward/aversion, pleasure,
incentive, and reinforcement
 most signaling is dopaminergic , some glutamatergic and GABAergic as
well
 Key areas: reward pathway
o cortico-basal ganglia-thalamo-cortical loop (key: basal ganglia)
 VTA, medial forebrain bundle, striatum, substantia nigra, amygdala,
hippocampus, thalamus, hypothalamus, cortex, others
What’s going on?
 Mimic neurotransmitters
o Heroin (endorphin and enkephalin)
o Marijuana (anandamide)
o Nicotine (acetylcholine)
 Alter neurotransmission by interacting with molecular components of the sending and
receiving process
o Cocaine - attaches to the dopamine transporter
 Alter neurotransmission by means other than increasing or decreasing the quantity of
receptors stimulated.
o Benzodiazepines - produce relaxation by enhancing receiving neurons’
responses to GABA
Pathophysiology
 Various substances cause superagonist-like effect; “hijack” on reward pathway
Which way does the dose
response curve shift in
tolerance? To the right

Exam 4 MECHCHEM III
o causes extreme pleasure, reinforcement, reward sensitization, decreased aversion,
chronic neurological and psychological changes
 Gene expression and neuroplasticity changes
o FOSB, CREB, NF- κ B
 decreased threshold for compulsive and reward seeking behavior ;
psychological dependence, significant changes in thought patterns and
personality
Pharmacokinetics Requirements
 compound must have extensive BBB penetration
 or be able to trigger a response that is directly interpreted by CNS
 rapid absorption : important for elevation of Cmax and reinforcement of activity
o this is why these substances are administered by routes such as injection,
inhalation, or snorting
o extended-release formulations are usually safer
 rapid elimination?