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opiates
What are Opiates?• Narcotics that
originate from the poppy plant
• Used to alleviate pain, suppress coughing, and treat diarrhea
http://www.lib.fit.edu/pubs/librarydisplays/arts/poppy.jpg
History• Humans have used poppies for medicinal and
recreational purposes since early civilizations• Traded throughout western Europe, Mediterranean,
Middle East, and Asia minor– Used as currency
• “Opium” comes from the Greek opos (juice), and “morphine” from the Greek god of dreams, Morpheus
Opium Wars• In the 1800’s, British merchants began trading
contraband opium for more valuable Chinese products (tea, silk, etc.)
• Commissioner Lin, a Chinese diplomat, sent a letter to Queen Victoria asking her to stop the trade
• Requests ignored Opium Wars
http://www.emsc.nysed.gov/ciai/socst/ghgonline/turnpoint/images/content/tp45/hong.jpg
Where Opiates Come From
• When the poppy loses its petals, the bulb is ready to be cut
• The liquid leaking out of the bulb is opium gum
• The gum is boiled and strained, resulting in blocks of morphine
http://www.rehab-international.org/wp-content/uploads/2008/01/opium.thumbnail.jpg
Creation: Heroin• Made with a variety of
chemicals– acetic anhydride, sodium
carbonate, activated charcoal, chloroform, ethyl alcohol, ether, and acetone
• Original purity of 90%• Dealers dilute drugs with
caffeine, baking soda, baby powder, etc.
• Usually <40% pure by the time it gets to a user
http://www.justthinktwice.com/images/pic_heroine3.jpg
How Opiates Feel• One to two minute rush
– euphoria, relief of tension• Four to five hour high
– warmth, drowsiness, satisfaction, mild dizziness, apathy
• First time: causes nausea/vomiting, often unpleasant – effects decrease over time
Morphine• Triple carbon ring• One ring with N-CH3
on it
http://z.about.com/d/chemistry/1/7/f/e/morphine.jpg
http://www.drugs-forum.com/opiate-chemistry.htmlhttp://www.thetoadband.com/Toad/Toad/Images/Morphine_sulfate2.jpg
Heroin• Similar to morphine
(opiate alkaloids)• Some differences,
highlighted by the orange boxes
• Carbonyl instead of hydroxyl groups
http://img.freebase.com/api/trans/image_thumb/wikipedia/images/commons_id/1017373?maxheight=510&mode=fit&maxwidth=510
http://www.drugs-forum.com/opiate-chemistry.html
Codeine• Difference from
morphine is shown in the orange box
• Has H3CO instead of hydroxyl group
http://upload.wikimedia.org/wikipedia/commons/e/ed/Codeine.png
http://www.drugs-forum.com/opiate-chemistry.html
Vicodin (Hydrocodone)
• Different conformation • Methyl instead of OH• Single bond and C=O
instead of double bond and OH
http://upload.wikimedia.org/wikipedia/commons/c/cc/Hydrocodone.svg
http://media.canada.com/8975269b-0529-4353-a446-596d133824d2/cnsphoto-strachan-house.jpg
Prescription Opiates• Prescribed for pain relief• Generic names: hydrocodone, oxycodone, morphine
sulfate, dihydromorphine• Brand names: Demerol, Lorcet, Vicodin, Norco,
Lortab, Percocet/Percodan, Oxycontin, RMS/MS Contin, Dilaudid/Palladone
• Often acetominophen added to decrease addictive properties, but increases risk of overdose resulting in liver problems
http://babydollsandbeerbottles.files.wordpress.com/2009/08/pill_bottle_and_pills1.jpg
http://erstories.net/wp-content/uploads/2008/06/pills-red-and-blue.jpg
What should the doctor do?
• Read the scenario• Discuss with your group• Answer the question: how should the patient
be given morphine? • Be prepared to justify your answer• Why do the different methods of drug
administration have different effects?
Source: “Understanding Neurobiology through the study of Addiction.” NIH.
What should the doctor do?
• Inhalant or injection• Goal: quick relief of pain so fracture can set• Disadvantage of inhalants: amount of drug
that enters blood more variable (some exhaled)
• With injection, all of the drug enters the bloodstream
Source: “Understanding Neurobiology through the study of Addiction.” NIH.
How Opiates Work• Attach to endorphin (a.k.a. opiate) receptors• Two kinds of opiates
– Agonists: activate receptors– Antagonists: block receptors, prevent action of
agonists• Concentrated in reward pathway and pain
pathway
Opiates And Endorphins
• Opiates have similar structures to endorphins, enkephalins, and dynorphins
• All are peptides
http://theoncologist.alphamedpress.org/cgi/content/full/9/6/717/F1
Opiate Receptors• Three kinds: mu,
delta, and kappa receptors
• Morphine acts as a strong agonist at the mu subtype and as a weak agonist at the delta and kappa subtypes
• All G-protein coupled receptors
http://www.nida.nih.gov/pubs/teaching/largegifs/slide-5.gif
G protein Cascade
http://theoncologist.alphamedpress.org/content/vol9/issue6/images/large/717_fig2.jpeg
Mu Opiate Receptors• Primary target for opiates• Highly concentrated in the thalamus,
cerebral cortex, visual cortex, and basal ganglia– Number of receptors varies
between individuals (genetic)– More receptors more pain
tolerance • Also, highly concentrated in nucleus
accumbens (in reward pathway)• Mice lacking mu receptors are more
sensitive to pain and do not become morphine dependent
https://www.scientificamerican.com/article.cfm?id=personal-pain
Pain Pathway• Nociceptors (pain-sensing
neurons) perceive pain reflex and message sent to brain
• Neurons in pain pathway synthesize endorphins
• Endorphins suppress glutamate release in pre-synaptic neurons and hyperpolarize post-synaptic neurons– Prevent the passage of
nociceptive signals• Opiates work like endorphins
– Only stronger because self-administered and we can control how much we receive
http://www.dana.org/uploadedImages/Images/Spotlight_Images/DanaGuide_CH09B05_P167a_spot.jpg
Reward Pathway• Stimulated normally by
food, sex, water, etc.• VTA (ventral tegmental
area) connects to the nucleus accumbens and prefrontal cortex
• Neurons in VTA contain dopamine, which is released in the nucleus accumbens and prefrontal cortex in response to the rewarding stimulus
http://www.drugabuse.gov/pubs/teaching/Teaching2/largegifs/slide11.gif
Dopamine Release• Gluatamte (excitatory) usually
causes neighboring neurons to release GABA (inhibitory) dopamine neuron blocked– Prevents over-excitation
• Endorphins and opiate agonists disrupt these inhibitory mechanisms – Block GABA response– Dopamine release
sensation of pleasure
http://www.drugabuse.gov/pubs/teaching/Teaching2/Teaching4.html
Dopamine Release
http://www.cnsforum.com/content/pictures/imagebank/hirespng/moa_heroin_delta_kappa.png
Action of Opiate Agonists
• Binding to endorphin receptors in pain pathway (thalamus, brain stem, spinal cord) analgesia
• Binding to receptors in reward pathway dopamine released person feels good
http://www.drugabuse.gov/pubs/teaching/Teaching2/Teaching4.html
Effect on the Rest of the Body• Vomiting center in brain (causes stomach muscles to
contract)– First uses vomiting/nausea– Effect dulls over time
• Respiratory center in brain (regulates breathing)– Inhibits decreased frequency and depth of
breathing– Overdose stop breathing
http://mayoclinic.com/images/image_popup/r7_respiratory.jpg
Effect on the Rest of the Body• Endocrine System
– Slightly lowers body temperature, cortisol, and testosterone production
– With tolerance, effect dulls• Pupils contract (miosis)• Histamine released widened veins, flushed
appearance, itching, sweating• Intestines (also have opiate receptors)
– Inhibit intestinal peristalsis constipation
Negative Effects• Can cause circulatory collapse, coma, cardiac
arrest, depressed appetite and sex drive• Related dangers (injection): HIV, Hepatitis B
and Hepatitis C• Relatively few long-term health effects (not
like alcohol/smoking)• Very easy to overdose• Worst “side” effect: addiction
http://www.waukeshafp.org/images/residents_faculty/injection.jpg
Who is the Addict?• Read about Pat and Chris
• Discuss with your group: who is the addict?• Be prepared to justify your answer
Source: “Understanding Neurobiology through the study of Addiction.” NIH.
Who is the Addict?• What did your group decide: who is the
addict? Why?• What are the differences in why and how
Chris and Pat take morphine?• How does this affect whether or not they are
are addicted?
Source: “Understanding Neurobiology through the study of Addiction.” NIH.
Who is the Addict?• Difference in reason for taking drugs
– Pat took to escape problems, also expected high– Chris took to reduce pain, without motivation for
getting high• Pain patients are actually at a low risk for
becoming addicted
Source: “Understanding Neurobiology through the study of Addiction.” NIH.
Tolerance and Dependence• Tolerance
– Develops quickly to pain-relieving effects of opiates– Morphine binds to receptors enzyme that causes cell to
continue impulse firing inhibited– Frequent use adaptation no longer causes enzyme
change– Need increasing amounts to relieve pain
• Dependence– Drug needed to function normally– Very uncomfortable withdrawal (nausea, muscle spasms,
cramps, anxiety, fever, diarrhea)
Addiction• Can be dependent but not
addicted– Reward pathway underlies
addiction, pain pathway underlies dependence
• Myth: therapeutic painkillers produce high rate of addiction– Patients managing pain can
experience withdrawal– Not addicted because do not
want it after taken off • Addiction to one opiate is
often treated by another
http://www.drugabuse.gov/pubs/teaching/Teaching2/Teaching4.html
House
http://www.youtube.com/watch?v=gQmlsmOZl6c
Drug Addiction Treatment
• Addiction is a chronic disease• Often thought of as self-inflicted• Initial choice to use, but afterwards compulsive
• Similar to other chronic diseases (ex. hypertension, diabetes)
• Voluntary choices also contribute to severity of other chronic diseases
• Treatment requires medical compliance• Adherence to a doctor’s treatment plan
Treatment• Which disease has the highest rate of medical
compliance?• Medical compliance is following a physician’s
treatment orders
Disease Medical Compliance
Heroin Addiction ?
Hypertension ?
Diabetes ?
Treatment• Heroin treatment has a higher rate of medical
compliance than other chronic diseases• As a result, treatment is often more successful than
treatment for other chronic diseases• Successful treatment usually uses a combination of
behavioral and pharmacological treatments
Disease Medical Compliance
Heroin Addiction 60%
Hypertension <30%
Diabetes <50%
Source: “Understanding Neurobiology through the study of Addiction.” NIH.
Behavioral Treatment
• In conjunction with pharmacological treatments
• Addicts learn to deal with the environmental factors that could trigger drug use
• Counseling individually or as a group• Relapse
– Does occur– Is considered a part of treatment process
Pharmacological Treatments
• Opiate receptor agonist– Binds to opiate receptor – Therefore prevents other agonists from binding
(competes with them)– Example: Methadone
• Opiate receptor antagonist– Entirely blocks other agonists from binding to
receptor– Example: Naxolone
Source: “Understanding Neurobiology through the study of Addiction.” NIH.
Treatment: Methadone• Opiate receptor agonist
• Treats heroin addicts– Because heroin causes release of extra dopamine,
addicts need an opiate to occupy the receptor• Methadone is used to occupy the receptor
– Can be taken orally in liquid or pill form– Withdrawal suppressed for 24-36 hrs– Does not produce a euphoric high
• Methadone withdrawal is slower
http://www.drugscope-dworld.org.uk/wip/24/images/methadone.JPG
Methadone problems
• Highly addictive• Sold in large quantities on
the black market• High risk of overdose• Use needs to be
supervised by drug counselors or medical personnel
http://content.answers.com/main/content/img/oxford/Oxford_Chemistry/0192801015.methadone.1.jpg
Treatment: Naxolone
• Opiate receptor antagonist
• Used in cases of overdose
• Causes effect only after opiate use
• No narcotic effect cravings still persist
http://opioids.com/naloxone/naloxone.jpg
Treatment: Buprenorphine
• Partial agonist• Agonist properties: can’t get
high because activation does not occur fully
• Not nearly as addictive as methadone so is better for treatment– No withdrawal symptoms or high
http://www.drugs.com/pro/images/23aa1bb3-cecf-4e62-29bb-48488bb66fc3/xen-0327-1.jpg
How Buprenorphine
Works
http://www.naabt.org/education/images/Receptors_HiRes.jpg
How Buprenorphine
Works
http://www.naabt.org/education/images/Receptors_HiRes.jpg
How Buprenorphine
Works
http://www.naabt.org/education/images/Receptors_HiRes.jpg
How Buprenorphine
Works
http://www.naabt.org/education/images/Receptors_HiRes.jpg
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