Drugs of Abuse- Linger Flashcards
what is dependence
i) Defined, in part, as the compulsive use of a substance despite significant problems resulting from such use
ii) According to the DSM-IV, to be diagnosed as substance dependent, three of the following criteria must be met in a 12 month period:
(1) Preoccupation with use of the chemical between periods of use
(2) Using more of the chemical than had been anticipated
(3) The development of tolerance to the chemical in question
(4) A characteristic withdrawal syndrome from the chemical
(5) Use of the chemical to avoid or control withdrawal symptoms
(6) Repeated efforts to cut back or stop the drug use
(7) Intoxication at inappropriate times (such as at work), or when withdrawal interferes with daily functioning (such as when hangover makes person too sick to go to work)
(8) A reduction in social, occupational or recreational activities in favor of further substance use
(9) Continued substance use in spite of the individual having suffered social, emotional, or physical problems related to drug use
what is the psychological component of dependence
(1) Dependency of the mind that can lead to psychological withdrawal symptoms (such as cravings, irritability, insomnia, depression, anorexia, etc)
(2) Similar to the neurotic behavior patterns of the persistent coffee drinker or cigarette smoker
(3) When drug use becomes compulsive, physiologic dependence and tolerance are likely to develop
physiological (physical) component of dependence
(1) An altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome
(2) Withdrawal syndrome is characterized by states of increased anxiety, insomnia, and CNS excitability that may progress into convulsions in the case of sedative-hypnotics or ethanol
what is abuse and what criteria define abuse
i) According to the DSM-IV, abuse is defined as a pattern of substance use leading to significant impairment in functioning
ii) Of the nine criteria listed above for dependence, only one must be present in a 12 month period
what is addiction
i) Essentially the same definition as psychologic dependence, but addiction is a more outdated term
ii) Consists of compulsive, relapsing drug use despite negative consequences, at times triggered by cravings that occur in response to contextual clues
iii) Genetic component: the relative risk for addiction (addiction liability) of a drug correlates with its heritability, suggesting that the neurobiologic basis of addiction common to all drugs is what is being inherited
what is tolerance
i) A decrease in responsiveness to a drug following repeated exposure
ii) The dose response curve shifts to the right
iii) May be due to pharmacokinetic changes (reduction in drug concentration or shorter duration of action due to changes in drug metabolizing enzymes) or pharmacodynamic (changes in receptor function)
iv) Example drug: diazepam
what is sensitization
i) An increase in response with repetition of the same dose of the drug (also known as reverse tolerance)
ii) Conditioning is a form of sensitization
iii) The dose-response curve shifts to the left
Example drug: cocaine (repeated daily administration of cocaine to rats produces an increase in motor activity that increases over several days even though the dose remains constant
what is withdrawal
i) Consists of adaptive changes that become fully apparent once drug exposure is terminated
ii) The only actual evidence of physical dependence
iii) Generally due to readaptation of the CNS to the absence of the drug of dependence
iv) Example: decreased expression of GABAA receptors and increased expression of NMDA receptors due to chronic ethanol exposure causes hyperarousal of the CNS during ethanol withdrawal
what is the prime target for addictive drugs
the mesolimbic DA system
ii) Originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brainstem, which projects to the nucleus accumbens, the amygdala, the hippocampus, and the prefrontal cortex
iii) Most projections of the VTA are DA-producing neurons: large quantities of DA are released in the nucleus accumbens and the prefrontal cortex when the DA neurons of the VTA are activated
iv) As a general rule, all addictive drugs activate the mesolimbic DA system
where do neurons in the mesolimbic dopamine system project?
originate in the VTA
project to nucleus accumbans prefrontal cortex amygdala hippocampus
what is the dopamine hypothesis of addiction
i) Dependence-producing drugs activate the mesolimbic DA system, releasing DA
ii) The pleasure-related (hedonic) effect results from activation of this pathway, rather than from a subjective appreciation of the diverse other effects (such as alertness or disinhibition) that the drugs produce
iii) Numerous scientific studies support this hypothesis
(1) Deletion of dopamine D2 receptors in mice eliminates the reward properties of morphine without eliminating other opiate effects
(2) D2 receptor deletion does not prevent the occurrence of physical withdrawal symptoms in morphine-dependent animals, suggesting that the dopaminergic pathway is responsible for the positive reward but not for the negative withdrawal effects
what are the 3 molecular targets of addictive drugs
(1) Gio-coupled receptors
(2) Ionotropic receptors (ion channels)
(3) Monoamine transporters
which drugs have the highest (4-5 rating) rating of addiction)
opioids
nicotine
cocaine
amphetamine
which drugs activate G-protein coupled receptors
Opioids - mu (Gi)
cannabinoids (Gi)
GHB (gamma-hyroxybutyric acid)
LSD, mescaline, psilocybin
which drugs activate ionotropic receptors and ion channels
nicotine - nAChR - agonist
alcohol (GABA, 5-HTR, nAChR, NMDA)
benzodiazepines (GABA) positive modulator
Phencyclidine, ketamine (NMDA) - antagonist
which drugs bind to transporters of biogenic amines
Cocaine (DAT, SERT, NET)- inhibitor
Amphetamine (DAT, NET, SERT, VMAT) - reverse transport
Ecstasy (SERT>DAT, NET) - reverse transport
what is the target of nonaddictive drugs of abuse
a) Nonaddictive agents primarily target cortical and thalamic circuits rather than the mesolimbic dopamine system and therefore alter perception without causing sensations of reward and euphoria
which drugs are considered non addictive
lysergic acid diethylamine (LSD) , mescaline, psilocybin
Phencyclidine (PCP) and ketamine
i) Lysergic acid diethylamine (LSD), mescaline, psilocybin
effects?
(1) Repetitive exposure leads to rapid tolerance (tachyphylaxis)
(2) Animals will not self administer hallucinogens, suggesting they are not addictive in nature
effects of PCP and ketamine
(1) Developed as general anesthetics (ketamine is still used for this purpose)
(2) Club drugs sold under names such as angel dust, Special K, Hog
(3) Psychedelic effects last for about 1 hour and also include increased blood pressure, impaired memory function, disorientation, nystagmus, and visual alterations
(4) Classification of these NMDA antagonist as nonaddictive agents has been questioned due to animal research that shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents
long term use of PCP?
irreversible schizophrenia-like psychosis
long term effects of LSD
iii) LSD can cause flashbacks of altered perception years after consumption
MOA of drugs that activate G protein coupled receptors
cause disinhibition of DA neurons
MOA of opioids
(1) µ,κ, and δ receptors are G protein-coupled receptors that inhibit adenylyl cyclase when activated
(2) In the VTA, µ opioids cause an inhibition of GABAergic inhibitory interneurons, which leads to a disinhibition of dopamine neurons (see figure below)
(3) µ receptors cause euphoria when activated and are implicated in the reward effects of opiates (commonly abused µ opioids are morphine, heroin, codeine, oxycodone, and meperidine)
what are common opioids of abuse
heroin codeine oxycodone morphine meperdine
withdrawal symptoms of opioids
(4) Withdrawal symptoms include intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, fever
treatments for opioid abuse
Naloxone
(i) MOA: pure opioid antagonist that reverses effects of a dose of opiates within minutes
(ii) Provokes an acute withdrawal syndrome in situations where a dependent person has opiates in their system
(b) Methadone, buprenorphine
(i) Long-acting opioids used for substitution therapy (half-life 25-52 hrs)
(ii) Tolerance and physical dependence develop more slowly in comparison to other opioids (e.g., morphine)
(iii) Given with supervised intake
(iv) Abrupt discontinuation precipitates a withdrawal syndrome
cannabinoids MOA?
2-arachidonyl glycerol and anandamide
(2) Endocannabinoids are called retrograde messengers because they bind to presynaptic CB1 receptors and inhibit the release of either glutamate or GABA
(3) The exogenous cannabinoid Δ9-tetrahydrocannabinol (THC) causes disinhibition of DA neurons by presynaptic inhibition of GABA neurons in the VTA (similar to opioids)
what are the effects of THC
weed
(4) Effects of THC include euphoria, relaxation, feelings of well-being, grandiosity, and altered perception of passage of time
use of cannabinoids in medicine
(5) The THC-induced effects of increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain have led to the use of cannabinoids in medical therapy
withdrawal from cannabinoids?
(6) Chronic exposure leads to dependence with a mild and short-lived withdrawal syndrome (includes restlessness, irritability, mild agitation, insomnia, nausea, cramping)
dronabinol?
(a) FDA-approved THC analog used for anorexia and weight loss in AIDS patients and cancer-chemotherapy induced nausea and vomiting
Nabilone
(a) THC analog used for the treatment of refractory nausea and vomiting associated with cancer chemotherapy and as an adjunct in chronic pain management
Gamma-hydroxybutric acid (GHB)
MOA?
Effects?
receptor targets?
(1) GHB is produced during the metabolism of GABA, but the endogenous function is unknown
(2) Activates the GABAB receptor with low affinity and produces euphoria, enhanced sensory perceptions, feelings of social closeness, and amnesia before causing sedation and coma (originally introduced as a general anesthetic)
(3) Also known as liquid ecstasy or the date rape drug (has been used in date rapes because it is odorless, readily dissolved in beverages, reaches maximal plasma concentration 20-30 minutes after ingestion, and has an elimination half-life of 30 minutes)
(4) Recreational use only inhibits GABA neurons but at higher doses GHB hyperpolarizes DA neurons and inhibits DA release
(5) GHB targets GABAB receptors on both GABA and DA neurons, but those on GABA neurons are more sensitive to GHB and lead to disinhibition of DA neurons when activated
buprenorphine
partial mu opioid receptor agonist
nicotine
MOA?
withdrawal symptoms?
(a) MOA: selective agonist of the nicotinic acetylcholine receptor (nAChR)
(b) Neuronal nAChRs are expressed on DA neurons in the VTA; activation fulfills the DA requirement of addictive drugs
(c) Though highly addictive, withdrawal is mild compared with opioid withdrawal and involves irritability and sleeplessness
treatment for nicotine abuse
x3 options
(a) Nicotine: gum, lozenge, inhalers, transdermal applications
(b) Bupropion
(i) Antidepressant with unknown mechanism of action
(ii) Used alone or in combination with nicotine-replacement therapy and/or behavioral therapy
(c) Varenicline
(i) Derivative of the plant-extract cytisine
(ii) Partial neuronal nAChR agonist
(iii) Only approved for treating smoking cessation
(iv) Prevents nicotine stimulation of mesolimbic dopamine system associated with nicotine addiction
withdrawal of barbituates
delirium
life threatening cardiovascular collapse
treat with symptom management:
- assist respirations
- increase BP
benzodiazepine withdrawal and treatment
Sleep disturbance, depression, anxiety, seizure
treat with flumazenil
MOA of cocaine and effects
(1) In the peripheral nervous system, cocaine inhibits voltage-gated sodium channels and can be used as a local anesthetic
(2) Blocks the DAT and increases the DA concentrations in the nucleus accumbens (rewarding effects)
(3) Blocks the NET and activates the sympathetic nervous system, which leads to an acute increase in arterial pressure, tachycardia, ventricular arrhythmias, and pupil dilation**
acute symptoms and overdose of cocaine use
(4) Typical acute symptoms of use include loss of appetite, hyperactivity, and lack of sleep while overdose may lead to hyperthermia, coma, and death
(5) Exposure increases risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures
what is the treatment for cocaine intoxication
(9) No antidote; intoxication management remains supportive with agents to control heart rate/rhythm (β-adrenergic receptor antagonist propranolol) and seizures (sedative-hypnotic diazepam)
amphetamines MOA
(1) MOA: cause the release of endogenous biogenic amines by reversing the action of biogenic amine transporters at the plasma membrane
(a) Amphetamines are taken up into the cell by the DAT
(b) Amphetamines block the intracellular VMAT and deplete synaptic vesicles of their neurotransmitter content, which causes levels of DA and other amines (serotonin, norepinephrine) to increase in the cytoplasm
(c) Increasing levels of amines in the cytoplasm cause the DAT, SERT, and NET to work in reverse and release amines into the synapse
Another way of putting it:
Amphetamine (Amph) competitively inhibits DA transport. Once in the cell, amphetamine interferes with the vesicular monoamine transporter (VMAT) and impedes the filling of synaptic vesicles, depleting vesicles. Cytoplasmic DA increases. This leads to a reversal of DAT direction, strongly increasing nonvesicular release of DA, and further increasing extracellular DA concentrations.
withdrawal symptoms of amphetamines
(3) Withdrawal consists of dysphoria, drowsiness (insomnia in some cases), and general irritability
ecstasy (MDMA) MOA
(1) MOA: similar to amphetamines (reverses the action of biogenic amine transporters)
(2) Preferential affinity for the SERT and strongly increases the extracellular concentration of serotonin
effects of ecstasy (acute toxic effects)
(3) Heavy users of MDMA report long-term cognitive impairment due to continued serotonin depletion
(4) Acute toxic effects include hyperthermia, dehydration, serotonin syndrome (mental status change, autonomic hyperactivity, neuromuscular abnormalities), and seizures
withdrawal from ecstasy
withdrawal consists of a mood “offset” characterized by depression lasting up to several weeks, possible increased aggression
schedule 1 drugs
Schedule I The drug or other substance has a high potential for abuse.
The drug or other substance has no currently accepted medical use in treatment in the United States.
There is a lack of accepted safety for use of the drug or other substance under medical supervision.
All research use is illegal under federal law
Examples of Schedule I substances include heroin, lysergic acid diethylamide (LSD), marijuana, and methaqualone.
examples of schedule II drugs
morphine, phencyclidine (PCP), cocaine, methadone, and methamphetamine.
The drug or other substance has a high potential for abuse.
The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions.
Abuse of the drug or other substance may lead to severe psychological or physical dependence.
No telephone prescriptions, no refills.
examples of schedule III drugs
The drug or other substance has less potential for abuse than the drugs or other substances in schedules I and II.
The drug or other substance has a currently accepted medical use in treatment in the United States.
Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence.
Prescription must be rewritten after six months or five refills.
Anabolic steroids, codeine and hydrocodone with aspirin or acetaminophen, and some barbiturates are examples of Schedule III substances.
examples of schedule IV drugs
The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule III.
The drug or other substance has a currently accepted medical use in treatment in the United States.
Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III.
Prescription must be rewritten after six months or five refills; differs from Schedule III in penalties for illegal possession.
Examples of drugs included in schedule IV are propoxyphene plus aspirin (Darvon), pentazocine, meprobamate, diazepam, and alprazolam.
acamprosate
NMDA receptor antagonist
