What is substance intoxication?
- Reversible substance-specific syndrome due to recent exposure
- Maladaptive behavior or psychological changes
- Not due to medical condition or another mental disorder
What substances are lethal in intoxication? Mechanism?
- Alcohol: MVAs, impaired judgment, reckless behavior, aspiration, respiratory depression
- Benzodiazepines: MVAs, impaired judgment, reckless behavior, respiratory depression (in combo w/ other sedatives)
- Barbituates: respiratory depression, coma, death
- Opioids: respiratory depression, coma, death
- Cocaine: idiosyncratic (no particular dose), AMI, CVA
What is tolerance?
- Increased amounts needed to achieve desired effect,
- Diminished effect with continued use of same amount
What is withdrawal?
- Characteristic withdrawal syndrome develops when levels decline
- Substance likely to be consumed to relieve withdrawal
What substances are lethal in withdrawal? Symptoms?
- Alcohol: delirium tremens
- Benzodiazepines: seizures/related complications
What is substance abuse (def)? DSM IV
A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period:
1. Recurrent use resulting in failure to fulfill major obligations at work, school or home
2. Recurrent use in physically hazardous situations
3. Recurrent substance-related legal problems
4. Continued use despite recurrent substance-related social / interpersonal problems
What is substance dependence (def)? DSM IV
A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period:
3. Larger amounts or longer period than intended
4. Desire or difficulty to cut down or control use
5. Time spent in substance related activities
6. Activities are given up or reduced
7. Continued use despite negative consequences
*With physiological dependence: evidence of 1 or 2; without physiological dependence: no evidence of 1 or 2
Polysubstance dependence (def)? DSM IV
Use of 3+ classes of substances without any single substance predominant
- Criteria for dependence is met only for the totality
1. cocaine + alcohol + darvocet = PSD
2. Primarily alcohol, uses cocaine and amphetamine only when intoxicated = alcohol dependence and cocaine and amphetamine abuse
How does DSM-5 define substance use disorder?
A problematic pattern of substance use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
1. Substance is often taken in larger amounts or over a longer period than was intended.
2. There is persistent desire or unsuccessful efforts to cut down or control substance use.
3. Great deal of time spent in activities necessary to obtain, use, or recover from effects.
4. Craving, or a strong desire to use the substance.
5. Recurrent use resulting in failure to fulfill obligations at work, school, or home.
6. Continued use despite social or interpersonal problems caused by the substance.
7. Important social, occupational, or recreational activities given up or reduced.
8. Recurrent use in situations in which it is physically hazardous.
9. Continued use despite physical or psychological problems caused by the substance.
Mild = 2-3
Moderate = 4-5
Severe = 6+
What is addiction (def)?
- Compulsive drug-seeking and drug taking with loss of control over drug use
- Chronic relapsing disorder
What is the immediate target of addictive substances?
The neural synapse
- All drugs of abuse initially affect the brain by influencing the amount of NT present at the synapse or by interacting with specific NT Rs
What are some of the molecular targets of drugs of abuse: Opioids?
What are some of the molecular targets of drugs of abuse: Cocaine?
Indirect agonist at DA Rs
- Inhibits DA transporters
What are some of the molecular targets of drugs of abuse: Amphetamine?
Indirect agonist at DA Rs
- Stimulates DA release
What are some of the molecular targets of drugs of abuse: Ethanol?
- Facilitates GABAa
- Inhibits NMDA glutamate R function
What are some of the molecular targets of drugs of abuse: Nicotine?
Agonist at nicotinic ACh receptor
What are some of the molecular targets of drugs of abuse: Cannabinoids?
Agonist at CB1 and CB2 Rs
What are some of the molecular targets of drugs of abuse: Phencyclidine?
Antagonist at NMDA glutamate
What are some of the molecular targets of drugs of abuse: Hallucinogens?
Partial agonist at 5-HT2A Rs
Convergence to common final pathway?
- Variety of immediate targets explains the different acute responses to intoxication with the various drugs
- However, all are positively reinforcing after short-term exposure, suggesting there are certain regions of the brain where drug effects converge to elicit a common neurobiological response
What results from NT-receptor activation?
Biochemical cascades of IC messengers
- G proteins (GTP-binding membrane proteins)- couple EC Rs to IC proteins
- Regulation of 2nd messengers- cAMP, Ca, NO, phosphatidylinositol
- Protein phosphorylation- dramatically alters protein function
Virtually every process in a neuron can be affected
Repeated drug exposure alters ____ and ____, producing molecular and cellular changes as a result of ________
Repeated drug exposure alters gene expression and protein synthesis, producing molecular and cellular changes as a result of repeatedly disturbed IC pathways
- Addiction process
What are the parts of the Mesolimbic Dopamine System? Located where? Project where?
It is the "Reward Circuit"
Ventral Tegmental Area
- Clusters of DA-ergic neurons in the midbrain near substantia nigra
- Origin of the mesolimbic DA tracts
- Projects to nucleus accumbens
- Caudal portion of anterior horn
- Projects to cortex
What does the Mesolimbic Dopamine System control?
It is the "Reward Circuit"
- Influences motivated behavior and activity related to reward
- Mediates the reinforcing effects of opiates, ethanol, nicotine, stimulants, and cannabis...
- Acute reinforcing effects of drugs of abuse
- Relapse, triggers
- Adaptation after long term drug abuse: structural and functional
What process underlie adaptation after long term drug abuse: structural and functional?
Gene expression, protein synthesis
What is the Dopamine Theory?
DA Rs in NAcc mediate reinforcing stimuli
- Rats self administer dopamine, cocaine, amphetamine directly into the NAcc
- Opiates are self-administered into the VTA (activate DA neurons via disinhibitory mechanisms, stimulate dopamine release in NAcc)
- Ethanol, nicotine, cannabis cause increased DA release in NAcc DA release in NAcc: final common pathway in the acute reinforcing effects of many abused drugs!
Characteristics of alcohol as a substance?
- High level of social acceptance
- Long history of use (>3000 years)
- Pleasant and healthful effects in low doses - 1-2 drinks/day decreases risk of AMI, CVA, dementia, gallstones
__% of men and __% of women consume alcohol
__% of drinkers have experienced and adverse event
__% lifetime prevalence of abuse and dependence in men; __% in women
90% of men and 75% of women consume alcohol
60% of drinkers have experienced and adverse event
15-20% lifetime prevalence of abuse and dependence in men; 10% in women
Comorbidities of alcohol?
- 50% of alcoholics have a co-morbid psychiatric illness
- Women: anxiety and mood disorders
- Men: other substances, conduct do, antisocial pd
- Bipolar disorder and secondary alcoholism
- 25-66% of alcoholics develop a secondary depression
- Alcoholism is as great a risk factor for suicide as depression
- 25% of suicides are alcohol-related
T/F: vulnerability to alcohol abuse and dependence is genetically influenced? Proof?
- Genetic influences: 60% of overall vulnerability
- 4x increased risk in close relatives of an alcoholic patient
- Identical twins > fraternal twins
- Increased rates in adopted-away sons and daughters of alcoholic patients
Genetically-controlled contributing factors to risk of alcoholism?
- Alcohol metabolizing enzymes
- Independent psychiatric conditions
- Low level of response to alcohol
Environmental characteristics may interact with genetic influences to explain additional vulnerability (e.g. acceptance of drinking in home)
Neurobiology of Alcohol?
- GABA-A R system: potentiation
- NMDA glutamate Rs: inhibition
- 5-HT3 Rs: potentiaion
- Nicotinic cholinergic R: potentiation/inhibition
- Mu opioid Rs: promotes agonist binding
- Reinforcing properties (increased DA release in NAcc) of mesolimbic DA system
What is GABA?
Major CNS inhibitory NT
- Modulates polarization of neurons
Characteristics of the GABA-A receptor?
Binding results in (mechanism and symptoms)?
Cl ion channel and subunits; bound by:
- Barbiturates Binding of agonists results in:
- Increased affinity for GABA
- Increased Cl influx
- Less excitable neurons
- Anxiolysis, sedation, increased seizure threshold
Alcohol intoxication levels?
- Decreased motor and cognitive function
- Decreased coordination and judgment; mood lability
- Confusion, blackouts, N/V, nystagmus, severely disordered behavior
- Decreased VS; stupor
- Coma, death
Management of alcohol intoxication?
- No antagonist to reverse effect
- Supportive care: nutritional support, fluids, IV thiamine, promote safety
Alcohol withdrawal characterized by what?
When does alcohol withdrawal begin?
2+ of the following:
- Autonomic hyperactivity (increased HR, BP, RR, temp, sweating)
- Psychomotor agitation
- Auditory, visual, tactile hallucinations/illusions
- Grand mal seizures It may begin as soon as the levels start going down
- Peak at 3 days
- Lasts 7-10 days
What is the most severe form of alcohol withdrawal?
Most likely in who?
Delirium Tremens (DTs)- 1/3 of patients with seizures will develop this
- Increased in medically compromised populations
Symptoms of Delirium Tremens (DTs)?
- Fluctuating/clouded consciousness
- Perceptual disturbances
- Mortality: infection, emboli, cardiac arrhythmiaas, metabolic disturbances, hyperkalemia, hyperpyrexia, dehydration
Management of alcohol withdrawal?
- Lorazepam (Ativan)- PO, IM, IV; minimal live metabolism
- Chlordiazepoxide (Librium)- PO, IM, longer half life Carbamazepine Valproate Gabapentin
- Dose BZDs with goal of calm sedation
- Taper BZDs as tolerated - Monitor closely
- Replete with IVF, thiamine, folate, Mg, MVI
What is Alcohol-Induced Persisting Amnestic Disorder?
Wernicke's encephalopathy- thiamine deficiency
- Abrupt onset encephalopathy
- Truncal ataxia
Treat with IV thiamine prior to glucose
Korsakoff's psychosis- chronic
- Severe anterograde amnesia
What are some alcohol induced disorders
(can mimic virtually any psychiatric condition and will resolve with sobriety)
- Sleep disorders
- Sexual dysfunction
Alcohol Use Disorder (Dependence) defined how?
A pharmacogenetic disease
- Disease causing agent (alcohol) interact with the genetic background of the "host" organism (human) to produce the manifestations of the disease
- Genetics and the environment interact to produce both the propensity to develop dependence and the level of alcohol intake
Treatment of Alcohol Use Disorder?
Process of intervention
- Denial is major defense mechanism
- Motivational interviewing/family intervention
- Summation of small cognitive events produces change
Detoxification- process of treating withdrawal
Rehabilitation - Outpt, partial hospitalization (IOP), inpt
- Team approach: MD, LMSW, LCDC, group therapy
- Psycho-education, basic congitive-behavioral appraoch
Aftercare and relapse prevention
- "Step down programs", residential aftercare
- 12 step programs: Alcoholics Anonymous and Narcotics Anonymous
(first step = "we admitted we were POWERLESS over alcohol, that our lives had become unmanageable"; getting over denial)
What is the most common defense mechanism used in substance use disorders?
Denial, often to the point of delusions
When to treat of comorbid psychiatric illness?
- Alcohol induced disorders can mimic virtually any psychiatric condition and will resolve with sobriety
- Independent psychiatric illness is common and must be treated appropriately when symptoms do not resolve with abstinence
Pharmacological Interventions for Alcohol Use Disorder?
1. Treatment of comorbid psychiatric Sx to educe tendency to "self medicate"
2. Direct efforts to produce adverse effects with ingestion or to modify NT systems mediating alcohol reinforcement
Three medications approved by FDA for alcohol dependence:
Characteristics of Disulfiram (Antabuse)?
- Alcohol sensitizing agent
- Aldehyde dehydrogenase inhibitor
- Ingestion of alcohol causes increased acetaldehyde concentration -> disulfiram-ethanol reaction (DER)
- Warmth, flushing, N/V, tachy, palpitations, hypotension, SOB, disaphoresis, dizzy, blurred vision, seizure, CHF, CV collapse Abstain for 12 hrs prior to initiating, and 2 weeks after discontinuation
**Works by solidifying the daily decision not to drink!
Characteristics of Naltrexone (ReVia)?
- Opioid antagonist (decreases cravings and euphoria of alcohol intoxication, promotes abstinence, reduces relapse to heavy drinking/inhibition of priming, reduces number or drinking days)
- Preferable after detox, may start while drinking
- PO daily (at least 2 yrs -> lifetime)
- Depot form: IM Q4 weeks
- Mild dysthymia
- Reversible elevation in LFTs
How does the activity of Naltrexone play on genetics?
- Relatives of alcoholic have decreased baseline levels of endogenous opioids
- Naltrexone treatment will increase levels of endogenous opioids, especially in alcoholics and relatives of alcoholics
What is a major limitation of Disulfiram?
Reminds someone no to drink, but can't reduce cravings (like the other 2)
What subgroups are responsive to Naltrexone?
- Complex patients, comorbidity
- More severly dependent patients
- Strong family history of alcoholism
- Genetic responsivity (mu opioid receptor polymorphism)
Characteristics of Acamprosate (Campral)?
- Side effects?
Amino-acid derivative and GABA analogue
- Affects GABA and glutamate neurotransmission
- GABA agonist/NMDA antagonist (increases GABA and decreases glutamate)
- Reduces cravings for alcohol in abstinent pts
- Reduces relapse to drinking in alcohol dependent pts
Combined therapy for alcohol use/dependence disorders?
1. Natrexone (+)
2. Acamprosate (negative trial)
3. Naltrexone and acamprosate (no better)
4. CBT for alcohol dependence (+)
Naltrexone = drug of choice
- Will still see them prescribed with one another
(may even be on all 3; no contraindications)
Other agents for alcohol use disorder?
What is go-to drug for alcoholism?