1. Pharmacology – II [PHL 322] Opioids Analgesics Dr. Mohd Nazam Ansari

2. What is Misuse? Misuse = “Non-medical use” or any use that is outside of a medically prescribed regimen Examples can include: Taking for psychoactive “high” effects Taking in extreme doses Mixing pills Using with alcohol or other illicit substances Obtaining from non-medical sources

3. Commonly Misused Rx Drugs Classified in 3 classes CNS Stimulants: ADHD, weight loss  E.g. Ritalin, CNS Depressants (Sedatives - Hypnotics): treat anxiety and sleep disorders  E.g. Xanax, Ativan, Valium, Opiates: pain-killers  E.g. Morphine, Codeine

4. What are opioids? Opioids are the most powerful analgesics available Opiates: are the alkaloids found in opium, a white liquid extract of unripe seeds of the poppy plant (e.g. morphine and codeine). Opioids: are derivatives of opiates, any compound that binds to opiate receptors in the CNS or GIT. 1.Endogenous opioid peptides produced in the body (endorphins, dynorphins, enkephalins) 2.Semi-synthetic opioids (heroin, oxycodone, hydrocodone) 3.Fully synthetic opioids (Demerol, methadone, fentanyl, tramadol) Oral, transdermal and intravenous formulations

5. Effects of Opioids Desired action is analgesia Unwanted actions on both CNS and PNS: Analgesic tolerance Physical dependence Respiratory depression  Main cause of death from opioid overdose  Combination of opioids and alcohol is especially dangerous Nausea, vomiting, sedation, euphoria, dysphoria Acute urine retention Constipation (inhibition of GIT motility and decreasing biliary and pancreatic secretions to cause indigestion) Suppression of cough by direct inhibition of cough center. Pupil constriction (meiosis) Slurred speech Impaired attention/memory Seizures Slowed heart rate

6. Opioid Receptors Receptors located throughout body, all opioid receptors belongs to a group of G-protein coupled receptors Receptor types Mu (µ), delta (δ), kappa (κ), Sigma (σ) Mu: receptors produce the most profound analgesia, and can cause euphoria, respiratory depression, physical dependence and bradycardia. Kappa: receptors trigger a lesser analgesic response, and may cause meiosis, sedation and dysphoria. Delta: receptors modulate mu receptor activity. Sigma: receptors provide little to no analgesia. Some investigators classify sigma receptors as phencyclidine, rather than opioid, receptors. Side effects: constipation, sedation, itch, mental status changes

7.  2 nd messenger systems G-proteins G-protein Opioids have been proposed to inhibit neurotransmitter release by inhibiting calcium entry, by enhancing outward movement of potassium ions, or by inhibiting adenylate cyclase (AC), the enzyme which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).

8. Opioids or narcotic analgesics: classified based on their pharmacology action at various receptor subtypes: Pure agonists (bind and stimulate receptors), e.g. morphine, methadone, fentanyl Pure antagonists (bind and block or inhibit activity), e.g. naltrexone Partial agonists (bind and stimulate, but with less than full activity at certain receptor subtypes), e.g. Buprenex (buprenorphine) – does produce some analgesic effects, but does not depress respiration as much…a good thing Mixed agonist/antagonists (stimulating some receptors while blocking others). e.g. Talwin (pentazocine) which is a weak, less efficacious analgesic (agonist at kappa, blocks mu) Classification

9. Endogenous Opioids Produced naturally in body Naturally increased when one feels pain or experiences pleasure Act on opioid receptors Produce euphoria and pain relief Examples: endorphins, enkephalins, dynorphins, endomorphins

10. Morphine A pure opioid agonist The most potent & efficacious analgesic we have today still Routes: oral, IM, IV, rectal (avoids nausea/ vomiting) Sustained release preparations: MS Contin, Oramorph, Kadian, Avinza Pharmacological effects: Analgesia Relaxation Calm euphoria Sedation Reduced cough reflex Respiratory depression Meiosis

11. Codeine A most commonly prescribed opioid analgesic in the world (often combined with aspirin or acetaminophen) Low potency Pain relief via 10% conversion to morphine Note: some SSRIs will block the conversion of codeine to morphine via liver enzyme inhibition, and will block/lessen the analgesic effects of codeine

12. Semi-synthetic Opioids Hydrocodone with Tylenol: Norco, Lortab, Vicodin, Lorcet Hydrocodone with ibuprofen: Vicoprofen Hydromorphone: Dilaudid Oxycodone with Tylenol: Percocet Oxycodone with aspirin: Percodan OxyContin

13. Heroin x3 more potent than morphine Intense “rush” esp. if smoked or used IV Legal for clinical use outside USA, not inside USA When used along with free-base cocaine (“crack”) --- increased euphoria, decreased anxiety & paranoia, Dilaudid (hydromorphone), Numorphan (oxymorphone) x6-10 more potent than morphine Slightly less sedating, about same degree of respiratory depression

14. OxyContin Used to treat pain associated with arthritis, lower back injuries, and cancer Most commonly in tablet form: 10mg, 20mg, 40mg, 60mg, and 80mg Dose: every 12 hours, half-life 4.5 hours Abuse: may be chewed, crushed, snorted or injected

15. Synthetic Opioids Methadone Demerol (meperidine) Fentanyl Partial Agonists Buprenorphine Tramadol

16. Methadone Synthetic opioid agonist Analgesic, CNS depressant Effects last 24 hours; once-daily dosing maintains constant blood level Prevents withdrawal, reduces craving and use Facilitates rehabilitation Clinic dispensing limits availability

17. Buprenorphine for Opioid Dependence FDA approved 2002, age 16+ Mechanism: partial opioid agonist Analgesic properties Ceiling effect Lower abuse potential Safer in overdose Formulations Sublingual administration Subutex (Buprenorphine) Suboxone (4:1 Bup:naloxone) Dose: 2mg-32mg/day Once-daily dosing

18. Opioid Withdrawal Dysphoric mood Nausea or vomiting Diarrhea Tearing or runny nose Dilated pupils Muscle aches Goosebumps Sweating Yawning Fever Insomnia

19. Opioid Detoxification Medications used to alleviate withdrawal symptoms: - Opioid agonists (methadone, buprenorphine) - Clonidine - Other supportive medications  Anti-diarrheals,  Anti-nausea agents,  Ibuprofen,  Muscle relaxants,  Anti-anxiety medications

20. Thanking you