|Current focus of addictive drug||Focus on behavior of the individual: compulsive drug seeking and drug use; chronic condition consisting of remissions and relapses|
|Lay persons understanding of addiction||Think of physical dependence properties, that person feels they can't live without drug and needs drug to feel well|
|Tolerance||Repeated administration leads to decline in effect. Normal response to many drugs|
|Physical dependence||Cells and receptors make compensatory changes in response to drug (opposite direction of what drug does), drug needed to maintain homeostasis.|
|Withdrawal syndrome||Occurs when drug is withdrawn from someone with physical dependence. Symptoms are opposite of the effects of the drug.|
|Psychological dependence||Intense desire to re-experience effects of a drug (euphoria), occurs with drugs that stimulate brain's reward system. May experience dysphoria when drug not present|
|DSM-IV Criteria for Substance Dependence||Need 3+ of following, occur at any time in same 12-month period: tolerance, withdrawal, larger doses than intended, desire to cut down use, time spent obtaining/using/recovering, give up activities, continue use despite knowledge of problem it causes|
|What is worse? Substance dependence or substance abuse?||Dependence|
|DSM-IV Criteria for substance abuse||1+ of following occurring w/in 12-month period: recurrent use result in failure to fulfill obligations, use when physically hazardous, substance-related legal problems, use despite persistent social problems. AND if sx never met criteria for dependence|
|Pharmacodynamic mechanisms of tolerance||Decrease in # of receptors or changes in signal transduction pathways w/in neurons|
|Examples of short-term PD mechanisms of tolerance||Phosphorylation of receptors: diminish responsiveness
Internalization of receptors: fewer receptors on surface
|Examples of long-term PD mechanisms of tolerance||Changes in gene regulation: less responsive
Neural circuit rewiring: create or remove synapses
|Mechanisms of tolerance besides PD||PK (induction of hepatic enzymes) and behavioral (learn how to hide or compensate for behavioral effects of a drug)|
|How does cocaine stimulate brain's reward system?||Blocks dopamine transporter (DAT), increasing DA levels at nucleus accumbens|
|How does amphetamine stimulate brain's reward system?||Causes DAT to work in reverse, increasing DA levels at nucleus accumbens|
|How does nicotine stimulate brain's reward system?||1. Activates receptors on DA neurons in VTA, activating DA neurons and cause DA release at nucleus accumbens.
2. Activates opioid peptides in nucleus accumbens, causing release of endogenous opioids which inhibit nucleus accumbens
|How do opioids stimulate brain's reward system?||1. Inhibit GABA interneurons in VTA (inhibit the inhibitor), allowing DA to be released at nucleus accumbens.
2. Inhibit nucleus accumbens directly at mu receptors
|How does alcohol stimulate brain's reward system?||No receptors. Inhibits GABA > inhibit DA neurons. (allows for activation of DA neurons, and release of DA at nucleus accumbens)|
|How does PCP stimulate brain's reward system?||Antagonist of glutamate, blocks the excitation of the nucleus accumbens|
|What is dopamine's action at the nucleus accumbens?||Dopamine receptors on nucleus accumbens are D2, which are Gi coupled (inhibit the neurons)|
|What is the signal in the brain for pleasure?||An inhibition of nucleus accumbens neurons|
|What factors determine the intensity of a drug's high?||Pharmacokinetic factors–the faster a drug gets into the brain, the better the high|
|Paradox of familiarity||Pharmacists have a higher rate of substance abuse/dependence problem compared to the general population|
|3 General approaches to pharmacological treatment of drug addiction||1. Substitute similar agent and gradually decrease dose.
2. Decrease craving or reduce withdrawals.
3. Produce adverse reaction when drug of abuse is taken
|How does ethanol act as a CNS depressant?||potentiates GABA effect on Cl-, inhibits effect of glutamate and NMDA and AMPA|
|Effects of ethanol||CNS DEPRESSANT, cutaneous vasodilation, diuresis, increase sexual desire, decrease sexual performance|
|Tolerance to ethanol||Innate based on genetics/ethnicity.
Acquired due to PK and PD mechanisms, but lethal dose may not increase.
Cross-tolerance with other CNS depressants
|PD tolerance of ethanol and concern||Causes down-regulation of GABA receptors. Other drugs that act at GABA receptors will see cross-tolerance, especially benzodiazepines.|
|Withdrawal syndrome of ethanol: symptoms and treatment||Tremor, irritability, nausea, seizure, tachycardia, HTN.
Treat with BZDs
|Ethanol addiction treatments||Naltrexone, acamprosate, disulfiram|
|Naltrexone (ReVia) MOA||Orally active opioid antagonist, decreases craving and high/euphoria|
|Acamprosate (CAMPRAL) MOA||Blocks NMDA receptors & activates GABAa, decreases craving|
|Disulfiram (ANTABUSE) MOA||Inhibits aldehyde dehydrogenase (ALDH), makes drinking unpleasant|
|What ethanol metabolite produces side effects? What side effects does it produce?||Acetaldehyde, produces flushing, nausea, HA, increase heart rate|
|Effects of cocaine||CNS STIMULANT, local anesthetic|
|Forms of cocaine||HCl salt is water soluble (IV, snorted)
Free base form (crack, smoked)
|Toxicity of cocaine||CV problems, sexual problems (initial heightened orgasm, then eventually impotence), psychiatric problems|
|Tolerance and withdrawal of cocaine||Tolerance does develop. Withdrawal symptoms are not life threatening and not consistently seen. Psychological dependence is major problem.|
|Pharmacological treatment for cocaine abuse||No treatment available.|
|Effect of nicotine||CNS stimulant!|
|Withdrawal symptoms of nictoine||Irritability, anxiety, dysphoria, difficulty concentrating, restlessness, decreased heart rate, increased appetite/weight gain|
|PHarmacological treatments of nicotine addiction||Nicotine replacement therapy (NRT). BUproprion. Varenicline|
|Bupropion use in nicotine addiction||Reduces craving and withdrawal symptoms, reduces anxiety and depression associated with quitting|
|MOA of varenicline||Partial agonist at subtype of nicotine recpetor in brain responsible for euphoria. Decreases craving and reduces withdrawal.|
|SE of varenicline||Nausea, insomnia, HA, weird dreams|
|Affinity of Chantix vs nicotine for receptor||Chantix>nicotine. Using NRT while on Chantix not logical, not recommended.|
|Active ingredient in marijuana||THC (delta-9-tetrahydrocannabinol)|
|Effects of marijuana||Gives "high" mellowed out feeling. Impairs cognition, memory, perception of time, coordination. Occasionally anxiety or dysphoria|
|Tolerance, dependence, and withdrawal of marijuana||All are minor and not severe. NOT A GATEWAY DRUG.|
|Logic fallacy of marijuana as a gateway drug||Post hoc, ergo propter hoc-it happened before so it was caused by.
Marijuana is more readily accessible than crack, heroin, etc!
|Examples of drugs/drug classes that "one pill can kill"||Antiarrhythmics, antipsychotics, benzocaine, CCBs, beta-blockers, chloroquine, clonidine and imidazolines, TCAs, methyl salicylate, opiates and lomotil, sulfonylureas|
|Benzocaine toxicity||Found in orajel, used for teething babies. Toxic if ingested high quantities|
|Methyl salicylate toxicity||Found in Bengay and IcyHot, smells like wintergreen. Very concentrated form of aspirin.|
|Toxicity management principles||Good supportive care (70% of the time)|
|What is a toxidrome?||Collection of physical signs that suggest a specific class of poisoning|
|Opiate toxidrome||COMA, RESPIRATORY DEPRESSION, MIOSIS.
peripheral effects: bradycardia, hypotension, decreased GI motility
|Treatment of opiate toxicity?||Naloxone-will rapidly reverse resp and CNS depression. SHOULD ONLY BE USED WITH CAUTION, IF AT ALL.|
|MOA of naloxone||Pure opioid antagonist at all opioid receptor sites|
|Limitations of naloxone||Much shorter duration of action than most opioids. Patient can re-sedate, resp depression, or apnea.
May induce withdrawal in chronic opioid users
|Rule of thumb for using naloxone||Watch 4 hours after last dose for relapse of toxicity, retreat.|
|What class of non-opiate drugs in an OD can mimic the opiate toxidrome?||Imidazolines: clonidine, tetrahydrozoline (Visine), oxymetazoline (Afrin)|
|Anticholinergic toxidrome||Flushed skin, dry mucous membranes, mydriasis (dilated pupils), delirium, hallucinations, hyperthermia, tachycardia|
|Anticholinergic agents||Antihistamines, TCAs, phenothiazines, skeletal muscle relaxants, antiparkinson meds|
|Cause of death in TCA overdose||Die a cardiac death, not anticholinergic|
|Treatment for anticholinergic OD||Good supportive care. Do not use physostigmine in TCA OD|
|Sympathomimetic toxidrome||Similar to anticholinergic toxidrome. Two differentiation symptoms: diaphoresis, increased bowel sounds|
|Classic sign of BZD OD?||Coma with stable vital signs
(if taken with alcohol, can cause death)
|Flumazenil||Benzo agonist/antagonist. Can cause BDZ withdrawal, lower seizure threshold, cause seizures in patients who are benzo dependent|
|Treatment of sympathomimetic OD?||BENZODIAZEPINES!!! treat anxiety, tachycardia, HTN, hyperthermia, and seizures!|
|Treatment for BZD OD?||If just in coma with stable vitals, observe. Good palliative care.|
|Sedative-hypnotic toxidrome||Hypotension, bradycardia, bradypnea, hypothermia, altered mental status, decreased bowel sounds, dry skin, slurred speech, ataxia, normal pupils|
|3 Z's||zolpidem, zaleplon, eszopiclone|
|Cholinergic toxidrome: muscarinic||Diarrhea/diaphoresis, urination, miosis, bradycardia/bronchorrhea, emesis, lacrimation, salivation|
|Cholinergic toxidrome: nicotinic||Mydriasis, tachycardia, weakness, HTN, fasciculations, seizures|
|Treating cholinergic toxicity||Atropine for muscarinic symptoms, pralidoxime for nicotinic symptoms, Valium or BDZs for seizures, agitation|