Drug Groups used for 1. (“”) analgesics 2. NonNon--opioidopioid analgesicanalgesic--antianti--inflammatoryinflammatory analgesics (NSAIDs) 3. Drugs to increase effects Psychology 472 – Antidepressants Pharmacology of Psychoactive – Anticonvulsant ––NMDANMDA--antagonistsantagonists (e.g., dextromethorphan) Drugs – (e.g., Sativex) Listen to the audio lecture while viewing these slides

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Opiates NaturallyNaturally--OccurringOccurring

Two sources: Natural plant product Endogenous transmitters with morphinemorphine-- comes from poppy like actions ((ge.g., endorphins ) plant, Opium poppy: and – Not the same variety as the garden plant.

All other opioids are eieitherther semi synthetic Difficult to synthesize in or totally synthetic. the lab

Opium Poppy

1 TERMINOLOGY Narcotic: Opium: Exeudate of the opium poppy – Contains morphine and codeine as natural From narcos: products. – any sleep-sleep-inducinginducing drug Opiate: A drug derived from the opium Today - An illegal drug poppy – (Morphine or codeine) Opioid: Agonist with morphinemorphine--likelike activity ––--Synthetics

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Groups of Opiates Antagonists Pure Agonist: Morphine, , Dilaudid, Numorphan, Demerol, , . Have affinity for receptors but is devoid of morphine action. Partial Agonist: – Especially Mu receptors (Buprenex, al so in Su boxone ) Pure Antagonist: (Narcan), Mixed AgonistAgonist--AntagonistAntagonist: (ReVia, Trexan, Vivitrol), (Talwin), (Stadol), N (Revex) (Nubain), (Dalgan)

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Background SHORT HISTORY

Are derived from the opium poppy or are Is mentioned in recorded history around synthetic copies 3400 B. C. in Mesopotamia Many uses Is beinggygyp,, used by Egyptians, Greeks, – RliRelieve pa in Europeans, Chinese, by 400B.C. – Induce sleep – Primarily used in medicine – Reduce sensation – Pleasure 1500 began to be used for pleasure in India – Becomes very important in commerce

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2 1805 Opium Wars Morphine was first isolated and perfected by March 18, 1839 Friedrich Sertuerner. By Chinese Decree, all traders are Named after the god of Dreams and Sleep, Morpheus required to surrender their opium. – Clldit“MCalled it “Morp hinum ” The British respond with Warships and the Follows. It ended in 1842 with the Chinese giving Hong Kong to the British.

18561856--18601860 More History The British renew hostilities with the Chinese over Opium Trade (and During the American Civil War, 400 000 Smuggling) soldiers became addicted to morphine Second Opium War occurs 1874 Wright synthesizes Heroin – French Aid of the British. – Used to treat opium and morphine addiction – Ended with legalization of Opium Trade.

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Laudanum: Medicinal Opium

Commonly opium mixed with Red Wine or Used in all sorts of Port. medicines (OTCS) Potentially dangerous if not properly mixed and products or if too much opium was present.

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3 Legal Issues arise… Opiate Receptors

The Harrison Narcotics Act passes in 1914 in Approximately 17 have been reported attempts to end drug abuse (particularly of Four main groups Heroin) It requires doctors, pharmacists and others who prescribed narcotics to register and ––MuMu (μ), pay a tax. – K(Kappa (κ), This was not the first attempt to legislate drugs ––DeltaDelta (δ) or to tax the use, just the most successful. – Nociceptive Others include – Epsilon (ε), Lota (ι) , Lambda (λ) Zeta (ζ)

Includes subgroups (e.g. μ1 , μ2, μ3) 20

Response Depends on the Receptor Activated More Examples Mu 1 Mu and Delta 1 – Supraspinal analgesic properties – Agonists activate mesolimbic dopamine Effects occur above the spinal cord system Mu 2 – Get a rewarding effect, – Respiratory Depression Delta 2 – Dependence – AitAgonists use nonnon--diitdopaminergic system Kappa Receptor Kappa – Sedation – Activation suppresses physical and psychic – Spinal Anesthesia dependence of mu and delta agonists Delta Delta – Site for endogenous opiates – Activation increase the dependence of Mu – Dependence 21 agonists. 22

Opiate Types Many Products Contain Opium Biologically active opiates Opium – Morphine, codeine, , Morphine SemiSemi--syntheticsynthetic opioids Codeine (Methylmorphine) – Dilaudid, , Percocet, Heroin, Demerol (Meperidine or ) , ,, , Heroin (Diacetylmorphine) dipropanoylmorphine, and (Dilaudid) Darvon/Darvocet and buprenorphine; Fentanyl Fully synthetic Opioids Percocet – fentanyl, pethidine, , and Others ; http://www.opiates.com/opiates/opiatehttp://www.opiates.com/opiates/opiate--library.htmllibrary.html

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4 Other Compounds that bind on Endogenous Opioids Opiate Receptors Are produced naturally in the body is a KK-- receptor agonist – Endorphins – No real analgesic effects – Enkephalins – Classified as a hallucinogen – Dynorphins DtDextrome thhthorphan – Endomorphins. – Has no analgesic effects – Used in cough medicines

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Actions of Opiates More Actions Analgesia – Usually from opiates acting in the brain and/or Respiratory depression the spinal cord – This is what kills you from an overdose/sedation. – Can also impact other areas as well. – Decreases respiratory center's sensitivity to higher levels of carbon dioxide in blood. Reduce thalamocortical processing and DthhflDepresses the cough reflex higher CNS functions. – Antitussive action can be separated from Inhibits (hyperpolarizes) neurons. other actions Acts presynaptically on glutamate neurons Decreases nausea and vomiting to inhibit glutamate release Causes constipation – Used as a last resort for major diarrhea

More Action Overall Effects on the Body

Pupil constriction () Impact all muscles – Skeletal, heart – Reduces the inhibitory effect of GABA on Also Impacts lungs, brain, and eyes dopamine neurons Muscles lose their ability to contract over time Cough and nausea centers are suppressed Digestive system slows down

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5 Opium O.P.", "hop", "midnight oil", "tar", "dope", and "Big O Brownish, tartar--likelike substance Usually smoked (Use an opium pipe) – Active alkaloids (morphine) are vaporized – Then inhale the vapors Not used as much today – Other metabolites (morphine, heroin) are more popular

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Morphine Some Slang Terms

Most refined form of Opium M, glad stuff, happy stuff, happy powder, white Taken by injection or orally nurse, red cross, first line, God's Own Medicine, Comes in liquid or pill form Vitamin M, Big M, Emma, Emmy, Miss Emma, Lady M, white lady, cube, cube juice, mo, morf, Commoninthe60Common in the 60’ s and 70’ s, use decreases since the 80’s morph, morpho, mofo, hard stuff, shit, dope, dry grog, white merchandise, uncle, Uncle Morphy, – Hard to get morphy, coby, cobics, gold dust, monkey dust, – Replaced by synthetic opiates number 13, unkie, mojo, needle candy, others.

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Pharmacokinetics Actions Decreases pain Poorly absorbed when taken orally – Morphine and friends are unbeatable at this time For users Alters mood, reduces anxiety, creates euphoria Cough suppression – Smoked or Injection preferred method Miosis Slowly crosses the bloodblood--brainbrain barrier. Causes sleep Causes decreased gastrointestinal motility Achieves same level in fetus as in – Decreases diarrheal pregnant mother – Used as a last resort (important for cholera)

Side effects – Nausea, vomiting – Respiratory depression

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6 Metabolization Withdrawal Metabolized to an active metabolite: Similar to other opiate withdrawal morphinemorphine--66--glucuronide.glucuronide. – Restlessness, drug craving, sweating, extreme Both have halfhalf--liveslives of about 3–3–55 hours. anxiety, depression, irritability, fever, chills, With impaired renal function can retching, panting, cramping, insomnia, accumulate the active metabolite and can explilosive dihdiarrhea, itintense ac hes an d pa ins become toxic. Not lifelife--threatening,threatening, but can seem unbearable.

Heroin (Diacetylmorphine) Slang Terms for Heroin Comes in different colors Smack, gear, golden brown, brown, dope, Rapidly crosses bloodblood--brainbrain barrier; stuff, crap, shit, horse, white horse, charlie smoked, snorted, or injected. horse, chick, brother, antifreeze, Aries, Slang terms Aunt Hazel, birdie powder, bird shit, bird, – Dragon chasing" (heating of heroin with boy, bomb , Witch Hazel, sweet Jesus, barbital on a piece of foil), scat, blanco, chica, cheva. – Madak and "ack ackack"" (smoking of cigarettes Older terms H, horse, harry containing mixed with heroin powder) Word “Heroin” usually only by people Metabolized to monoacetylmorphine, working in criminal justice system and morphine, and codeine. pharmacology classes.

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Pharmacokinetics THE RITUAL IV or smoking are most common methods of ingestion – Intravenous injection = slamming, hooting up"). BLACK TARTAR--MEXICOMEXICO Intravenous injection – Provides the most intense rush ONE TENTH OF A GRAM – Occurs within seven to eight seconds. A HIT Smoking – Is becoming more popular THE WORKS – Purity levels are higher – Decreased risk for BBPs – Reaches peak effects within 10 to 15 minutes. 41 42

7 Withdrawal Hydromorphone (Dilaudid, Palladone)

Usually begins in 6 to 24 hours of 10 times as potent as morphine discontinuation of the drug Considered the gem of opiates Similar to other opiates discussed Dilaudid dose = 11––22 mg – StiitdSweating, anxiety, depress ion, genera lflil feeling Effect s i n 30 t o 60 m inu tes of heaviness, cramping, excessive yawning or Metabolized in the liver, sneezing, tears, sleep difficulties, cold sweats, chills, severe muscle and bone aches; nausea IV halfhalf--lifelife about 2 hours. and vomiting, diarrhea, cramps, fever

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Slang Side Effects

Dillie,, Delilah, D, dilly, dill, K1, K2, K3, K4 Similar to other opiates K8, M8, Big D, others LightLight--headedness,headedness, dizziness, sedation, constipation, nausea, vomiting, sweating, others

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Withdrawal Meperidine (Demerol) Begins within 24 hours after the last dose 1/10th as potent as morphine Increase in severity over the next 72 Short action, rapid onset of withdrawal hours. Most gone after 3-3-55 days, Exerts more excitatory effects than Some symptoms morphine because of active metabolite, normeperidine – Like other opiates discussed – Causes tremors, delirium, hyperreflexia, – Restlessness, yawning, sweating, chills, convulsions. diarrhea, irritability, anxiety, joint pain, weakness, abdominal cramps, insomnia, Both substances accumulate in persons nausea and vomiting, others with reduced renal function.

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8 Oxycodone and OxyContin Side Effects Used to treat chronic pain OxyContin Like other opiates – Is the brand name of a timetime--releaserelease formula of – euphoria, memory loss, constipation, fatigue, oxycodone dizziness, nausea, lightheadedness, Metabolized by cytochrome P450 enzyme headache,,y dry mouth, anxiety, others system in the liver, Can have withdrawal symptoms like other – Can have drug interactions opiates – Issues with alcoholics

Legally sells for $.10 per mg. Selling illicitly for $1 per mg.

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Fentanyl and Derivatives Methadone Fentanyl, , alfentanyl and others Synthetic Opiate Called White Is long lasting Is a White Powder Uses Rapid onset and short duration of action – Rapid addictive properties Treatinggp chronic pain 100 times stronger than morphine – Heroin addiction Can be 100-100-20,00020,000 times stronger than heroin Taken orally usually with fruit juice – Under right conditions, one dose size of a salt grain can kill 30 people Reduces craving and withdrawal Effects and side effects similar to other opiates Lasts up to 72 hours Often sold in patches Is very addictive 52

Uses Propoxyphene (Darvon)

Two uses: – Prevention of withdrawal in opioidopioid--dependentdependent Structurally similar to methadone persons (e.g., methadone maintenance Less potent than codeine; more potent ppgrograms ) than aspi r in Federal regulations clearly differentiate Orally, not much potential for abuse these uses and who can prescribe. OpioidOpioid--likelike at high doses, intravenous

9 Partial Opioid Agonists Tramadol (Ultram) Buprenorphine (Buprenex) Another Partial Opioid agonist Partial mu agonist Partial agonist at mu receptors. There is a ceiling to the respiratory Blocks reuptake of serotonin and nor depression and the “high.” epinephrine, LongLong--acting,acting, 24 hours – Has antidepressant effect. Very hard for naloxone to compete with it. Many side effects: drowsiness, dizziness, May be an alternative to methadone for nausea, vomiting, constipation, headache treating addiction.

Mixed AgonistsAgonists--AntagonistsAntagonists Some Mixed AgonistsAgonists--AntagonistsAntagonists Agonists at one receptor; antagonists at a second receptor Kappa agonists, poor mu agonists, even Produce analgesia by mu antagonists – Agonistic action at kappa receptors, – Nalbuphine (Nubain) – Weak or antagonistic action at mu receptors. – Pentazocine (Talwin) Low doses cause moderate analgesia, higher doses not much more. – Butorphanol (Stadol) – Dezocine (Dalgan) Side effects: – Dysphoria, anxiety, hallucinations.

Opiate - Related Drugs Tolerance to Opiates

Increases metabolism at neuronal and liver levels Dextromethorphan Get up regulation of receptors – Is and OTC cough suppressant Alters brain biochemistry Clonidine – RliRelieves some w ithdrawa l symp toms Resu lt - Tolerance Naloxone (opioid antagonist) – used for overdoses) USERS ALSO BECOME CROSS TOLERANT

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10 Conclusion WITHDRAWAL Physical Lots of different types of Opiates – Described with most drugs Lots of different effects Psychological – Depression Need to consider other drug use when – MdMood sw ings users are tkitaking op itiates – Hypersensitivity to pain Withdrawal symptoms are usually NOT life Look for withdrawal effects when clients threatening are in treatment Feel like a extreme case of the flu Can cause to use again

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