Psyc 181 Exam 3 Review Sheet

Opioids
- Opiates: alkaloids found in the opium poppy (naturally occurring) - Opioids: includes opiates (naturally occurring) and synthetic, endogenous opioids Types of Opioids 1. Naturally occurring (opium, sap from opium poppy) - 2 major active alkaloids: o Morphine: named after morpheous (god of Dreams), contains ~10% opium by weight, pain killer, more addiction potential compared to codeine o Codeine: methylmorphine, contains ~0.5% opium, used mainly as a cough suppressant 2. Semi-synthetics - Heroin: diacetylmorphine, addition of 2 acetyl groups to morphine, ~10x more potent than morphine, pharmacological effect usually thought to be identical to morphine ( in brain: heroin is converted to morphine) - Semi-synthetic analgesics: o Hydromorphone (Dilaudid) o Hydrocodone ( Hycodan, Vicodin: o Oxycodone (Percodan, Oxycontin) 3. Synthetics - Phenylpiperidines o Fentanyl china white: more potent than heroin o Carfentanil (Wildnil): stronger than Fentanyl, used to sedate large animals o Meperidine (Demerol, MPPP): frozen addicts were trying to make MPPP but made MPTP instead - Methadone & Congeners o Methadone (Dolophine): slow onset, long acting, stronger than propoxyphene, used for heroin addicts o Propoxyphene (Darvon): weak, short acting, analgesic potency near aspirin Benzomorphans o Pentazocine (Talwin): non-addictive opiate, can be hallucinogenic at large doses, makes you feel bad so low addiction potential - Analgesic Potency o Mild to moderate pain: codeine, propoxyphene (Darvon) o Moderately severe pain: meperdine (Demerol) o Severe pain: heroin, hydromorphone (Dilaudid) 4. Opioid antagonists - Naloxone (Narcan): used for opium overdose, immediate withdrawal, lasts 2-3 hrs; also used to treat alcoholism - Naltrexone: control of opiate users in treatment facilities; lasts 24 hrs - Suboxone (buprenorphine + naloxone): Naloxone blocks the effets of opiates, then buprenorphine( slow, long acting opiate without the high) kicks in 5. Endogenous opioids - Endorphins(discrete, hypothalamic-endocrine related), enkephalins & dynorphins( wide distribution, local circuit and short axon projections) - Low levels of morphine and codeine are in the brain - Opioid peptide gene families (3 different gene families): POMC, Proenkephalin, Prodynorphine Major Effects - Analgesia: relief of pain in absence of impairment in other sensory modalities (analgesia selectively disrupts pain while anesthesia disrupts all sensations) - Euphoria Pleasure: produce sense of well being(long lasting), reduce anxiety, positive feelings Other Effects - Nausea & vomiting: biggest problem in medical use - Respiratory depression: can cause death - Miosis: pinpoint pupils - Gastrointestinal effects: causes constipation, used to treat severe diarrhea - Cough suppression: what codeine is mainly used for (not very effective)

- Motor effects: slows motor activity Tolerance, Withdrawal, Sensitization - Analgesic effects show rapid tolerance - Withdrawal symptoms include: sweating, diarrhea, wet dog shakes, cold , clammy, depression and irritability - Withdrawal is usually gone within 2 weeks - Withdrawal is a short term and occurs after drug is used persistently and at a high dose - Sensitization includes psychomotor stimulant and rewarding effects - Drugs that are more addictive = easier to sensitize Mechanism of Action - Primary action on opioid receptors located in CNS &/or periphery - Different effects are due to action at different receptor subtypes; receptors in different locations - all opioid receptors are G protein receptors - cellular actions are inhibitory (shut cell off) - 3 subtypes: o Mu (): prefer morphine and endorphine as ligands o Delta(): prefer Enkephalins as ligands o Kappa(): prefer ketocyclazocine & dynorphins as ligands Analgesia - Primary pain afferent is in dorsal horn of spinal cord; opioids inhibit incoming pain signals thus reducing pain perception in brain - Supraspinal actions: o stimulate PAGanalgesia and inhibit cells in dorsal horn o 1 sites seem most important o Specific blockades of 1 shifts dose-response curve for morphine analgesia up to 12 fold to right - Heroin vs. Morphine o Difference pharmacokinetic: heroin is more lipid soluble get to brain faster o Recent evidence for different receptors: morphine, not heroin, analgesia abolished in MOR1 knockout mice Reinforcing Effects - all classical opioid drugs of abuse have a preference for sites ( may contribute but little is known) - compounds are not self-administered (psychomimetic and aversive in humans) Opiod/DA Interaction - intra-VTA opioid support SA (self administration) and CPP (conditioned place preference) - DA antagonist or 6-OHDA lesion impair SA - DA antagonist into VTA or ACC impair SA - Opioids dont bind directly to DA receptors, but work through disinhibition (inhibition of inhibition) o GABA inhibits DA transmission in VTA-accumbens DA system (less DA); Opioids inhibit GABA (inhibits an inhibitor increase DA transmission) Mechanism - compounds: increase DA firing, increase DA release in ACC, accompanied by locomotor activation - compounds: decrease DA cell firing, decrease DA release, decrease locomotion Respiratory Depression: separate 2 site for respiratory functions? - specific 1 antagonist (naloxonazine) shifts analgesia dose- response curve for morphine to right - not shift dose-response curve for respiratory depression measures (elevation of pCo2, depression of pO2) Gastrointestinal Effects - and sites: in stomach, small and large intestine; decreased motility; common bioassay ability to inhibit intestinal contractions

Nicotine
nicotine is an alkaloid in tobacco (5% by weight) tobacco smoke consists of: carbon monoxide, thousands of particulates, nicotine major psychoactive agent

- one cigarette has ~9 mg of nicotine but only 1 mg is absorbed by smoking Routes - Inhalation (smoking): via lungs (25% reaches brain within 7 sec); very effective - Oral (chewing, moist snuff, gum): via oral membranes; less addictive - Nasal (snuff): via membranes of nasal cavaties Absorption - most routes very effective (cigarettes are the fastest) - rapid repeated administration unique to cigarettes Metabolism and Excretion - Kidney and liver - Short half life (~2 hrs) - Milk (why nursing mothers are advised not to smoke) Peripheral Effects - Sympathetic: increase heart rate, increase blood pressure, secretion of NE and E from adrenals, vasoconstriction - Parasympathetic: increase stomach acid, increase intestinal motility - Toxic dose at 60 mg ( half a cigar) CNS Effects - Psychomotor performance: increase in motor activity - Reinforcement Mechanism of Action - nicotine works on nicotinic acetylcholine receptor - Acetylcholine was the first transmitter identified in the peripheral nervous system Receptors and Metabolism - Muscarinic receptor= G protein- coupled; Nicotinic receptor= ligand-gated - Agonists: muscarine, nicotine - Antagonists: o atropine, o -bungar-toxin: in venom o curare: used in surgery to immobilize people (patients are still awake); was also used for torture
Sedativehypnotics&anxiolytics DiversegroupofcompoundsthatdepressCNSandbehaviorAlcoholBarbituratesNonbarbituratehypnotics Anxiolytics Additiveeffects Crosstolerance

Alcohol:LargeclassoforganiccompoundsMostnotingestedisopropylalcohol(rubbingalcohol),methyl alcohol(methanol,woodalcohol)Formthatconsumedethylalcohol(ethanol,grainalcohol),productof fermentation(yeastconsumessugar)

Historyofuse:Usedfromprehistoric timesStillmostwidelyuseddruginthe world Pharmacokinetics:AbsorptionanddistributionUsuallyoraladministrationMostabsorbedinsmallintestine Easilydistributesthroughoutbody,especiallyhighlyvascularizedareaslikeCNS EliminationandexcretionSmallamountseliminatedunchanged(~10%insweat,tears,urine,breath) Metabolismmostmetabolizedinliver alcoholdehydrogenaseETOH> acetaldehyde>H2O&CO2 enzymeratelimiting(68g/hr) Methanol>formaldehyde+

formicacid Oxidation:Microsomalethanoloxidizingsystemusuallyonly510%ofmetabolismupto5060%withchronic consumptionroleincrosstolerancetobarbiturates EffectsonphysiologyandbehaviorNoacceptedmedicaluseexceptasasepticBloodcirculationInhibitionof ADH(antidiuretichormone) Effectsoncognitionandaffect100150mg/100ml(legallimitabout80)disinhibition150300mg/100ml sedativeeffects300mg/100mlstupor400mg/100mllethal,respiratorydepression FetalAlcoholSyndromeAlcoholreadilycrossesplacentaCausesneurotoxicsyndromecharacterizedby neurobehavioralproblems(hyperactivity,learningdisabilities,depression,psychosis) Influencesbraindevelopment,especiallyduringperiodsofrapidneurogenesis,leadingtodecreasedbrainweight How?KnownthatblockadeofNMDAreceptorsduringdevelopmenttriggerswidespreadapoptoticdegeneration inratbrain(apoptosis=thecontrolleddestructionofcells)AlcoholisaknownNMDAreceptorantagonist ApoptoticneurodegenerationNotseewithantagonistsoragonistsatdopaminereceptors,muscarinicantagonists, otherglutamatereceptorantagonistsDoseewithbabituratesandbenzodiazepines(whichactprimarilyatGABAA receptors)AlcoholeffectsmaybeduetocombinationofactionsatNMDAandGABAAreceptors Long Intermed. Short Ultrashort Phenobarbital(Luminal) Pentobarbital(Nembutal) Secobarbital(Seconal) Thiopental(Pentothal) 812hr 28hr 14hr 530mi

Mechanismsofaction Manyactions:Effectsonmembranefluidity,EffectsonmembraneboundproteinsGABAAreceptorNMDAreceptor EffectsonCAneurotransmission

Barbiturates
HistoryandderivationBarbituricacidvonBayer(1864),Barbital(1903),Phenobarbital(1912,Luminal) ClassesDurationofaction

Medicaluses:sleepinduction,anticonvulsants,anaesthetics,sedatives,alcoholwithdrawal,anxiolytics IllicitUse:"downers"and"goofballs"UsedforeffectssimilartoalcoholOftenwithotherdrugswithstimulantsor opiatesRapidtoleranceSeverewithdrawalLowsafetymarginrespiratorydepression,50%ofdrugrelated suicides Anxiolytics:Meprobamate(Miltown),Benzodiazepines(BZ),Chlordiazepoxide(Librium),Diazepam(Valium ),Oxazepam(Sevax),Nitrazepam(Moyodon),Flurazepam(Dalmane)Over17onmarkettodaySecond GenerationAnxiolyticse.g.,buspirone,serotonergicactions Medicaluses:Pathologicalanxiety,Severeemotionaldistress,Relieffromagitationandalcoholwithdrawal, Sedation(sleepinducing),Presurgerysedation(e.g.Versed) Therapeuticeffects:CalmingandrelaxationaredesiredeffectsSideeffectsmotorincoordination,intoxication(like alcohol),memoryloss(amnesiae.g.,Versed),sedation&sleep,deepsleepandcoma,respiratorydepression AbuseNotselfadministered,lowpreferenceControversyaboutoverprescriptionDaterapecasesRohypnol (flunitrazepam),MickyFinn(chlorylhydrate),GBHMechanismsofactionEarlystudiesmanytransmitter

systemsimplicated,nonspecificmembraneeffects,potentiationofGABAeffectsDiscoveryofBZbindingsites (1977)concentratedinnewlyevolvedstructures(cortex,hpc,amygdala),correlatewithanxiolyticeffects,closely relatedtoGABAAreceptorsites

GABAneurotransmissionUbiquitousinhibitoryneurotransmitterHyperpolarizesneuronsDistribution ThroughoutCNSlocalandprojectionneurons ReceptorsGABAAionotropicGABABmetabotropicPartofcomplexsupramolecularcomplexcomposedoffive subuits,eachwithnumberofisoformsFormschloride(Cl )channelGABAincreasesCl conductance, hyperpolarization(inhibition)AgonistmuscimolAntagonistbicuculline MajorsiteofactionofsedativehypnoticsBZandBARBactatdifferentsitesonthisiontophoreanddifferentsite thanGABAEvidenceforuniquesites:nodirectactionbyself,notinhibitGABAbinding,noteffectGABArelease DifferentmechanismsDifferentactionoffrequencyvs.durationofCl channelopeningsBarbituratesincreaselong durationopenstates,nochangeinnumberofopeningsBenzodiazepinesnotchangeduration,justfrequency Inverseagonists EndogenousligandsatBZsiteSteroidmetabolitesofprogesteroneanddeoxycorticosterone Summary:Sedativehypnoticsinfluencemanysystems MajorsiteGABAAcomplexmultiplebindingsites OtherantianxietydrugsSSRIAntidepressantsfluoxetine(Prozac),paroxetine(Paxil),sertraline(Zoloft), fluvoxamine(Luvox),citalopram(Celexa)escitalopram(Lexapro):Inhibit5HTreuptaketransporter,andtoa lesserdegree,theNEreuptaketransporter(e.g.,tricyclics&SNRIs)Alterregulationof5HTor5HTreceptors Fewer,lesssignificantsideeffectsthanBZsUnscheduledwithnoabusepotentialbuspirone(BuSpar)5HT1A receptoragonist:Lesseffective,butfewersideeffects