Pharmacology of Drugs of Abuse Lecture Notes PDF

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 32 Drugs of Abuse Dependence Versus Addiction (a) physical dependence = dependence (b) psychological dependence = addiction (c) all addictive drugs induce feelings of euphoria and rewa...

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 32 Drugs of Abuse Dependence Versus Addiction (a) physical dependence = dependence (b) psychological dependence = addiction (c) all addictive drugs induce feelings of euphoria and reward (d) tolerance develops, higher doses required to achieve the same effect (e) absence of the drug induces withdrawal (f) dependence is defined by the signs of withdrawal (g) addiction on the other hand is compulsive, relapsing drug use despite negative consequences Addictive Drugs (a) all increase dopamine (DA) levels in the CNS (b) increased DA in the mesolimbic system leads to reward and reinforcement Dependence: Tolerance and Withdrawal (a) pharmacokinetic tolerance: less drug arrives at the receptor, shorter duration of action at the receptor (faster removal) (b) pharmacodynamic tolerance: changes in the mu receptor, receptor densitization, receptor internalization (c) withdrawal is poorly understood except to say signs of withdrawal indicate dependence Addiction: A Disease of Maladaptive Learning (a) addictive individual have relapses (b) relapse triggered by (1) reexposure to drug (2) stress (3) exposure to context that recalls prior drug use (c) interesting that patients being treated for Parkinson’s with DA agonists may become pathologic gamblers (d) DA agonists can result in 1 of 7 patients developing addiction- like behavior (e) only a small number of dependent users progress to addiction (f) see Table 32-1 for a list of addiction potential for different drugs from a low of 1 to a high of 5, also note the three level classification (G protein receptor coupled, ionotropic receptor  2 binders and drugs that bind to reuptake pumps) Nonaddictive Drugs of Abuse (a) some drugs of abuse do not lead to addiction such as drugs that do not induce sensations of reward and europhea like the hallucinogens and dissociative anesthetics (b) LSD, PCP (angel dust) Pharmacology of Drugs of Abuse (a) all addictive drugs increase DA levels in the mesolimbic projections (b) addictive drugs put into three grpups (1) Act through G-protein coupled receptors opioids GHB hallucinogens (LSD, PCP) (2) Act through inotropic receptors or ion channels nicotine alcohol benzodiazepines dissociative anesthetics some inhalants (3) Bind to monoamone transporters cocaine amphetamines ecstasy Drugs that Activate G10 Coupled Receptors Opioids (a) all inhibit adenylyl cyclase through G-protein coupled receptors (b) naloxone reverse opioid overdose (c) methadone or buprenorphine used as substitute for morphine in drug treatment programs Cannabinoids (a) endogenous cannabinoids (pot made by the brain) include 2-arachidonyl glycerol and anandamide (b) these are called endocannabinoids (endogenous cannabinoids)  3 (c) they inhibit the release of GABA and glutamate (d) marijuana contains the active ingredient, tetrahydrocannabinal (THC) (e) THC disinhibits DA neurons through inhibition of GABA neurons (f) the relative risk for addiction is low at a 2 (g) dronabinol and nabilone are two FDA approved forms of THC used to treat a wide range of disorders including pain and nausea following chemotherapy Gamma-Hydroxybutyric Acid (GHB) (a) binds to GABAB receptors (b) causes europhoria, enhanced sensory perceptions, amnesia (c) easily dissolves in alcohol drinks and is called the “date rape” drug LSD, Mescaline & Psilocybin (a) induce neither dependence nor addiction (b) often produce flashbacks up to years latter (c) drugs increase glutamate release in the cortex (d) another main target is the 5HT2A receptor Drugs That Mediate Their Effects Via Ionotropic Receptors Nicotine (a) activate nicotinic Ach receptors (b) nicotine excites projection neurons and causes release of DA which explains potential for addiction (c) addictive potential is 4 on a scale of 1 to 5 (highest) (d) cytosine and varenicline used to treat addiction, both block Ach receptors linked to DA release Benzodiazepines (a) moderate risk for abuse (b) dependence is very common (c) addiction is rare (d) withdrawal occurs within days after stopping the drug (e) rewarding effects may occur because GABAA receptors modulate (disinhibit) mesolimbic DA system resulting in reward effects  4 Alcohol (a) withdrawal syndrome begins 6-12 hours after last drink tremor, nausea, vomiting, excessive sweating, agitation, anxiety (for the alcoholic) (b) 12-24 hours after last drink visual and auditory hallucinations (c) 24-48 hours after last drink generalized seizures (d) 48-72 hours after last drink delirium tremens (alcohol withdrawal) 5-15% mortality (e) treat with supportive measures including benzodiazepines Ketamine & Phencyclidine (PCP) (a) developed originally as general anesthetics (b) only ketamine still used as an anesthetic (c) both antagonists of NMDA receptors (d) post-op patients reported vivid dreams and hallucinations (e) low potential for addiction but long-term use can lead to psychosis closely resembling schizophrenia Inhalants (a) recreational use of chemical vapors such as nitrates, ketones, and aromatic and aliphatic hydrocarbons (toluene etc) (b) sniffing = inhalation from an open container (c) huffing = inhalation from a soaked cloth (d) bagging = breathing in and out from a bag filled with solvent (e) mechanism of actions not well understood Drugs That Bind to Transporters of Biogenic Amines Cocaine (a) highly addictive (relative risk = 5) (b) heat cocaine in alkaline solution = free base = crack cocaine  5 (c) crack is the form of cocaine that can be smoked (d) in CNS, drug blocks reuptake of DA, 5HT, and NE (e) rewarding effects may come from increase of DA in nucleus accumbens (f) increase in NE levels leads to increased blood pressure (g) no pharmacological treatment for cocaine addiction exists Amphetamines (a) cause release of NE and DA from synaptic vesicles (b) drugs taken up by reuptake transporters into neurons where the drug depletes storage vesicles (c) highly addictive Ecstasy (MDMA) (a) derivative of amphetamine related compound methylene -dioxymethamethetamine (MDMA) (b) ecstasy is a designer drug sold at rave party (c) strong blocker of 5HT reuptake Clinical Pharmacology of Dependence and Addiction (a) summary chart on pages 588-589 is well done and should help Drugs to Learn: G10 Coupled Receptor Opioids morphine naloxone heroin codeine oxycodone meperidine methadone buprenorphine Cannabinoids marijuana THC hashish dronabinol  6 rimonabant Gamma hydroxybutyric acid (GHB) Hallucinogens LSD mescaline psilocybin Ionotropic Receptor Actions nicotine benzodiazepines ethanol ketamine phencyclidine (PCP) Inhalants nitrates ketones aliphatic and aromatic hydrocarbons Biogenic Amine Transporters cocaine amphetamine Ecstasy (methylenedioxymethamphetamine) MDMA NMDA Receptor Antagonist acamprosate (N-methyl-D-aspartate (NMDA) receptor antagonist Additional Drugs Required in Bold listed below Opioid Receptor Antagonist naloxone naltrexone Synthetic Opioid methadone Partial mu Opioid Receptor Agonist buprenorphine Nicotine Receptor Partial Agonist varenicline  7 Benzodiazepine oxazepam N-methyl-D-aspartate (NMDA) antagonist acamprosate Cannabinoid Receptor Inverse Agonist rimonabant Drugs Used To Treat Dependence And Addiction Opioid Antagonists naloxone naltrexone Synthetic Opioid Agonist methadone Partial mu Opioid Agonist buprenorphine Nicotinic Receptor Partial Agonist varenicline Benzodiazepines oxazepam lorazepam N-Methyl-D-Aspartate (NMDA) Glutamate Receptor Antagonist acamprosate Cannabinoid Inverse Receptor Agonist rimonabant Alcohol acamprosate (NMDA antagonist) Additional Drugs: LSD cocaine phencyclidine (PCP) amphetamine ketamine alcohol morphine heroin marijuana tetra-hydrocannabinol dronabinol nabilone  8 gamma-hydroxybutyric acid (GHB) bupropion oxazepam lorazepam Drugs According to Mechanism of Action Actions Through G-Protein Coupled Receptors opioids heroin morphine codeine oxycodone meperidine cannabinoids marijuana tetrahydrocannabinol THC) hashish dronabinol nabilone gamma-hydroxybutyric acid (GHB) hallucinogens lysergic acid diethylamide (LSD) phencyclidine (PCP) ketamine mescaline psilocybin Actions Through Ionic Channels or Ionotropic Receptors nicotine alcohol benzodiazepines dissociative anesthetics inhalants nitrates ketones aromatic hydrocarbons barbiturates  9 Actions Through Monoamine Transporters (Reuptake Pumps) cocaine amphetamines ecstasy