Opiods Flashcards
Full agonist analgesics
Methadone
Heroin
Fentanyl
Morphine
Codeine
Partial and “mixed” agonists
Buprenorphine
Nalbuphine
Antagonists
Naloxone
Naltrexone
Methylnaltrexone
What is an analgesic
drug that relieves pain
Endorphins
“endogenous morphines”
begin with an enkephalin motif (Tyr-Gly-Gly-Phe-) (required for activity at the opioid receptors)
enkephalins
Derived from preproenkephalin and proopiomelanocortin
Act at delta and mu receptors
Actions similar to morphine, both analgesia and addiction
Short-lived, having mainly the minimal required structure
Found in brain, adrenal medulla, gut, immune system
Regulate pain pathways, emotions (particularly anxiety), GI tract, immune system
dynorphins
Dynorphin A and B and neoendorphins α and β, larger peptides
Derived from prodynorphin
Act at mu, kappa, and NOP receptors
CNS localization and released in response to pain
Longer-acting analgesia than the enkephalins
endorphins
Mainly β-endorphin
Larger peptide, 31 amino acids
Derived from proopiomelanocortin (POMC)
Acts at kappa, mu, delta receptors
Found in brain, pituitary, adrenal medulla
The longest-acting of the endogenous peptides
Endomorphins and Nociceptin/Orphanin FQ
The other members of this peptide family Physiological roles not yet clear
The spectrum of opioid effects
All mediated by morphine
CNS effects
a. Analgesia, spinal or supra-spinal
b. Euphoria
c. Sedation
d. Respiratory depression (a limiting side effect)
e. Cough suppression (another use)
f. Miosis (very useful for diagnosis of overdose)
g. Truncal rigidity (chest and abdominal muscles)
h. Nausea and vomiting
i. Body temperature changes
j. Sleep effects
Peripheral organ effects
a. CV system – some bradycardia
b. GI system – constipation
c. Biliary tract – constriction, biliary colic
d. Renal – decreased function, multiple components
e. Uterus – may prolong labor
f. Endocrine
- increased ADH (decreased urine output)
- increased prolactin, somatostatin
- decreased LH (low T in males, dysmenorrhea or amenorrhea in females)
g. Skin – pruritis; flushing, itching; in part due to histamine release
h. Immune system – one source of opioids endogenously; very complex effects
Opiate
a compound purified from the juice or resin of the opium poppy
Opioid
any compound with actions similar to the opiates and act at opioid receptors
Narcotic
from the word for sleep; often used in connection with opioids; but now generally refers to illegal use and/or addiction; of opioids or most any other addictive and/or illegal drugs
Opioid receptors, mechanisms, effects
All are agonists at specific G protein-coupled receptors, termed the opiate receptors
Mu receptors
Mediate morphine-like actions
- analgesia, sedation, anti-anxiety, euphoria, dependence
- respiratory depression, slowed GI transit
Expressed in CNS, spinal cord, periphery
.
Kappa receptors
Mediate pentazocine-like actions
- analgesia, sedation, dependence
- dysphoria, hallucinations, miosis
Expressed in CNS, spinal cord
Delta receptors
Mediate dynorphin-like actions
- analgesia, euphoria, dependence, tolerance
Expressed in CNS, periphery
NOP receptors
Nociceptin/orphanin FQ receptors, the “newest” set of receptors
Respond to the endogenous peptide nociceptin, aka orphanin FQ
But only weakly to most opioid analgesics
Not currently a clinical target, but much research
Morphine mainly acts at
mu and kappa receptors
All full agonist opioid analgesics act at
mu receptors
Mechanisms for opioid analgesia
- Inhibition of pain signaling
- Acts at both peripheral and spinal levels to block pain transmission
- Pro-analgesic effects
- Acts at higher brain levels to block response to pain - Multiple specific neuronal pathways and brain regions involved
- Beyond the scope of this course
Tolerance
“desensitization” of opioid receptors
need increasingly larger amounts of drug for some effect
Dependence
need drug to feel normal
Withdrawal
the unpleasant responses that a drug-dependent person experiences if the
drug is NOT continuously available and used
Addiction and abuse
“psychological dependence” in addition to “pharmacological” dependence
“Opioid Abuse Epidemic”
“physician-driven” epidemic; opioids over-prescribed
Morphine
gold standard drug
oral administration
pain relief in 5-15 min (primarily for acute pain)
max effect in 60-90 min
4-5 hour duration
contin= continued release
IR=immediate release
ER= extended release
blocks pain transmission at spinal levels
acts at higher levels to block response to pain
raises pain threshold
Overdose, nausea, vomiting, constipation (little or no tolerance), miosis (no tolerance), pruritus,
cannot be used in patients with decreased respiratory reserve, head injuries, CNS tumors, pregnancy
Drug interactions: CNS depressants
Codeine
only given orally for mild to moderate pain (often given with acetaminophen)
also used for cough impression
less potent than morphine
metabolized by CYP2D6
analgesia
Converted to morphine
More likely to cause constipation than morphine
Less addicting than morphine (schedule II drug, mixed into soda)
some patients are ultra-rapid metabolizers (concerning in children)
Fentanyl
synthetic opioid
extremely potent analgesic (chronic pain, anesthesia, CV surgery)
Schedule II drug
more rapid onset than morphine and longer duration
multiple routes of administration
no histamine release
truncal rigidity
high addiction/abuse potential
Heroin
more potent than morphine
more rapid CNS entry
shorter acting
extremely high abuse and addiction potential
schedule I drug (no approved uses
Methadone
synthetic opioid (long-lasting analgesic)
unrelated to morphine or codeine
oral or IM at low dose
slow metabolism by CYP2B6 and CYP3A4
Schedule II
CV effects (QT prolongation)
major use for opioid abuse
methadone maintenance therapy (slow onset, high oral potency, long duration
Partial agonist opioids
agonists when given alone
act as antagonists when on board with full agonists
Mixed agonist-antagonist
Agonists at one receptor type
antagonists at another receptor type
drug class unique to opioids
Nalbuphine
kappa receptor agonist (analgesic component)
mu receptor antagonist (avoid respiratory depression)
no oral admin due to rapid first-pass metabolism
similar potency to morphine
15 minute onset with 4-5 hour duration
Buprenorphine
partial agonist at mu receptors (celing on respiratory depression)
antagonist at kappa receptor
mu receptor analgesia without kappa receptor side effects
opposite of nalbuphine
Schedule III drug
no oral admin due to rapid first-pass metabolism
used to treat opioid dependence and cocaine abuse
precipitates withdrawal symptoms in people using full agonists
Loperamide
anti-diarrheal
full agonist
orally admin
NO CNS action (not an analgesic)
not a scheduled drug
Diphenoxylate
ainti-diarrheal
Schedule V
prescription-only (high doses may cause opioid effects)
Dextromethorphan
used for cough (antitussive effects like codeine)
not an analgesic
acts on opioid receptors
Naloxone
prototype opioid antagonist counteracts opioid effects such as respiratory depression (only due to opioids)
treatment of acute opioid overdose (respiratory depression, miosis, coma)
binds partial agonist agents
given IV (not potent orally)
rapid-acting but short duration
will cause withdrawal
Naloxone
prototype opioid antagonist counteracts opioid effects such as respiratory depression (only due to opioids)
treatment of acute opioid overdose (respiratory depression, miosis, coma)
binds partial agonist agents
given IV (not potent orally)
rapid-acting but short duration
will cause withdrawal
Naltrexone
more orally effective and longer duration of action than naloxone
used to treat opioid dependence
used to prevent effects of opioids so they won’t be used
used to treat alcohol dependence
Methylnaltrexone
treatment of opioid-induced constipation
drugs given with naloxone
morphine
oxycodone
buprenorphine
