Opioid Agonists/antagonists Flashcards
Opioid receptor
Serpentine molecule embedded in cell membrane
- 1 terminal ending exposed to extracellular envi
- other terminus is intracellular
Types of opioid receptors
Mu, Kappa, Delta, Sigma
Presynaptic function of opioid receptors
Inhibits neurotransmitter release (ACh, Dopamine, norepinephrine, substance P, GABA)
postsynaptic function of opioid receptors
Decreases neuronal excitability through hyperpolarization of cell membranes
Mu receptor subtypes
Analgesia (supraspinal & spinal)
Euphoria, ventilatory depression, bradycardia, urinary retention, physical dependence
Kappa subtype receptors
Analgesia (supraspinal & spinal)
Dysphoria, sedation, miosis
Delta subtypes receptors
Analgesia (supraspinal & spinal)
Ventilatory depression, urinary retention, modulation of Mu activity
Tissues for receptor distribution
Brain
Spinal cord
GIT
UIT
Synovium
Leukocytes
Uterus
Pure opioid agonist binding affinity
Produces dose-dependent increase in effect until max stimulation of receptor achieved
Effect increases as dose (or plasma concentration) increases until it plateaus at max effect
Partial opioid agonist binding affinity
Binding at given receptors causes an effect that is less pronounced than that of a pure agonist
Produces dose-dependent increase in effect, but plateaus at max effect less than max effect of full agonist
Opioid agonist-antagonist binding affinity
Causes stimulators effect at one receptor but blocks effect or causes less pronounced effect at another
Effects of these drugs depends on previous opioid exposure
Opioid antagonist affinity
Binds to receptor with high affinity & produces no effect
- reverses receptor mediated effects of agonists by inhibiting binding of agonist & displacing previously bound agonist due to greater receptor affinity of antagonist (competitive binding)
Full agonist classifications
Morphine, hydromorphone , methadone, oxymorphone, fentanyl
Partial agonist classifications
Buprenophine
Agonist-antagonist classifications
Butorphanol
Antagonist classifications
Naloxone, nalmefene, naltrexone
Different potency
Ex fentanyl and morphine have different potency meaning one will act quicker with less drug
Different efficacy
Ex morphine and buprenophine
Drugs given at same amount will have greater or less effect than the other
PD absorption considerations
Lipophilic /absorption rate
Bioavailability via SQ & IM
Low oral bioavailability
Transdermal absorption - fentanyl bypasses GIT and skips first pass hepatic effects
Transmucosal absorption - buprenorphine by passes first pass metabolism, variable absorption
PD considerations - distribution
Morphine is hydrophilic
P-glycoprotein efflux pumps limit CNS effects
- limit BBB crossing
- ex loperamide ->reduced central effects
PD considerations - mutations
Homozygous mutation in MDR1 gene
- BC, Aussie, GS, shetlands, sheepdogs, whippets
- significant central effects
- morphine, methadone, fentanyl, buprenophine, oxycodone
PD considerations - metabolism & elimination
Metabolized through hepatic microsomal enzyme
Morphine - phase III glucuronidation to morphine-3-glucuronide (EXCEPTION, poor glucur, rapidly metabolizes morphine through sulfate conjugate
Elim through biliary or renal
^ elim time in geriatric
Remifentanil met is via plasma esterase
Which of the following best describes the opioid & classification?
Buprenophine - full Mu agonist
Methadone - partial Mu agonist
Fentanyl - Mu antagonist & K agonist
Oxymorphone - full Mu agonist
Oxymorphone - full mu agonist
CNS effects - analgesia
Inhibition of presynaptic NT release & post hyperpolarization of neuronal membranes = v excitability = v transmission within spinal cord
^^regulation of supraspinal descending antinociception pathways
- epidural = saturate spinal opioid receptors = effects on C-fibers & A-delta fiber nociceptors
Which opioid is more hydrophilic ?
Morphine
CNS effects - sedation
Dose-dependent sedation, more profound sedation w phenothiazines and alpha-2s
CNS effects - excitation
High does or rapid IV= excitation (^ plasma concentration quickly achieved)
Cats & horses can exhibit Dysphoric /excitatory behavior lasting few hours
CNS effects - dysphoria & euphoria
Vocalizing, thrashing, ataxia, hypersensitivity
CNS effects - thermoregulation
Hypo response: dogs, rabbits, birds (more profound w phenothiazines/inhalants)
Hyper response: cats, horses, rum, pigs
Cats: hydromorphone, morphine, buprenophine, butorphanol, up to 5 hours post extubation
Respiratory effects
Direct depression from brainstem
(Mediated by supraspinal Mu2 opioid receptors)
Decreased responsiveness to ^ CO2
Dose dependent resp depression
(Consider ICP, lung disease)
Antitussives effects
Panting
Opioids cross placenta = resp depression of neo
Cardiovascular effects - Bradycardia
Opioid induced medullary vagal stim
2nd degree atrioventricular block
Anti-muscarinics block/reverse this effect
Caution in young patients
-minimal effects of myocardial contractility, C output, arterial blood pressure (at clinical doses)
Peristaltic effects
Propulsion contractions decreased
- constipation, ileum, concerning in horses & rum
Non-propulsive contractions increased
- occasionally causing defecation
- dogs>cats
Endocrine effects
Histamine release - morphine, meperidine
Nausea & vomiting - direct stim of CTZ, IV<IM
Urinary effects
Mu effect - increases ADH & natriuretic peptide, v urine production
Kappa effect - decreases ADH, diuresis
Immune system effects
Morphine, fentanyl, codeine, methadone = Immunosuppression
Ocular effects
Dogs, rabbits, rats = miosis
Cats, horses, rum = mydriasis
Potential for substance abuse
Regulated substance
Tolerance & physical dependence
Opioid induced hyperalgesia
Gene expression affecting opioid metabolism
Process of selection opioids
Degree of pain
Duration of pain/procedure
Sedation requirement
Adverse effects
Specific species requirements/limits
Available routes of admin
Cost
Morphine
Analgesia, sedation, peak onset, side effects, routes
Analgesia - severe pain
sedation - excellent sedation
peak onset - 15-30 minutes, duration 3-4 hrs
side effects - histamine release, mania in cats/horses, vomiting, renal disease may impair clearance
routes - SQ, IM, IV, epidural
Hydromorphone
Analgesia, sedation, peak onset, side effects, routes
Analgesia - severe pain
sedation - good sedation
peak onset - 15 min, dur 4-6 hours
side effects - vomiting if IM, less histamine release, panting in dogs, hyperthermia in cats
routes - SQ, IM, IV
Methadone
Analgesia, sedation, peak onset, side effects, routes
Analgesia - severe
sedation - good
peak onset - 15, dur 4-6hr
side effects - no histamine release, no vomit, panting in dogs
routes - SQ, IM, IV
Fentanyl
Analgesia, sedation, peak onset, side effects, routes
Analgesia - severe
sedation - good
peak onset - 6-8 minutes, duration 30-60 minutes
side effects - no histamine, no vomiting, bradycardia, chest rigidity (v compliance)
routes - IM, IV, transdermal
Buprenorphine
Analgesia, sedation, peak onset, side effects, routes
Analgesia - mild to moderate
sedation - minimal
peak onset - 45-90 minutes, dur 6-8 hrs
side effects - high affinity for receptor, plateau effect, not effectively reversed w antagonist
routes - PO, Transmucosal, IM, IV
Butorphanol
Analgesia, sedation, peak onset, side effects, routes
Analgesia - mild
sedation - good
peak onset - 10-15 minutes, dur 1-2 hrs
side effects - high affinity for receptor, plateau effect, can reverser effect of pure Mu agonists
routes - SQ, IM, IV
Which of the following opioids should be avoided in a dog diagnosed w cutaneous & visceral mast cell tumors?
Buprenorphine
Methadone
Morphine
Oxymorphone
Morphine
Because of histamine release
Reasons and effects of reversing effects with antagonists
Opioid overdose or excessively sedated or obtunded from opioids
^ alertness, responsiveness, coordination, ^awareness of pain
Naloxone
Prototypical Mu antagonist
Onset: 2-5 min
0.01-0.04 mg/kg IV -> lasts 20-40 min
Opioid effects could reoccur
Nalmefene, naltrexone
4x as potent as Naloxone
Onset: 2-5 min
Duration: 1-2 hours
Methlynaltrexone
Quaternary derivative of naltrexone
Controls GIT side effects of opioids (ileus) without effecting centrally mediated analgesia
Considerations for clinical use
Systemic use
Regional or local admin
Parenteral sustained release
Injectable subcutaneous
Which is the best option in a cat that needs an abdominal explore, but also presented w hepatic and renal dysfunction?
Buprenorphine
Remifentanil
Methadone
Remifentanil - metabolized by plasma esterases
Oral opioids
Tramadol, codeine, hydrocodone
Tramadol with dogs & horses
Metabolized by O-desmethyltramadol (M1) via P450 enzymes which determines the strength of analgesia
Dogs & horses produce less M1 = weak analgesia
Cats produce substantial M1 = effective analgesia
