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Lecture 5 Downers Part 1 Downers Opiates/ __________________ Sedative-Hypnotics Alcohol (covered in the next lecture) Opiates/Opioids Based on the __________________poppy Refined versions and synthetic versions Opium Morphine Codeine __________________ Hydrocodone __________________ Heroin All developed to treat pain, diarrhea, coughs and other illnesses What’s the difference? __________________ Opium extracts and semisynthetic opium preparations Extracts: Morphine, codeine, thebaine Semisynthetic: heroin, hydrocodone, oxycodone, hydromorphone Opioids Synthetic __________________ Methadone, oxymorphone, naloxone Historical Overview __________________first Limited abuse potential Bad taste- limited strength __________________ Much stronger euphoria and well-being “chasing the dragon” Heat heroin on tin foil and inhale fumes through a straw Extremely high abuse potential Morphine etc… __________________is 10x stronger than opium __________________is 2x stronger than opium Heroin: an attempt to find a more effective painkiller without addictive properties __________________stronger than morphine Very fat soluble Morphine is only partly fat soluble (not as strong) Injecting… Not only did the __________________and pain relief occur as with inhaling With injecting, an intense __________________ occurred Historical note Opiates were in many __________________and medications Iatrogenic addiction very common Physician induced __________________ 56-71% of opium addicts were women in the 1880s Where do we get this stuff? Golden Crescent __________________and __________________ Afghanistan grew 92% of the world’s supply in 2006 Golden Triangle __________________ (Burma), __________________, Laos 5-6% of the world’s supply US Heroin Majority has come from Mexico and Columbia __________________heroin Most popular on the US west coast Dissolves easily in water and is smoked easily Lots of impurities- also, very strong though (40-80% pure) Biological Effects of Opiates and Opioids Deals with: __________________ Pleasure __________________suppression Diarrhea control Substance P A neurotransmitter that seems to be responsible for the signaling of __________________ When pain gets intense, body releases __________________and enkephalins Neurotransmitters that attach to opioid receptors __________________the release of substance P, thus blocking the pain signal from beginning Not a perfect process: some pain signals still get through Opioids and Opiates Act like the endorphins and enkephalins __________________ substance P from being released Also __________________the receptors of substance P, so that the little that does get through doesn’t work Also works on emotional pain Activates the ____________________________________ Removal of stress can negatively reinforce the user to take more drugs Mechanisms for pleasure Works at __________________receptors in the reward centers Inhibits __________________ (an inhibitory NT) Leads to increased activity Activates __________________receptors (increases dopamine neuron activity) Increases the release of __________________ Here’s the link: Pleasure and Pain The area of the brain that signals pleasure is the ________________________________ that signals the removal of pain Further motivates a user to get more drugs into the system Also leads users to use to relieve withdrawal effects more than to use for the high or the rush __________________ is enough of a high for many users Main receptors for opioids Naturally occurring opioid __________________ More for the endorphins and enkephalins, than for drugs Found in the __________________, spinal cord, GI track, autonomic nervous system, and on various organs three main types Mu __________________ Sigma Where are they? Mu and Sigma: trigger __________________pathway, block pain, alter mood, contract pupils, __________________the autonomic nervous system Kappa: induces dysphoria (the opposite of euphoria) and mediates pain near the ________________________________________ Opiates/opioids affect the different receptors differently This is why some are better at blocking pain whereas others are better at inducing a high Other activities Inhibits the __________________center of the brain Located in the brainstem Some cough medicines used to have opiates in them Inhibits the brain areas that controls digestion and intestinal muscles Also located in the ____________________________________ Many opium addicts have severe constipation Opioids affect every part of the body Lowers blood pressure Messes with the __________________ Lowers breathing rate Messes with the __________________ Constricted pupils Messes with the __________________ Slurred speech or raspy voice Messes with ____________________________________ Coordination is slowed Messes with __________________ And we’ve already mentioned __________________centers in the brainstem __________________centers in the brainstem Makes users insensitive to pain Damages the __________________response Without pain, the body doesn’t respond in a way to fix areas that are damaged Even __________________desire Women have delayed periods Men produce less testosterone Desire is dulled Are they addictive? Of course Why? Tolerance develops __________________ __________________ metabolism of the drug Nerve cells are desensitized to the drug __________________ the drug faster Various other methods to compensate for the effects Your book describes a patient “After one year of opioid use… using five fentanyl patches, 20 Demerol tablets, and continuous morphine suppositories.” However __________________ develops at different rates for the different body systems May develop a tolerance to the pain relieving effects, but develop no tolerance to the __________________ __________________ Do opioids change the brain? Some evidence says there may be __________________effects from taking strong opioids Nestler (1997) gave rats lots of __________________ Found that their dopamine producing cells shrunk by about ¼ Body produces less dopamine naturally Less ability to feel pleasure after drug use stops Leads to a desire to use yet again Cross dependence very strong Basis of __________________as a treatment for heroin users Users build up a physical dependence on __________________ Can relieve the withdrawal symptoms with a less damaging drug: methadone Not all opioids work on the same receptors though (remember mu, sigma, and kappa), so some may create tolerances more than others (at at different receptors) Three stages of Opium withdrawal __________________withdrawal Body tries to go back to normal a bit too fast Cramps Uncontrollable jerking and kicking Vomiting Insomnia “Creepy crawlies” Delirium ____________________________________withdrawal Emotional disturbances still there, but physical symptoms of withdrawal are mainly gone Sleep problems and mood swings still Protracted withdrawal ____________________________________cued withdrawal Can last for years, even decades after the user has stopped using Norepinephrine plays a large role Opioids stop the release of ____________________________________ Body stores more and more When the user stops using, tons of norepinephrine is released in the brainstem Probably why withdrawal includes __________________- insomnia The main sleep area (locus coeruleus) is largely affected here More on withdrawal Opium withdrawal is almost never ____________________________________ Although it may feel that way Other issues Flesh eating bacteria Sedatives and Hypnotics Need to be careful of iatrogenic addiction __________________induced addiction Sedatives: calming drugs Valium, Xanax etc… __________________: sleep inducers Short-acting barbiturates and benzodiazapines How do they work? Typically will work on __________________ Serotonin __________________ Controls anxiety and restlessness More specifics please Not completely sure of the link, but here’s my take Book describes __________________ as causing: Muscle relaxation Heat loss Lowered __________________ Reduced coordination Sounds similar to alcohol to me Probably due to the affects on __________________ The main inhibitory NT in the brain What about serotonin and dopamine? __________________ Linked to mood and sleep changes __________________ Reinforces the desire to take the drug Hypnotics Work on the brainstem primarily __________________ Muscle coordination Quick History of Sedatives/hypnotics __________________ First used in the 1850s Metabolized slowly so… it could lead to toxic levels in the body ____________________________________ Used to treat DT’s and pregnancy symptoms The original “mickey” slipped into drinks Started in 1869 The famous ones __________________ Very popular in the 1930s and 40s Phenobarbital, secobarbital Low margin of safety, high addiction potential __________________ Popular in the 50s “mother’s little helper” Replaced barbiturates as the preferred sedative drug Benzodiazapines Librium, __________________, Xanax Work like barbiturates Less __________________though Other sedatives What about __________________, Ambien and Lyrica? Marketed as ____________________________________ Has NOT been proven experimentally Biological Effects Benzodiazapines Agonist to GABA, __________________, and serotonin Inhibits anxiety and stimulation; thus it calms Some of the ____________________________________ (the parts that they break down into) are active substances that can cause more effects Tolerance Typically develops as the liver becomes better at processing the drug ____________________________________reverse tolerance Older people need less of the drug than younger people __________________dependence Only happens quickly when patients take 10-20x the prescribed dosage With normal doses, it takes over a year Withdrawal Much of the dependence may be psychological- not physical If physically addicted, withdrawals can be __________________ If use isn’t tapered off slowly, __________________or death may occur Due to low GABA, and excess levels of norepinephrine and epinephrine If addiction was caused by long term normal dosages, withdrawal symptoms are __________________ Memory problems? May disrupt __________________systems in the brain Used as “date rape” drugs Barbiturates Act like benzodiazapines, although the symptoms/effects are more like __________________ A user’s current mood will typically be amplified with barbiturates (and alcohol) More likely to ____________________________________with barbiturates than with benzodiazapines Does tolerance develop? Two main types ____________________________________ tolerance Metabolism of the drug increases ____________________________________ tolerance Nerve cells are less sensitive to the drug Withdrawal and Dependence Tissue dependence happens after long periods of high use __________________can be very dangerous Very similar to the properties of benzodiazapines Ambien, Lunesta and others Most non-barbiturate, non-benzodiazapine sedatives work as an agonist to GABA Basically work very similarly to ____________________________________ Can become habit forming long term, but typically are safer than benzodiazapines