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13. Pain 4.Analgesics Opioids.doc

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Department
Pharmacology
Course
PCL102H1
Professor
Mac Burnham
Semester
Summer

Description
PAIN 4: THE OPIOIDS / OPIOID MECHANISMS OF ACTION / THE RECEPTOR CONCEPT Read : Kalant: Text Chapter (book of readings); Snyder “Stalking the Opiate Receptor”; Melzack, “The Tragedy of Needless Pain. Read for the next lecture: Carmichael et al. Dept Text Chapter (Book of Readings); Read for the next section Carlson, p. 3-9 OUTLINE The Opioid Drugs Molar Mechanisms Molecular Mechanisms – Approached Historically Molecular Mechanisms – Modern View FORWARD:  These are the analgesics for moderate / severe pain.  They are all we have for moderate / severe pain. 1. THE OPIOID DRUGS The names: • opiate analgesics o opiate suggests it comes from poopy; morphine and codeine • opioid analgesics o synthetic drugs that weren’t derived from the opiates – bind to the same receptor and do the same thing though • “narcotic analgesics” Usage:  Restricted due to laws governing use. This is because people get addicted to them. A Brief History: Known from antiquity:  galenical: opium (dried poppy sap from seed pod; Turkey or Greece)  galenical preps: laudanum, paregoric (teas etc.; liquid extraction) o Paragoric was used for dhierrea. The opiods and opiates all decrease motility in the G.I. tract  pure extract: morphine (Serturner, 1805)the first pure extract  semisynthetic: o heroin – late 19 Centrury; was supposed to be non-addicting  pure synthetics: o meperidine first pure synthetic does not constrict pupils (only one) o methadone, etc., etc. – 20th Century Current day: we have a very large number of drugs in this group. Commonly used opiates: from the poppy; not all opiates are analgesic  Morphine (pure extract; major analgesic)  Codeine (weak analgesic; binds to opiate receptor at high conc.) o a pro-drug for morphine, some people can’t convert it though and don’t get the pain killing effects  Thebaine (convulsant drug)  Papaverine (pure extract from poppy sap; smooth muscle relaxant) Note: only the L isomers are analgesic, the D isomers have no effect • except morphine and codeine, the D isomer stops coughing, but no analgesic effects Commonly Used Opioids:  semi-synthetic or pure synthetic; bind to the same receptors -all analgesic  Likewise: only the L isomers are analgesic • Meperidine (Demerol) o the first • Hydromorphone (Dilaudid) o derived from morphine • Hydrocodone o derived from codeine; semisynthetic of it • Levomethorphan: o pure synthetic, L isomer used as powerful analgesic o D isomer is dextromethorphan – used to stop coughing • Methadone (Dolorphine): pure synthetic o for maintenance; slow onset and long duration of action  crosses BBB very slowly, don’t get a high • Propoxyphene (Darvon) o Very weak one • Fentanyl (Sublimaze) o a widely used synthetic; used in hospitals quite a bit • Etorphine – o extremely potent –used to “tranquilize” wild animals • Oxycodone (Oxycontin) o a semisynthetic derived from thebaine o In the news lately due to media saying doctors are making people addicts with its use • loperamide (Immodium); synthetic opiod o antidiarrheal, replaced paregoric (don’t use it anymore) o over the counter because it doesn’t get into the brain and many more…. The Partial Agonists: drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. • nalorphine (derived from morphine) • pentazocine, cyclazocine • buprenorphine The Antagonists: have affinity (they bind) but do not cause any physiological response downstream (no efficacy) • naloxone (longer acting) • naltrexone (shorter acting; instant withdrawal for addicts) Note: little effect on non-addicts (a phasic system, NOT tonic) BUT has a great effect on opioid addicts! o Recall: phasic is on sometimes, tonic is on all the time. Addicts put their pain over-ride system into constant activity and make it tonic. Therapeutic Actions: of most members; myriad effects most likely multiple receptors Analgesia (no ceiling / at high doses become general anesthetics) • lower-dose effects: “don’t care” about pain (but have sensory feeling) • high-dose effects: “don’t feel” pain (both suffering and sensation) • lower-dose: best against slow, burning pain • higher-dose: stops all pain (slow burning and fast pain) Euphoria: detached, dreamy Query: really euphoria? Or just take away the feelings of depression? Sedation: • sometimes bad (for normal functioning) • sometimes desirable (preanesthetic, neuroleptanalgesia) o neuroleptanalgesia is an intense analgesic and amnesic state produced by the combination of narcotic analgesics and neuroleptic drugs Anti-tussive: stop coughing; mediated by different receptors • different receptor R and L isomers both work o body does not result in addiction Anti-diarrheal : • paregoric, loperamide o again, different receptors in the G.I. tract Side Effects (ADRs) (assort differently among opioids) • Sedation o When undesirable. Video with doctor – sedation reduced his normal function • Respiratory suppression o cause of death in overdose • Miosis: pinpoint pupils; small pupils o generally goes along with sedation, meperidine doesn’t cause • Nausea o area postrema or Chemical Trigger Zone (CTZ): area on the floor of fourth ventricle and does not have a BBB. It’s one of the two vomit centers. Senses poisons in the blood and induces vomiting  Very sensitive to all dopaminergic agonist and opioids seem to resemble dopaminergic agonists in some way. • Apomorphine: stimulates dopamine receptors (D2) autoreceptors • Enodcrine suppression: lowered LH, FSH, testosterone, estrogen o Lose sex drive, shrinking of the testicles etc. • Poikilothermia: an action on the hypothalamus. o Loss of temperature regulation. Adapt to temperature of external environment • Constipation: when undesirable (recall, they stop diarrhea) • Catalepsy: high dose in animals o muscular rigidity and fixity of posture regardless of external stimuli • Excitation: restlessness, fever, seizures (cats, pigs, horses, cows) o These drugs lower the seizure threshold. But the seizure threshold in humans is very high, so it doesn’t do much. It is much lower in cats, pigs, horses and cows. 2. MOLAR MECHANISMS (Anatomical Sites of Action) Specifically, sites related to the sense of pain (not the suffering component) Techniques: Conclusions are based on experiments in which opioids are injected directly into the CNS to produce analgesia. 4 Major Levels seem involved: 1. Spinal Cord: Direct application of opioids to the dorsal horn produces analgesia. Suspected mechanism: action of opioids on enkephalergic receptors on terminals of primary pain afferent neurons. • Specific inhibition of pain; not touch threshold • Antagonized by naloxone • Not as profound as the analgesia produced by i.v. opioids o Because there are other mechanisms besides just the spinal cord 2. Central Grey: application of opioids produces analgesia. Suspected mechanism: activation of the descending inhibitory pa
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