substance misuse
consumption of a substance for purposes different from what is medically recommended
substance abuse
maladaptive pattern of substance use leading to clinical impairment or distress, characterized by at least one of:
- failure to fulfill major role obligations
- recurrent use in situations which it is physically hazardous
- substance-related legal problems
- use despite problems caused or exacerbated by the substance
substance dependence
maladaptive pattern of substance use leading to clinical impairment or distress, characterized by at least three of:
- tolerance
- compulsive use
- impaired control/relapse
- craving
- socio-occupational dysfunction
- persistent use despite psychophysical harm
- withdrawal
addiction
psychological compulsion towards a substance
environmental factors contributing to abuse/dependence
- low socioeconomic status
- early physical or sexual abuse
- social deprivation
- witnessing violence
- peer pressure
- cultural norms
- drug availability
individual factors contributing to abuse/dependence
- genetics
- poor impulse control
- anxiety and depression
- other neuropsychiatric comorbidities
3 ways comorbid conditions can be tied to substance abuse
- self medication with the substance to relieve syptoms of the mental illness
- causal effects of substance use may increase mental illness
- risk factors for mental illness and substance abuse may overlap
how to diagnose comorbid mental disorders with substance abuse
patient must be abstinent for 2-3 weeks before mental disorder symptoms can be evaluated
role of ventral tegmental area
release dopamine at amygdala, prefrontal cortex, and nucleus accumbens
amygdala governs
avoidance and fear
prefrontal cortex governs
decision making and behavioral control
nucleus accumbens governs
reward and salience
the response to environmental stimuli is ultimately governed by
dopaminergic systems
how does habit formation occur
natural stimuli needed for the survival of the organism and species are coupled with rewarding responses which when repeatedly activated lead to repetition of behavior
what system is involved in habit formation
dopaminergic mesolimibic system
the perception of natural reward comes from
phasic release of dopamine in the nucleus accumbens
-tolerance can develop
role of the amygdala
processing of fear and information related to danger and other emotional responses
cravings originated from what part of the brain
amygdala
drug seeking behavior is driven by
nucleus accumbens
hypofunction of prefrontal cortex facilitates rewarding response by
- poor impulse control and problems in decision making
- facilitating activation of amygdala and nucleus accumbens
tolerance
time dependent reduction in responsiveness to the same dose of a substance
release of corticotrophin releasing hormone/factor causes
- activation of stress response
- increase of heart rate and blood pressure
- activation of amygdala and cravings
2 types of triggers for cravings
- cues linked to specific locations/times controlled by hippocampus
- stress triggers release of CRF and norepinephrine leading to amygdala activation
how long must a person be off a substance to reduce risk of relapse
about 7 years
stages of dependence
- binge/intoxication
- withdrawal/negative effects
- preoccupation (no money, arrest, overdose)
- abstinence/treatment
- relapse
non-specific mechanisms of action of ethanol
- enhances membrane fluidity
- inhibits numerous proteins and enzymes
specific mechanisms of action of ethanol
- enhances GABA-A receptor function
- inhibits NMDA receptors
- activates 5-HT3 receptors (stimulates vomiting)
- may inhibit GABA-B receptors
who is at greatest risk of alcoholism
anxious and depressed patients
absorption of ethanol
rapidly absorbed from small intestine and colon
- maximal blood concentration in 30-90 minutes
- absorbed through lungs and skin
distribution of ethanol
- distributed uniformly in tissues and body fluids
- readily crosses placenta and BBB
metabolism of ethanol
mostly done by alcohol dehydrogenase which converts ethanol into acetaldehyde, which is where the headache, hypotension, and N/V come from
acetaldehyde is metabolized by aldehyde dehydrogenase
elimination of ethanol is not
concentration dependent and is thus zero order
alcohol concentration associated with respiratory depression and death
> 400 mg/dl
treatment of acute alcohol intoxication
- gastric lavage
- endotracheal intubation
- rebalance of electrolytes
- infusion of thiamine THEN glucose (to avoid making acidosis worse)
neuropsychiatric effects of chronic alcohol consumption
Wernike’s encephalopathy and korsakoff syndrome
GI effects of chronic alcohol
- anemia
- esophageal cancer
- vitamin and protein deficiency
- cirrhosis
- acute pancreatitis
symptoms of alcohol withdrawal
- motor agitation
- anxiety
- insomnia
- reduction of seizure threshold
- delirium tremens (delirium, agitation)
treatment options for seizures in alcohol withdrawal
long acting benzos like chlordizepoxide and diazepam
thiamine deficiency leads to
- accumulation of pyruvic acid and acidosis
- impairment of krebs cycle and reduced ATP synthesis
cause of beriberi
thiamine deficiency
dry beriberi
neurological signs and symptoms
wet beriberi
CV signs and symptoms
wernicke-korsakoff syndrome is caused by
thiamine deficiency in alcoholism
wernicke’s encephalopathy symptoms
- confusion
- cerebellar ataxia
- ophthalmoplegia
korsakoff syndrome symptoms
- psychosis
- loss of short term memory
- rhythmical to-and-fro motion of eyeballs
disulfiram MoA
blocks aldehyde dehydrogenase
aversive therapy, makes patient have all the negative symptoms
drugs to use in alcoholism
disulfiram
naltrexone
acamprosate
acamprosate MoA
- GABA-A activator and NMDA blocker
- substitution effect
avoid acamprosate in who
those with renal impairment
avoid naltrexone in who
opiate dependent patients
when to use ethanol as an antidote
for methanol or ethylene poisoning
methanol gets converted into
formic acid which is highly toxic
properties of inhalants
very similar to alcohol
activation of opioid receptors causes
- increase in K efflux
- decrease in Ca influx
rate at which opioids undergo tolerance
very rapidly
central effects of opioids
- sedation
- respiratory depression
- antitussive
- N/V
- epileptogenesis
- temperature regulation
- miosis
- motor tone
mechanism of opioid respiratory depression
- depressed rhythm generation
- desensitization of brainstem chemoreceptors which normally respond to increasing PCO2
neuroendocrine effects of opioids
- decrease in adrenal hormones
- decrease in gonadal hormones
- increase in prolactin
- these do not undergo tolerance*
CV effects of opioids
- peripheral vasodilation and orthostatic hypotension
- histamine release
- reduces cardiac work and oxygen consumption
acute administration of opioids can induce what CV effects
arrhythmias and hypovolemic shock
opioid effects that undergo tolerance
- euphoria
- analgesia and sedation
- respiratory depression
signs of opioid withdrawal
- diaphoresis
- rhinorrhea
- lacrimation
- insomnia
- diarrhea
triad of symptoms associated with opoid overdose
coma
pinpoint pupils
depressed respiration
treatment of opioid overdose
- ventilatory support
- IV naloxone
mechanism of cocaine
blocks dopamine transporter which causes more dopamine to be available in nucleus accumbens
symptoms of cocaine withdrawal
- depression
- fatigue
- vivid and disturbing dreams
- sleep disturbances
- irritability
- increased appetite and weight gain
- cravings for a long time
effects of methamphetamine
- high blood pressure
- chest pain
- rapid heart rate
- heart attack
- grinding teeth
bath salts
- cathinone
- methcathinone
- mephedrone
- MDPV
methylenedioxymethamphetamine (MDMA) characteristics
- amphetamine derivative with greater action on serotonin transporter
- causes relaxed euphoric state with no hallucinations
caffeine MoA
A2A adenosine receptor antagonist which makes the body think there is lots of ATP, increasing activity of neurons and other cells
main receptor involved in nicotine dependence
alpha-4-beta-2
nicotine MoA
mimics effects of acetylcholine and directly activates dopamine cells
withdrawal symptoms of nicotine
irritability
restlessness
increased appetite
decreased heart rate
lethal dose of nicotine
50-60 mg
signs of nicotine overdose
- paralysis and coma
- arrhythmia and respiratory failure
treatment of nicotine poisoning
- activated charcoal and GI evacuation
- IV benzo for seizure management
- respiratory support
pharmacological therapy for nicotine dependence
- bupropion-DA and NE reuptake inhibitor
- varenicline - partial nicotinic agonist
- clonidine - counters autonomic effects
adverse effects of partial nicotinic receptor agonist
insomnia
headache
nausea
hallucinogens dependence and withdrawal risk
very low
mechanisms of hallucinogens
- stimulation of 5-HT2a/2c receptors (LSD)
- NMDA antagonist (phencyclidine aka PCP)
- muscarinic antagonist (scopoloamine)
- selective kappa opioid activation (salvinorin)
hallucinogen that doesn’t cause memory loss of the event
salvinorin
effects of phencyclidine
- schizophrenia-like manifestations
- violent behavior
- increased HR
- increased BP and temp
- decreased pain sensation
- risk of suicide
psychoactive ingredient of cannabis
THC
THC MoA
partial agonist of cannabinoid CB1 and CB2 receptors
CB1 receptors control
memory thought processing perception movement *all impaired by THC*
CB2 receptors are found where
immune cells
THC is anti-inflammatory
endocannabinoids
anandamide
2-arachydonoyl-glycerol (2-AG)
endocannabinoids MoA
reduce GABA and glutamate release through retrograde activation of presynaptic CB1 receptors
main retrograde system for homeostatic control in CNS
depolarization-induced suppression of inhibition/excitation (for GABA/glutamate)
synthesis of endocannabinoids
stimulation of postsynaptic neurons causes the synthesis of anandamide and 2-AG; typically after CB1 and CB2 receptors are activated the endocannabinoids undergo reuptake in both terminals and are degraded
cannabidiol MoA
FAAH inhibitor which prevents anandamide from being degraded and increases anandamide levels
the reason cannabis does not lead to habit formation and physical dependence
the suppression of GABA and glutamate in the VTA has opposite effects on dopamine release
behavioral effects of cannabis
- short term memory impairment
- altered preception
- increased appetite
other effects of cannabis
- hypothermia
- reduction of N/V
- reduction of pain
cognitive and psychosocial effects of cannabis with substantial evidence
- learning, memory and attention impairment after acute use
- development of schizophrenia
cognitive and psychosocial effects of cannabis with limited evidence
- impaired academic achievement
- impaired social functioning
- learning, memory and attention deficits (after sustained abstinence)
potential uses for cannabis
- chronic pain
- anti emetics
- MS spasticity
- short term sleep disturbances
- decreasing weight loss with HIV/AIDS