Opioid Analgesics I Med Chem Flashcards
Introduction to opioid and opium . . . origin? structures?
Physiological effects of opium has been known for centuries. In 1803,
Serturner, a 23-year old German pharmacist, succeeded in isolating the first
alkaloid, morphine, from opium. Isolation of other alkaloids followed.
Morphine is the major constituent of opium from P. somniferum,
representing about 10 percent of the total. Other phenanthrene alkaloids, such as
codeine and thebaine, represent smaller amounts of this species. More recently P.
bracteatum has been grown. It contains almost entirely thebaine, a C-ring
modification of morphine, which is useful for synthesis of many other opioid
agonists and antagonists.
Pharmacological Properties Of Morphine And Related Compounds. . . effects on dif system of the body. . . CNS, eye, respiration, GI tract
CNS: analgesia, drowsiness, mood changes, mental clouding. Analgesia is
produced without loss of consciousness. At higher doses, some nausea and
vomiting is noted, and respiratory depression, the major toxic symptom, is
pronounced.
Eye: pupil is constricted. Enhanced responsiveness to light is noted.
Respiration: a continuous depression of respiration.
Gastrointestinal Tract: Peristaltic movements are markedly decreased in
both small and large intestine, leading to constipation and delayed digestion.
Pharmacological Properties Of Morphine And Related Compounds
Mechanism of Action
Several naturally occurring opioid peptides have been found
which elicit analgesic activity which seem to compete for these receptor sites.
These are the enkephalins (5 amino acids) and endorphins (15-31 amino acids).
Several classes of opioid receptors have been partially characterized based
primarily on binding assays in different tissues and pharmacological effects
including behavioral effects.
Opioid Receptor Subtypes . . . drugs, effects, etc
Pharmacological Properties Of Morphine And Related Compounds. . . Clinical Uses
1.) Primarily relief of severe, acute pain - renal or biliary colic, acute myocardial
infarction, extensive surgical procedures, burns, trauma, pulmonary edema;
2) Severe chronic pain - malignancies, other drugs are also used.
Pharmacological Properties Of Morphine And Related Compounds
Agents Used:
Propoxyphene was a commonly used agent (and one of the least
effective). Morphine is still the standard drug for severe pain. Meperidine and pentazocine are also greatly used; they also suffer from dependencies, although that is a minor factor in choice of agent. The agents differ in duration of action -meperidine is shorter than morphine, and probably produces less respiratory depression. Codeine and propoxyphene are both ranked with the non-narcotic analgesics in their clinical indications.
Morphine and Pentacyclic Analogs . . . general
Bioavailability is increased by i.m., s.c. or i.v. administration. Oral
administration results in decreased blood levels (and decreased potency) based both on poor absorption of some compounds and first pass metabolism effects (e.g., glucuronidation and sulfation of phenols). Major routes of metabolism of morphine-like compounds are similar. The major route of metabolism of morphine is O-3- and O-6-glucuronide formation. The O-6-glucuronide is a very potent analgesic. N-Dealkylation occurs as well. Codeine is O-dealkylated, suggesting morphine may be the active species. Heroin is very rapidly hydrolyzed to 6-monoacetylmorphine, suggesting this metabolite is responsible for many of the pharmacological effects. Additional products include
morphine, and its metabolites.
Morphine and Pentacyclic Analogs: Codeine
Codeine is about ten times less potent than morphine as an analgesic orally and i.m. As an analgesic, it is used for mild to moderate pain, many times in combination with acetaminophen. It is also a very useful antitussive.
C-ring changes
Meperidine and Other Piperidines . . .Meperidine (Demerol) structure/ properties
Meperidine and Other Piperidines
Metabolism of meperdine is by expected routes: N-demethylation, and ester hydrolysis.. . Other Piperidines
….Fentanyl transdermal system is available for chronic management in patients requiring opioid analgesics. Patches are replaced at 72 hour intervals.
Open Chain Compounds
Basic structural features of u-opioids
Antagonist and Mixed Agonist-Antagonists (N-Agonists-u-Antagonists). . . general
The key to antagonist activity seems to reside in the N-substituents.
Interestingly, most all N-three carbon substituted compounds have antagonist activity (e.g., propyl, allyl, isopropyl, etc.). N-Ethyl and N-butyl compounds have little agonist or antagonist activity but compounds with longer chains have agonist activity. The finding that N-allylnormorphine is an analgesic in man led to synthesis
and testing numbers of antagonists as potential analgesics. Many of these agents are mixed agonist-antagonists. Only a few agents are thought to be pure antagonists and these are usually not analgesics. Some of the mixed agonist- antagonists are good to excellent analgesics with effective analgesic properties and are less addictive. Unfortunately, many cause anxiety and/or hallucinations.
Antagonist and Mixed Agonist-Antagonists (N-Agonists-u-Antagonists)
Agents Used as “pure” Antagonists
Antagonist and Mixed Agonist-Antagonists (N-Agonists-u-Antagonists)
Agents Used as “mixed agonist-antagonists” Analgesics
Opioid Peptides
