OPIOID AGONISTS AND ANTAGONISTS
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Transcript of OPIOID AGONISTS AND ANTAGONISTS
OPIOID AGONISTS AND ANTAGONISTS
Dr. Robert L. Copeland
Narcotics Those drugs which possess both an analgesic (pain relieving) and sedative properties.
Opioid refer to drugs in a generic sense, natural or synthetic, with morphine- like actions
Classification of OPIOIDS
Natural phenanthrene
morphine 10% codeine 0.5% thebaine 0.2%
semisynthetic heroin oxymorphone Hydromorphone
synthetic meperidine methadone morphinians benzamorphans
Chemistry
Morphine pentacyclic alkaloid (five ring structure) oxygen bridge at 4,5 position three major rings (a, b, c) phenolic groups (s/a hydroxyl, alcoholic, OH) at
position 3 and 6 modifications at those positions changes
pharmacokinetics and potency of drug nitrogen at 16 position (n16) changing it by adding an alkyl group converts it to
naloxone (i.e. go from a agonist to an antagonist)
Receptor Stimulation
muP hysical dependence E uphoria A nalgesia (supraspinal) R espiratory depression
kappaS edation A nalgesia (spinal) M iosis
delta analgesia (spinal & supraspinal) release of growth hormone
sigmadysphoria (opposite of euphoria) hallucination (both visual & auditory) respiratory and vasomotor stimulation mydriasis
OPIOID receptors
CNS distribution is not uniform they are at areas concerned with pain receptor locations beginning with highest
concentration areas 1. cerebral cortex 2. amygdala 3. septum 4. thalamus 5. hypothalamus 6. midbrain 7. spinal cord
Endogenous Opioid Peptides
Three distinct families of peptides have been identified: the enkephalins, the endorphins, and the dynorphins. Each family is derived from a distinct precursor polypeptide
These precursors are now designated as proenkephalin (also proenkephalin A), proopiomelanocortin (POMC), and prodynorphin (also proenkephalin B)
Endogenous Opioid Peptides
Enkephalins they are 5 amino acids long also have met enkephalin (methionine at 5' position)
and leu enkephalin (leucine at 5' position) enkephalins are neuromodulators
since they are small peptides, it was found that they came from larger peptides (pro enkephalins) proenkephalin gene codes for peptide 276 amino acid in length
cleavage of proenkephalin gives 4 to 5 pieces of activated enkephalins
Endorphin POMC is processed into melanocyte-stimulating
hormone (g-MSH), adrenocorticotropin (ACTH), and b-lipotropin (b-LPH); within the 91-amino-acid sequence of b-LPH are found b- endorphin and b-MSH
30 amino acid peptide last 5 amino acids are the same sequence as
enkephalins endorphins are neurohormones conservation between species little difference in humans
Prodynorphin yields more than seven peptides that contain leu-enkephalin, including dynorphin A(1-17), which can be cleaved further to dynorphin A(1-8), dynorphin B(1-13), and a- and b-neoendorphin, which differ from each other by only one amino acid.
Pharmacokinetics
absorption readily absorbed from GI tract, nasal mucosa,
lung subcutaneous, intramuscular, and intravenous route
distribution bound free morphine accumulates in kidney,
lung, liver, and spleen CNS is primary site of action
(analgesia/sedation)
metabolism/excretion metabolic transformation in liver conjugation with glucuronic acid excreted by kidney half life is 2.5 to 3 hours (does not persist in
body tissue) morphine 3 glucuronide in main excretion
product lose 90% in first day duration of 10 mg dose is 3 to 5 hours
Morphine administration oral morphine not given due to erratic
oral availability significant variable first pass effect from
person to person and have intraspecies effect (same dose will vary in person day to day)
IV morphine acts promptly and its main effect is at the CNS
CNS is primary site of action of morphine
analgesia sedation euphoria mood change mental cloudiness
Morphine analgesia
**Changes our reaction and our perception of pain severe cancer pain is tolerated more when person is
given morphine relieves all types of pain, but most effective against
continuous dull aching pain sharp, stabbing, shooting pain also relieved by
morphine
Morphine given to a pain free individual first experience is dysphoric not experienced in person in pain
Morphine sedation - morphine causes sedation effect, but no loss of consciousness
Morphine euphoria sense of well being reason why morphine is abused
Effects of morphine on respiration
There is a primary and continuous depression of respiration related to dose
decrease rate decrease volume decrease tidal exchange
mu receptor activation produces respiratory depression; with increase in dose can cause further respiratory depression
CNS becomes less responsive to pCO2 thereby causing a build up of CO2 rhythm and responsiveness causes irregular
breathing patterns; one will see periods of apnea
nausea and vomiting – Stimuation of CTZ, in area postrema of medulla
stimulation by stretch receptors causes nausea and vomiting
has afferents from gut and ear involved in motion sickness
pupil size
morphine causes miosis (pinpoint pupils) kappa receptor effect pinpoint pupils still responsive to bright light oculomotor nerve (CN3) is stimulated by
kappa receptor site if kappa receptor is blocked, mydriasis from
sigma effect will result atropine partially blocks effect indicating
parasympathetic system involved
Acute overdose
High doses (overdose situation) of morphine
excitatory and spinal reflexes high doses of many OPIOID cause
convulsions due to stimulation at sigma receptor
Cardiovascular effects
Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure
morphine causes the release of histamine and
suppression of central adrenergic tone and
suppression of reflex vasoconstriction
Morphine effects on the gastrointestinal system
increase in tone and decrease in mobility leads to constipation
decreased concentration of HCl secretion increased tone in stomach, small intestine, and large
intestine
delay of passage of food (gastric contents) so more reabsorption of water
**tolerance does not develop (i.e. same amount of effect each time) to this constipation effect
Morphine effects on various smooth muscles
biliary tract marked increase in the pressure in the biliary tract 10 fold increase over normal (normal is 20 mm H20 pressure) increase due to contraction of Sphincter of Oddi
urinary bladder tone of detrusor muscle increased feel urinary urgency have urinary retention due to increased muscle tone where sphincter
closed off bronchial muscle
bronchoconstriction can result **contraindicated in asthmatics, particularly before surgery
uterus contraction of uterus can prolong labor
Neuroendocrine Effects
inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and b- endorphin; the last two peptides are usually released simultaneously from corticotrophs in the pituitary. As a result of the decreased concentrations of pituitary trophic hormones, the concentrations of testosterone and cortisol in plasma decline. Secretion of thyrotropin is relatively unaffected.
Tolerance to morphine
nausea analgesia sedation respiratory depression cardiovascular euphoric not to:
miosis constipation
Toxicity of morphine
acute overdoserespiratory depression pinpoint pupils (miosis) coma Treatment1. establish adequate ventilation
1a. 4 point restraints needed2. give OPIOID antagonist (naloxone)
Naloxone it has no agonist activity it displaces morphine from all receptors,
reverses all of the effects of morphine its effects are immediate (3-5 min) duration is 30-45 minutes must be
reinjected often
Therapeutic uses of morphine
relief of pain terminal illness preoperative medications postoperative medications acute pulmonary edema constipating effect cough obstetrical analgesia
Drug interactions with Opioids
**in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation)
OPIOID and phenothiazines produces an additive CNS depression as well as
enhancement of the actions of OPIOID (respiratory depression)
this combination may also produce a greater incidence of orthostatic hypotension
OPIOID and tricyclics antidepressants can produce increased hypotension meperidine and MOA inhibitors results in severe and immediate reactions that include
excitation, rigidity, hypertension, and severe respiratory depression
OPIOID and barbiturates increased clearance
morphine and amphetamine enhanced analgesic effect
Codeine change in the methyl group on 3 position (substituted for the
hydroxyl group) one tenth the potency (analgesic properties) of morphine absorbed readily from GI tract the absorption is more regular than morphine and more
predictable given orally metabolized like morphine through glucuronic acid physical dependence is necessity of drug so you don't go through
withdrawal tolerance and physical dependence is protracted from morphine
since potency of codeine is low withdrawal from codeine is mild in relation to morphine antitussive drug for cough
Heroin (diacetylmorphine) at 3 and 6 hydroxy positions, there are acetyl
groups instead of hydroxyl groups it is anywhere from 3 to 4 times the analgesic
potency of morphine heroin is the most lipophilic of all the OPIOID morphine is the least lipophilic of all the
OPIOID OPIOID withdrawal is NOT fatal
When heroin is ingested, it crosses the blood brain barrier rapidly (morphine crosses slow) where it is hydrolyzed to monoacetyl morphine (acetyl group got cleaved off) and then it is hydrolyzed to morphine making more of the drug in the brain making it 3 to 4 times more potent
withdrawal symptoms of heroin similar to morphine, but more intense (rebound effect) mydriasis diarrhea vasoconstriction dysphoria etc.
Hydromorphone (trade name is dilaudid) have ketone at 6 hydroxyl position of morphine also strong agonist 9 times more potent than morphine more sedation than morphine so less euphoric feeling
so not abused much less constipation does not produce miosis tolerance and physical dependence is more intense
than morphine because of its high potency respiratory depression same as morphine
Fentanyl (Sublimaze) synthetic drug different structure than morphine 80 to 100 times more potent than morphine rapidly acting drug used as preoperative medication short acting (30-45 min) onset of action is 5 minutes very high potency highly abused ,known as china white as street name
Meperidine produced in 1940's
wanted drug with less addictive liability than morphine, but it has same addictive liability as morphine
same CNS actions as morphine sedation, analgesia, respiratory
depression potency same as morphine
unlike morphine: more respiratory depression more bronchoconstriction activity less constipation no antitussive activity **it causes mydriasis (not miosis) toxic effects similar to atropine
dry as a bone, blind as a bat, red as a beet, mad as a hatter have dry mouth
drug absorbed orally drug most abused by health care professionlas due to its
availability withdrawal similar to morphine
Methadone pharmacological activity similar to morphine,
same potency as morphine long duration of activity absorbed well orally 16 to 20 hour duration of action powerful pain reliever used in maintenance program for narcotic
treatment
Diphenoxylate (Lomotil) can be OTC drug now **therapeutic use is antidiarrhea drug (treats diarrhea) meperidine type drug has very little analgesic properties at therapeutic dose no antitussive effect at high doses it has analgesic problems causes respiratory depression and euphoria at high
doses
Antagonism of Morphine
two drugs: naloxone and naltrexone (pure antagonist)
Naloxone no analgesic activity at all competitive antagonist at mu, kappa, and sigma receptor displaces morphine and other OPIOID from receptor site reverses all actions of the OPIOID and does it rather
quickly it will precipitate withdrawal person on heroin, then naloxone will precipitate withdrawal,
but naloxone effects are seen in the first five minutes and it only lasts for 30 minutes:
increased blood pressure metabolized same as morphine through glucuronic acid and
excreted through kidney
Naltrexone same effect of naloxone except it is used orally so
can't use it if for person with acute toxicity long duration of activity single dose block action of heroin effects for 24 hours used for emergency treatment once stabilized, give patient naltrexone patient get no euphoric effect from heroin so person
gets off heroin (negative reinforcement) approved for use by the FDA also used for treatment of alcoholism