Opioids Flashcards
Describe the opioid receptors
3 major subtypes:
All opioid receptors:
• G protein-coupled (mainly Gi/Go)
• Share 55-58% sequence homology
• Widely distributed in CNS and periphery
δ (delta) receptors
• Most available agents are peptides and do not cross BBB
• Receptor activation produces analgesia in animal models
• Research is focused on developing clinically useful d agonists
κ (kappa) receptors
• Selective agonists produce analgesia mainly through spinal sites
• Produce miosis, ↓ GI motility (constipation), respiratory depression, dysphoria, disorientation, and depersonalization
μ (mu) receptors
• Clinically useful opioids act at this subtype
• Agonists produce analgesia, euphoria, respiratory depression, miosis, ↓ GI motility (constipation)
Define and name an opioid agonist, antagonist, partial agonist, and agonist-antagonist
Agonist (μ receptor activators; both full and partial)
o Strong: Morphine, Merperidine, Tramadol, Methadone, Hydromorphone, Fentanyl, Oxymorphone
o Partial: Codeine, Oxycodone, Dextromethorphan, Tramadol
Antagonist (receptor blockers)
o Naloxone, Naltrexone
Agonist-antagonist (capable of activating one opioid receptor subtype and blocking another)
o Buprenorphine
Morphine: Clinical uses
o Strong analgesic = relief of moderate-to-severe acute and chronic pain, preoperative sedation, and as a supplement to anesthesia; has also been used for analgesia during labor
o DOC for MI and cancer pain
Morphine: MOA
o Prototype strong agonist at μ receptors
o Weak agonist at δ and κ receptors
o Other clinical effects = cough suppression, hypotension, and nausea/vomiting
Morphine: adverse reactions & precautions
Adverse reactions:
Overdose
• Triad: pupillary constriction, comatose sate, respiratory depression
Drug interactions
• Additive CNS depression with ethanol, sedative-hypnotics, anesthetics, antipsychotic drugs, TCAs, antihistamines
• Use with MOAI’s → increased risk of hyperpyrexic coma
• Merperidine = indicated in serotonin syndrome when used with SSRIs
Precautions
o Pregnancy Risk Category C
o Increases to D if used for prolonged periods or high dose close to term
Describe the clinical importance of the bioconversion of morphine to morphine-6-glucuronide and morphine-3-glucuronide.
o Metabolized by hepatic enzymes:
• Morphine → morphine-6-glucuronide = analgesic activity like morphine
• Morphine → morphine-3-glucuronide (primary metabolite) = neuroexcitatory
Explain why codeine may not provide pain relief to some persons.
- Requires O-demethylation into morphine for analgesic activity
- Reaction occurs via CYP2D6 = Lots of genetic variability
- If patient has deficiency or inhibition of CYP2D6 = won’t be able to convert codeine into morphine → won’t get analgesic response
List the ACUTE symptoms of opioid intoxication and overdose
Analgesia = most powerful drugs available for pain relief
• MOA: do not alter the pain threshold of afferent nerve endings nor the conductance of impulses
• Instead: analgesia is mediated through changes in perception of pain at the spinal cord and higher levels in the CNS and the emotional response to pain
• There is no ceiling effect
Sedation and euphoria = may occur at doses lower than those required for maximum analgesia
Antitussive action (suppression of cough reflex) • Direct effect on cough center in medulla
GI effects:
• Constipation via decreased peristalsis
• Mediated by neurons in enteric nervous system
• Increases tone of circular muscles but decreases tone of longitudinal muscles
Respiratory depression:
• Inhibits respiratory center in medulla
• Most significant adverse effect of opioids
o Nausea/vomiting
• Activation of chemoreceptor trigger zone in medulla
Smooth muscle effects
• Contraction of biliary tract smooth muscle
• Increased ureteral and bladder sphincter tone
• Decreased uterine tone
• Miosis: characteristic of all opioids except meperidine (which has muscarinic blocking action)
Cholinergic effects (e.g. bradycardia) • Stimulation of medullary vagal nuclei
Pruritus and orthostatic hypotension
• Because opioids stimulate histamine release
Renal function is depressed
• Due to central (hypothalamic) and direct effects on kidney blood flow
Endocrine system
• Decreased production of LH → decreased libido, decrease in testosterone
• Women may experience amenorrhea and infertility and men may be unable to attain or maintain an erection
List the CHRONIC symptoms of opioid intoxication and overdose.
Tolerance: acquired drug insensitivity
• Decreased effectiveness with continuous or repeated agonist dosing
• Need to increase doses to maintain initial pain relief
• 10 mg of morphine IV = a standard starting dose for a treatment-naïve individual (whereas 100 mg IV may produce only minor sedation in a severely tolerant individual)
• Tolerance develops to all opioid effects except miosis and constipation
Cross-tolerance among μ-receptor agonists
• Can be partial or incomplete
• “Opioid rotation” dosing regimens can be beneficial in restoring analgesic effects
Dependence: Physical and psychological requirement for continued use
• State of adaptation manifested by a drug class-specific withdrawal syndrome (abstinence syndrome) produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, or administration of an antagonist
Addiction • Impaired control over drug use • Compulsive use • Craving • Continued use despite harm
Explain why naloxone can be used to treat an opioid analgesic overdose and describe the problems associated with the use of naloxone to treat methadone overdose.
- Pure competitive antagonist
* Precaution = can precipitate withdrawal syndrome in opioid-dependent people
List purported advantages of agonist-antagonist opioids compared to pure opioid agonists and factors that limit their usefulness.
Good
o Less analgesic activity
o Able to suppress withdrawal syndromes
o Less tolerance and dependence than full agonists
Bad o Long half-life = resistant to naloxone reversal • Respiratory depression o Sedation o Dizziness, sweating, nausea o Anxiety, hallucinations, nightmares
Explain how the pharmacology of buprenorphine and methadone make them useful agents for the treatment of opioid dependence.
Buprenorphine
o Partial μ agonist and κ antagonist
o Long duration of action
o Used to suppress withdrawal symptoms in dependency states
Methadone
o Full μ receptor agonist
o Outpatient treatment of opioid dependence
List the symptoms of opioid withdrawal, and treatments to address these symptoms.
Symptoms:
o Nausea, diarrhea, coughing, lacrimation, yawning, sneezing, rhinorrhea, diaphoresis, twitching muscles, abdominal and muscle pain and cramps, hot and cold flashes, and piloerection
o Without treatment, most symptoms resolve in 5-14 days
Newborn:
o Symptoms occur 1-4 days after birth
o Include: generalized tremors, hypertonicity with any form of tactile stimulus, hyperalertness, sleeplessness, excessive crying, vomiting, diarrhea, yawning, and fever
To avoid withdrawal symptoms = dose must be slowly tapered
o 10-20% decrease every 1-2 days will prevent withdrawal symptoms
o Alternately: give half the previous dose for the first 2 days, then reduce the dose by 25% every 2 days; when the dose reaches the equivalent of ~ 30 mg/day of PO morphine, this dose is given for 2 days, then DC the drug.
Clonidine 0.1-0.2 mg PO QID or by transdermal patch (provides 0.1 mg/ day for 7 days) can be used to treat autonomic hyperactivity symptoms
o An α2-agonist
