1.7 – Pharm: Substances Involved in Use Disorders Behavioral FDS – 2 hours 3/20/18 I. Key Terminology a. Tolerance: loss of efficacy of drug with repeated administration i. Pharmacokinetic to lerance: change in drug dist
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1.7 – Pharm: Substances Involved in Use Disorders Behavioral FDS – 2 hours 3/20/18 I. Key Terminology a. Tolerance: loss of efficacy of drug with repeated administration i. Pharmacokinetic to lerance: change in drug distribution or metabolism associated with lower blood concentrations after repeated administration of given dose ii. Pharmacodynamic tolerance: adaptive changes in receptor expression, receptor function, and/or subsequent signaling pathways with repeated stimulation by a substance involved in use disorders iii. Behavioral tolerance: psychological adaptation that allows a person with a substance use disorder to function in a socially acceptable manner despite mild-moderated intoxication iv. Conditioned tolerance: can occur when drug administration is paired with consistent environmental cues that anticipate a drug’s effects b. Sensitization: reverse of tolerance; it is an enhanced physiologic response with repetitive administration of a drug i. Lower drug concentrations are required to achieve a desired effect; can occur with stimulants c. Dependence: physiologic alteration of homeostatic set points in an organism receiving a drug that manifests in a set of symptoms (withdrawal syndrome) upon removal of the drug; favors continued use of drug by the organism d. Addiction: behavioral/psychological pattern characterized by drug craving and compulsive drug seeking and use, even in the face of negative consequences e. Substance Use Disorder: maladaptive pattern of substance use leading to clinically significant impairment od distress II. Neurobiology of Substance Involved in Substance Use Disorders a. Animal model and human studies have identified the mesolimbic system as a key mediator of drug-induced reward, and as a unifying target for most substances involved in use disorders b. Originates with the dopaminergic neurons in the ventral tegmental area (VTA), which project of multiple target structures: the nucleus accumbens, the amygdala, the hippocampus, and prefrontal cortex c. Most substances increase dopamine concentration in target structures of mesolimbic system, either by enhancing release, or by preventing reuptake d. Other important reinforcing, cross-reactive neurochemical changes associated with substance including increased serotonin, norepinephrine, nicotinic receptor stimulation, and endogenous opioid and cannabinoid activity, particularly in the VTA e. 3 classes of substances can be distinguished based on molecular targets: those that bind GPCRs, those that bind ligand-gated ion channels, and those that act on dopamine transport proteins III. Drugs Acting at GPCRs a. Opioids i. Can be used for management of acute and chronic pain ii. Analgesic effects derived from opioids come with euphoria, development of PK/PD tolerance, physiologic dependence, a sever withdrawal syndrome (intense dysphoria, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, yawning, fever, diarrhea, nausea, vomiting, muscle aches, tachycardia, and hypertension), and significant potential for opioid use disorder iii. Withdrawal symptoms are not life-threatening and typically last 7-10 days iv. Agents MC involved are oxycodone, hydrocodone, morphine v. Meperidine and fentanyl use disorder occurs nearly exclusively in healthcare professionals with access b. Heroin i. Injecting IV or smoking heroin rapidly produces high CNS concentrations, and a “rush” of intense euphoria followed by tranquility and sedation ii. Effects last for 3-5 hours; users continually oscillate between a docile “rush” state and onset of withdrawal characterized by irritability and marked aggression iii. Users rarely administer heroin in isolation; concomitant use of alcohol and/or other substances is common and can complicate detoxification and recovery iv. Additional complications can include bacterial infections, skin abscesses, hepatitis, and HIV/AIDS associated with IV injections v. Greatest potential for opioid use disorder all act as full agonists at µ-opioid receptors vi. Agonist stimulation inhibits adenylyl cyclase (and cAMP production), inhibits voltage-gated Ca currents, activates receptor-gated K currents vii. These signals inhibit presynaptic NT release, and reduce postsynaptic neuronal excitation viii. In the VTA, most mu-opioid receptors are expressed on GABAergic interneurons, which inhibit dopamine release ix. Stimulation of mu-receptors inhibits these GABAergic interneurons, which stimulates dopamine release
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