Linger Drugs of Abuse/ Dependence Flashcards
Abuse:
a pattern of substance use leading to significant impairment
Dependence:
the compulsive use of a substance despite significant problems resulting from such use
Psychological dependence is known as addiction
Physical/physiologic components are simply “dependence”
Withdrawal:
the only actual evidence of physical dependence
Results from adaptive changes due to chronic drug use
All drugs of abuse activate
the mesolimbic dopamine system
A 37 y/o woman was found unconscious after an alleged overdose. Upon examination, her respiratory rate was depressed (4 bpm), blood pressure was slightly low at 115/70 mm Hg, and her pupils were symmetrically “pinned” (maximally mitotic or pinpoint). She has one “fresh track” (needle puncture wound) and several “old tracks” (healed scars from needle puncture wounds) in her left arm.
What is the most likely drug of intoxication?
Cannabis Diazepam Heroin Ketamine Methamphetamine
Heroin
Which agent is most likely to provide life-saving reversal of Heroin overdose?
Buprenorphine Epinephrine Methadone Naloxone Naltrexone
naloxone
which receptor mediates the effects of heroin?
Mu
agonist
Opioid antagonists
naloxone- short acting, IV, IM, SubQ, nasal, used to treat oipioid overdose
Naltrexone- long-acting; oral
used to treat alcohol and opioid dependence
reduces alcohol craving and rate of relapse
Administration of an antagonist to a patient who has opioids in their syste may precipitate a withdrawal syndrome
patient taking naltrexone ending up in the hospital. What do we need to know re: pain relief?
narrower therapeutic window due to increased receptors
may respond to a much lower dose
opiate withdrawal syndrome treatment
monitor patient
pharm treatment may not be necessary
tapered doses of partial or full opioid agonists: buprenorphine or methadone
clonidine (off-label)- may reduce cravings, reduces anxiety symptos, reduces sympathetic outflow
opiate withdrawal syndrome
stage 1: anxiety, drug craving
stage 2: anxiety, insomnia, GI disturbance, rhinorrhea, mydriasiss, diaphoresis
stage 3: tachycardia, nausea/ vomiting, HTN, diarrhea, fever, chills, tremors, seizure, muscle spasm
The abuse potential of opioids is associated with their indirect effects on which receptor type?
Cannabinoid Dopamine GABA-A Mu-opioid NMDA
Dopamine
Mesolimbic dopamine system and the dopamine reward pathway
VTA: ventral tegmental area: activated by addictive drugs
MFB: medial forebrain bundle- contains dopaminergic neurons
Activation of the mesolimbic dopamine system by dependence-producing drugs causes dopamine to be released
opioid reward pathway
the euphoric “high” is caused by modulation of dopamine reward pathway (VTA to nucleus accumbens to amygdala)
presynaptic and postsynaptic opioid receptors modulate calcium influx and potassium efflux in the same manner as in the spinal cord.
DISINHIBITING (turning of GABA inhibition)
Molecular Targets of Drugs of Abuse
Class I: Activate GPCRs
Class II: Bind to ionotropic receptors and ion channels
Class III: Bind to Monoamine Transporters
Opioid mechanisms of action
presynaptic receptors inhibit Ca2+ influx through voltage-gated calcium channels
- inhibits release of excitatory neurotransmitters from the primary sensory neuron
Postsynaptic receptors increase K+ efflux
- secondary relay neurons are hyperpolarized and less likely to fire action potentials
Inhibit GABA release in the midbrain, which attenuates transmission in the descending pain pathways
Drugs that Activate Gio-coupled Receptors
Opioids, cannabinoids, GHB
Inhibiting Ca2+ influx and increasing outflow of K+ decreases the likelihood of an action potential and GABA release
Blocks the inhibitory effects of GABAergic neurons
Dopamine levels are increased because of dopamine neuron disinhibition
Drugs the Bind to Ionotropic Receptors
Nicotine, alcohol, benzodiazepines, barbiturates, phencyclidine, ketamine
Drugs that Bind to Monoamine Transporters
Cocaine
- Dopamine (and other amines) levels increase because of DAT (and other transporter) inhibition
Amphetamines and ecstasy
- Dopamine (and other amines) levels increase because of VMAT inhibition and reversal of DAT
General Treatment Strategies- Opioid dependence
Naltrexone – opioid antagonist for dependence only (precipitates withdrawal symptoms if any opiates are in the system)
Naloxone – opioid antagonist for detoxification and maintenance treatment (precipitates withdrawal if dosed too high or titrated too rapidly)
Methadone – long-acting opioid used for substitution therapy
Buprenorphine – partial agonist. used for substitution therapy; combined formulation with naloxone discourages abuse
General Treatment Strategies- Nicotine dependence
Nicotine – gum, lozenge, inhalers, transdermal application
Bupropion – antidepressant approved for smoking cessation
Varenicline – partial neuronal nAChR agonist approved for smoking cessation only
Dependence on drugs that bind to transporters of biogenic amines
No current antidote
Treat effects that result from norepinephrine release
A 47 y/o man has been diagnosed with hypertension and diabetes mellitus. History is positive for seizure disorder that is currently well-controlled by antiepileptic drugs. He is also a current tobacco user (2 packs per day for the last 18 years). He states that he has tried to quit in the past using nicotine gum, but it “just didn’t work.” He says he wants to quit in order to improve his health and is willing to try a combination of pharmacotherapy and behavioral counseling. Which drug is the most likely prescribed as a smoking cessation aid?
Bupropion Buspirone St. John’s wort Varenicline Venlafaxine
Varenicline
Buproprion is not great here because the pt has a history of seizures
Treatment of Nicotine Dependence
Combination of counseling and medication is more effective than either alone
Other techniques: acupuncture, hypnosis, mind-body interventions
Nicotine replacement therapy
- Bupropion
- Antidepressant with incompletely understood mechanisms of action
- May reduce cravings by increasing dopaminergic activity in the mesolimbic pathway
- Contraindicated in patients predisposed to seizure
Varenicline
- Partial agonist at neuronal nicotinic receptors
- Serious neuropsychiatric events (including depression, suicidal thoughts, and suicide) have been reported and warrant discontinuation
Ethanol Targets
Ionotropic Receptors
N-methyl-D-aspartate (NMDA) glutamate receptors
- Cation channel (Na+ and Ca2+)
- Glutamate is the primary excitatory neurotransmitter in the CNS (memory)
- Alcohol inhibits NMDA receptor channel opening
GABAA receptors
- Anion channel (Cl-)
- GABA is the primary inhibitory neurotransmitter in the CNS
- Alcohol enhances GABA’s effects on the GABAA receptor
↓ NMDA receptor function
↑ GABAA receptor function
Chronic Effects of Ethanol
CNS: changes in GABAA and NMDA receptor expression
Tolerance and physical dependence
Degenerative changes – generalized symmetric peripheral nerve injury
Wernicke-Korsakoff syndrome
Liver: 15-30% of chronic abusers develop severe liver disease
Alcoholic fatty liver → hepatitis → cirrhosis → liver failure
CV system: cardiomyopathy, heart failure, arrhythmias, hypertension, stroke, coronary heart disease
Increased risk of cancer (mouth, pharynx, esophagus, and liver)
Fetal alcohol syndrome
A 21 y/o female is brought to the ED unresponsive except to noxious stimuli. Her friends report an evening of heavy drinking to celebrate her 21st birthday. Respirations are 8 breaths/min and shallow. Blood pressure is 100/60 mmHg, pulse is 100 beats/min, and temperature is 36 C. A stat arterial blood gas determination reveals a pH of 7.29 (normal 7.36-7.44), PCO2 of 52 mmHg (normal 35-45), and HCO3 of 19 mEq/L (normal 21-27).
What pharmacologic interventions would you consider for this patient?
Respiratory support
prevent aspiration; consider anti-emetics
naloxone if any suspicion of additional drugs
fluid replacement if hypovolemic
short acting benzo (e.g. lorazepam) if convulsing
thiamine (IM), glucose (IV), electrolytes, etc.
Consider sedationin violent patients
A 50 y/o male alcoholic, unable to find any ethanol, ingests a large amount of methanol that he bought for his camp lantern. Which is the most likely consequence?
Atrioventricular conduction defect Blindness Bronchospasm Delirium tremens Metabolic alkalosis
Blindness
Which pharmacologic treatment should be initiated to reduce metabolism of methanol to toxic metabolites?
Disulfiram Ethanol Folic acid Fomepizol Thiamine
Fomepizol
if it’s not available, ethanol will also compete for alcohol dehydrogenase
highly motivated individuals can take disulfiram –> terrible hangover
Ethanol and methanol biotransformation
alcohol dehydrogenase
aldehyde dehydrogenase
NAD+ requirement is rate-limiting
Microsmal ethanol-oxidizing system
- consists priarily of CYP450s
- induced by higher concentrations of alcohol and chronic alcohol use
A 52 y/o male is found unconscious at home and brought to the hospital by his wife. She states that he regularly drinks half a gallon of vodka daily and has suffered an alcohol withdrawal seizure in the past. She does not believe that he ever abused street or prescription drugs. His BAC on admission is 520 mg/dL (0.52 mg%). Abnormal lab values are listed.
Aspartate aminotransferase 129 U/L (11-36)
Alanine aminotransferase 72 U/L (6-43)
Gamma-glutamyltransferase 992 U/L (10-61)
Total cholesterol 423 mg/dL (< 200)
liver enzymes suggesting hepatotoxicity
BAC in dependent patient with 520 mg/dl is not necessarily lethal like it would be for a non tolerant pt
His BAC on admission is 520 mg/dL (0.52 mg%). Abnormal lab values are listed.
After admission to the hospital the patient begins to seize. Which drug is most clinically effective in this situation?
Diazepam Disulfiram Flumazenil Fluoxetine Oxazepam
need to use a benzo here
diazepam is correct because it is fast-acting and we can administer IV
+ thiamine to prevent Wernicke
Time Course of Events During Ethanol Withdrawal Syndrome
Earliest signs and symptoms: anxiety, insomnia, tremor, palpitations, nausea, and anorexia
- Hallucinations and seizures are possible in severe syndromes
- Can persist, in a milder form, for several months after alcohol discontinuation
Delirium tremens typically develops 48–72 hours after alcohol discontinuation
Treatment of Alcohol Withdrawal Syndrome
Goals: prevention of seizures, delirium, and arrhythmias
Detoxification involves substituting a long-acting sedative-hypnotic drug for alcohol and then gradually tapering the dose
Benzodiazepines
- Long-acting (diazepam, chlordiazepoxide, clorazepate)
— Less frequent dosing and built-in tapering effect
— Active metabolites may accumulate (liver disease)
- Short-acting (lorazepam, oxazepam)
- – Rapidly converted to inactive metabolites (useful in patients with liver disease)
Antipsychotics for hallucinations
- Haloperidol (IM and IV preparations available) or risperidone (IM and oral)
Basic pharmacokinetics (ADME)
absorption, distribution, metabolism, elimination
half-life (t 1/2): the time required to change the amount of drug in the body by one-half during ELIMINATION
Treatment of Alcohol Dependence
Naltrexone:
Approved for the treatment of alcohol and opiate dependence
Opioid receptor antagonist
Reduces alcohol craving and rate of relapse short-term (12-16 weeks)
Acamprosate:
Weak NMDA receptor antagonist and GABAA receptor agonist
Reduces craving and relapse rates (short-term and long-term, > 6 months)
Disulfiram (Antabuse):
Inhibits aldehyde dehydrogenase
Causes extreme discomfort in patients who drink alcohol due to accumulation of aldehyde (flushing, throbbing headache, nausea, vomiting, sweating, hypotension, confusion)
Patient must be highly motivated
Topiramate, gabapentin, baclofen, ondansetron – not FDA approved (mid-level evidence)
A 22 y/o presents to the ED after falling and cutting her head at a bar. She and a friend had been there for about an hour and then the patient suddenly became drowsy and fell (she was still conscious when she fell). She can feel pain from the trauma. Her ventilatory rate and depth are depressed, but not to a worrisome degree. Her patellar reflexes are blunted and she is ataxic. She responds slowly to questions but is unable to recall anything that happened after arriving at the bar and sipping her first (and last) adult beverage.
With what was her drink most likely spiked?
Cocaine Flunitrazepam Oxycodone Phenobarbital Pure (grain) alcohol
Flunitrazepam
- rohypnol- benzo
What is the primary molecular target of flunitrazepam?
AMPA receptors GABA-A receptors GABA-B receptors mGluR receptors NMDA receptors
GABA - A receptors
rufies overdose. What is the most likely antidote?
Amphetamine Flumazenil Methylphenidate Naltrexone Physostigmine
Flumazenil
Dose Response Curves for Two Hypothetical Sedative-Hypnotics
Drug A: barbiturates, alcohols, and older sedative-hypnotics (linear)
Greater potential for serious ADRs, including death
Drug B: benzodiazepines and newer sedative-hypnotics (plateau)
