Opioid Narcotic Analesics And Related (Fitz) Flashcards
List generic names of soluble, bioavailable, opioid narcotic agonists used for analgesia/other indications
Codeine Fentanyl Heroin Hydrocodone Hydromorphone Meperidine Methadone Morphine Oxycodone Oxymorphone Tramadol
List generic names for opioid narcotic mu receptor antagonists used for management of opioid narcotic overdose/addiction/side effects
Naloxone
Naltrexone
Methyl naltrexone (GI specific)
List generic names of opioid partial agonists or mixed agonists/antagonists
Buprenorphine
Buprenorphine-naloxone
Pentazocine
List generic names of insoluble, poorly absorbed opioid receptor agonists used for diarrhea
Loperamide
Diphenoxylate
List generic names of most common opioid related anti-tussive agents (cough suppression)
Codeine
Dextromethorphan
Hydrocodone
What are the types of opioid receptors and their physiological ligands?
Ligands are peptides
Mu MOR: endorphins
Kappa KOR: dynorphins
Delta DOR: enkephalins, endorphins
Where are the opioid sites of action in the CNS/PNS?
Cortex and limbic system: thalamus and hypothalamus
Midbrain: periaqueductal gray
Medulla: reticular formation, locus ceruleus, raphe nuclei
Spinal cord: spinothalamic (mescencephalic, reticular tracts)
Describe the pain impulse at pre and post synaptic neurons. Describe opioid agonist-mediated signaling
Opioid receptors unoccupied
- Afferent sensory signal
- Increases Ca2+ influx (presynaptic)
- Increases glutamate discharge (presynaptic)
- Increases NMDA receptor-Na+ influx (postsynaptic)
Opioid agonist occupies opioid receptors
- Blunts afferent signal
- Blunts Ca2+ influx
- Blunts glutamate discharge
- Increases K+ efflux
Of the drugs that bind to mu opioid receptors, which are full agonists, partial agonists, and antagonists?
Full agonists:
Fentanyl
Morphine
Partial agonist/mixed
Buprenorphine
Mu/kappa mixed:
Pentazocine
Antagonist
Naloxone
Naltrexone
In detail, describe opioid binding and receptors
Opioids bind to G-protein-linked membrane receptors: mu, kappa, delta. Subtypes, splice variants confer diversity
Receptors are widely distributed throughout human body, including brain, spinal cord, gut, uterus, etc. Majority of clinically useful opioid analgesic drugs have significant agonist activity at mu receptors
Opioid receptors bind endogenous peptides and drugs
Describe the pain treatment ladder based on opioid-sparing rationale
Mild pain:
-NSAID, acetaminophen
Moderate/persisting/uncontrolled:
- Codeine
- Codeine-related +/- acetaminophen
- tramadol
Severe/persisting/uncontrolled:
- Morphine
- Fentanyl
- extended release forms
List analgesic mechs and clinical utility
Acetaminophen,NSAIDS
COX-1,-2
Tissue injury»acute or nerve injury
Opioids, prototype morphine
Mu receptor agonists
Tissue injury=acute stimuli>nerve injury
Anticonvulsant (gabapentin)
Ca2+ channel antagonists
Nerve injury>tissue injury=acute
Antidepressants (amitryptilene)
Reuptake inhibitor
Nerve injury>tissue injury»acute stimuli
What is the prototype mu agonist?
Morphine
Describe clinical effects of agonists acting on mu receptor MOR
Analgesia (supra-spinal) Euphoria CNS and respiratory depression Drug dependence Miosis (pupil contraction) GI, uterine motility
Describe clinical effects of agonists acting on kappa receptor KOR
Analgesia (spinal)
Sedation
Miosis
GI, uterine motility
Describe tolerance to morphine (mu agonist)
Tolerance: over time, for a given dose, response deteriorates, necessitating increase in dose or rotation to different opioid
-analgesia, euphoria, sedation, nausea, respiratory depression
No tolerance to
-miosis, constipation
Patient was recovering from surgery in post-anesthesia care unit (PACU). He had been receiving morphine IV for 2 hr for postsurgical pain. His resp rate was 7 per minute with shallow breaths. He did not respond to any stimuli
pH=7.15 (normal 7.4)
HCO3=22 (normal 24)
PaCO2=68 (normal 40).
Describe what happens with opioid and respiratory depression
- At baseline, pH7.4=normal
- Hypoventilation. Lungs retain CO2=retain acid
- CO2 contributes to H+ to blood - Rise in PaCO2=rise in H+
PH=7.15
Increase in CO2 + H2O H2CO3 Increase in H+ + HCO3
Describe morphine-induced respiration depression. Contraindciations to morphine?
Morphine (mu agonist) depress sensitivity to CO2
Dose-related drop of respiration rate (3-4/minute in severe toxicity), minute volume, tidal exchange
Contraindications:
- Brain injury
- Emphysema
What are clinical indications for morphine?
Post-operative pain
-procedures and surgery
Cancer pain
-primary and metastatic malignancy
Other pain
-Sickle cell crisis, trauma, severe diarrhea, dyspnea caused by pulmonary edema from left ventricular failure
What are the group 1 mu agonist opioid drugs?
Full agonists
Parenteral and oral
*Morphine
Methadone
Meperidine
Hydromorphone
Oxymorphone
Levorphanol
What are the group 2 mu agonist opioid drugs?
Full agonists
Short acting
*Fentanyl
Sufentanil
Remifentanyl
What are the group 3 mu agonist opioid drugs?
*Codeine-related
Hydrocodone
Oxycodone
In group 1, potency and bioavailability are important when switching from parenteral to oral dosing or rotating between opioids. They also dictate some of the clinical uses of these drugs.
Compare and contrast their equivalent dose and oral/parenteral potency ratios
Morphine: 10 mg dose and Low oral/parenteral potency ratio Methadone: 10 and high Meperidine: 60 and medium Hydromorphone: 1.5 and low Oxymorphone: 1.5 and low Levorphanol: 2-3 and high
Meperidine, hydromorphone, oxymorphone, and levorphanol differ from morphine in efficacy
Methadone and levorphanol have good oral bioavailability
Parenteral (IV, IM, SC, Patch, buccal) opioids have high bioavailability.
Oral morphine. First-pass metabolism. Poor bioavailability. Describe morphine’s metabolism breakdown
Morphine->UGT 1A1, UGT 2B7-> M-3-glucuronide, M-6-glucuronide (active metabolites)
Morphine->dehydrogenase->hydromorphone (active)
Morphine->CYP3A4->Normophine (inactive)
Describe characteristics of methadone
Mu agonist (full agonist)
Longer half-life (27 hrs vs morphine’s 2 hrs)
Better oral absorption/bioavailability (90% vs 20% morphine)
Useful for withdrawal/maintenance and detoxification
Describe cardiac effect of methadone
Can affect cardiac electrical conduction, producing QT-interval prolongation in acute overdose or during long-term methadone treatment
This effect is unrelated to its interaction with mu receptors
It delays cardiac repolarization by blocking flow of K+ ions through HERG channels (K+ channels)
Describe meperidine distinctions as mu agonist
Eye: pupil dilation (mydriasis)
Abuse difficult to detect via pinpoint pupils
Accordingly, those who abuse this drug can escape detection
Normeperidine, a toxic metabolite, accumulates and causes seizures
Describe group 2 mu agonists: short acting, high potency, full agonists
Sufentanil: kappa, delta, and mu agonists
Fentanyl, sufentanil, alfentanil, remifentanil are 100x more potent than morphine, methadone
Remifentanil: very short-acting
Describe remifentanil popularity
Group 2 mu, short acting, full agonist
Gaining popularity for analgesia for childbirth if regional analgesia is either contraindicated or not desired
It is metabolized by plasma and tissue esterases
Although it transfers across placenta, its rapid metabolism in fetus lowers risk for neonatal depression
Its rapid onset of action, within 1 minute following intravenous injection, is another advantage
Describe fentanyl: anesthesia and breakthrough pain
Strong group 2 mu agonist (meperidine analog) Used in anesthesia *Rapid onset & distribution (lipophilic) *Short duration of action (procedures) *Transmucosal (lollipop) Breakthrough pain (with morphine) *Transdermal patch delivery Slows onset and prolongs delvery
Caution: respiratory depression
*Abuse potential via heating patches
Describe codeine; moderate pain & cough
As a partial agonist at mu receptors, codeine has less potential for drug dependence & respiratory depression
Reliable oral absorption/bioavailability (50% vs 20% morphine)
*Analgesia - moderate pain
Some formulations contain acetaminophen
Anti-tussive: cough relief (mu-independent)
What drug is a safer antitussive agent than codeine?
Dextromethophan
It relieves cough independently of opioid receptors
Not analgesic
Not addictive
Why has codeine for pain relief following a tonsillectomy and/or adenoidectomy caused death in children with obstructive sleep apnea?
Codeine->CYP2D6->morphine
Ultrafast metabolizer: CYP2D6 gene duplication & ultrafast allele
-leads to life-threatening or fatal amounts morphine in body
Intermediate metabolizer: CYP2D6 heterozygous
Poor metabolizer: CYP2D6 gene deletion & slow allele
List drugs and their active metabolites
Morphine: M6G and M3G, hydropmorphone Heroin: Morphine Codeine: Morphine Oxycodone: oxymorphone Meperidien: normeperidine (toxic) Hydromorphone: None Oxymorphone: None Fentanyl: none
Describe opioids and the gut
Loperamide
Diphenoxylate
Anti-diarrheals
Interact with mu opioid receptors in gut
Poor solubility (limited risk of parenteral abuse)
Poor penetration of BBB (limited risk of dependence/toxicity)
Describe tramadol
*Moderate mu agonist
N-desmethyl active metabolite
Reliable oral absorption/bioavailabilty (70% vs 20% for morphine)
*Analgesia: moderate pain
*Inhibits catecholamine reuptake
Caution in patients in tricyclic or SRI anti-depressants
*Associated with seizures
Describe pentazocine
Mixed: kappa agonist plus mu partial agonist and delta antagonist
Supra-spinal analgesia
Can precipitate withdrawal (in abusers)
Side effects: tachycardia, hallucinations
Describe buprenorphine
Partial/mixed
Mu partial agonist plus kappa & delta antagonist
Analgesia
Can precipitate withdrawal (in abusers)
*office-based detox/maintenance in combination with naloxone
Describe heroin (illegal substance)
Di-acetylmorphine
Penetrates BBB rapidly->exaggerated euphoria->addiction liability
Describe addiction program compliance: % retention - 1 year
Methadone maintenance: 50-80%
Buprenorphine-naloxone: 40-50%
Naltrexone Maintenance: 10-20%
“Drug free”: 5-20%
What are signs of opioid analgesic overdose?
Respiratory rate
Describe mu receptor antagonists
Occupy but do not activate mu receptors Competitively inhibit (displace) heroin, morphine, fentanyl, etc (other mu agonists) from mu receptors *Antidote for opioid overdose
Describe naloxone
Can reverse coma and respiratory depression ~1 min after IV bolus
Depends on what opioid and what dose
Initial .04mg. If no response, then incremets to 15 mg
Short duration of action 1-2 hrs can lead to apparent relapse of overdose symtpoms
Antidotes for overdose can precipitate withdrawal
Describe naltrexone
Has a long duration of action (48 hrs for single dose orally) in overdose
Opioids increase smooth-muscle tone and inhibit coordinated peristalsis required for propulsion, which contributes to nausea and vomiting as well as constipation.
What strategies might work for opioid-induced side effects as constipation?
Methylnaltrexone
What is methylnaltrexone?
Quaternary derivative of naltrexone with restricted ability to cross BBB
It functions as a peripheral acting opioid antagonist, including actions on GI tract to inhibit opioid-induced decreased GI motility and delay in GI transit time, thereby decreasing opioid-induced constipation
Does not affect opioid analgesic effects or induce opioid withdrawal symptoms
