[Ref: SH(H)4:p90]
??? Not mentioned pethidine, diamorphine
Need more details on tramadol
The prototype opioid agonist
NB:
Conjugation with glucuronic acid in hepatic and extrahepatic sites (especially the kidneys)
* May be impaired by monoamine oxidse inhibitor
Renal metabolism is significant
* No decrease in systemic clearance in hepatic cirrhosis
In renal failure, elimination of metabolites is impaired
--> Accumulation of metabolite
--> Increased risk of ventilation depression
75-85% appear as morphine-3-glucuronide
* Inactive
5-10% appear as morphine-6-glucuronide
* Active --> can cause analgesia and ventilation depression
Unlikely to cause myocardial depression
Possible impairment of compensatory sympathetic response
--> Orthostatic hypotension
Morphine-induced hypotension can also occur from
* Bradycardia
* Histamine release
Dose-dependent ventilation depression
Via agonist effect at mu2 receptors
--> Depressant effect on brainstem ventilatory centres
--> Decreased respons to carbon dioxide
--> CO2 response curve displaced to the right
Ventilation depression
--> Decreased frequency
--> Compensatory increase in tidal volume
--> But overall minute volume still decrease
Factors which increase the ventilatory depressant effect
* Advanced age
* Natural sleep
Factors which decrease the ventilatory depressant effect
* Surgical stimulus
Cough reflex is depressed via actions on medullary cough centres
Codeine and dextromethorphan are used for this purpose
Opioids decrease cerebral blood flow and possibly ICP in absence of hypoventilation
But use with caution in head injury because
* Sedation effect
* Production of miosis
* Ventilatory depression (increased PaCO2 increases ICP)
Sedation often precedes the onset of analgesia
Opioids directly stimulates the chemoreceptor trigger zone in the floor of the 4th ventricle
May also have a vestibular component
--> Movement can exacerbate nausea
Skeletal muscle rigidity is common after large and rapid IV opioids
Common in the thoracic and abdominal muscles
Thus,
If large doses of opioid (e.g. fentanyl or sufentanil) is used as induction agent
--> Possible rigidity of chest
--> Difficulty in IPPV
Opioid can cause spasm of biliary smooth muscle
--> Increased intrabiliary pressure
--> Can trigger biliary colic
Spasm of GIT smooth muscles
* Constipation
* Biliary colic
* Delayed gastric emptying
Morphine can increase the tone and peristaltic activity of the ureter
Cutaneous blood vessel dilation in the face, neck, and upper chest
Opioids can be transfered to the fetus
--> Possible depression of the neonate
Prolonged exposure and abrupt withdrawal may induce immunosuppression
Ventilatory depressant effect is exaggerated by
Onset = 6-18 hours
Peak intensity = 36-72 hours
Duration = 7-10 days
Triad:
Other S&S:
650-fold more potent in analgesic effect than morphine
Binds to mu receptor with similar affinity as morphine
Synthetic opioid agonist at mu and kappa receptor
Analogs include:
Structurally similar to atropine
--> Mild atropine-like antispasmodic effect
Meperidine
--> (Demethylation)
--> Normeperidine
--> (Hydrolysis)
--> Meperidinic acid
Normeperidine has 1/2 analgesic potency as meperidine
* But also cause CNS stimulation (myoclonus seizures)
Similar to morphine, except:
Phenyl piperidine-derivative synthetic opioid agonist
* Structurally related to meperidine
In comparison with morphine:
With multiple doses or infusion
--> Progressive saturation of inactive tissues
--> Duration of action prolonged
* Context-sensitive half-time increases after infusion is over 2 hours
Metabolite = norfentanyl
* Minimal pharmacological action
Similar to morphine, except:
Thienyl analog of fentanyl
Analgesic potency is 5-10 times of fentanyl
* Due to greater affinity for opioid receptors
Thus,
Short duration due to rapid redistribution
--> Multiple doses saturate inactive tissues
--> Longer duration of action
(N-dealkylation)
--> Inactive metabolite
Shorter context sensitive half-time than alfentanil (60min) due to larger Vd
* Sufentanil = 123L
* Alfentanil = 27L
0.1-0.4 microgram/kg IV
--> Longer analgesia and less ventilation depression than fentanyl (1-4microgram/kg IV)
Analog of fentanyl
Efficient hepatic metabolism
--> 96% clearance within 60min
Most likely CYP3A4 involved
Noralfentanil is the major metabolite recovered in urine
Blunting of CVS response to direct laryngoscopy
* 15 microgram/kg IV 90 seconds before
Induction of anaesthesia
* 150-300 microgram/kg IV
* Production of unconsciousness in 45 seconds
Selective mu receptor agonist
Structurally unique because of the ester linkage
Therefore,
Susceptible to hydrolysis by
* Nonspecific plasma esterase, and
* Tissue esterase
Thus
Due to:
Thus remifentanil has minimal cumulative effect
Metabolism is by nonspecific plasma esterase and tissue esterase
Not by pseudocholinesterase
--> Not affected by cholinesterase difficiency or anticholinergics
Very little variability between individuals
--> Very predictable effect
Post-operatively, analgesic requirement is larger
--> Possible acute opioid tolerance
Not all data support acute opioid tolerance following remifentanil-based anaesthesia
Substitution of a methyl group for the hydroxyl group on carbon 3 of morphine
Effective antitussive
* PO 15mg
Maximal analgesia occurs at 60mg
* Similar to 650mg of aspirin
Alternative to morphine for moderate to severe pain
10 times more potent than morphine
Cause more nausea and vomiting
Great risk of physical dependence
Provides stable plasma concentration
Used for treatment of moderate to severe pain
Abuse potential is high
For treatment of chronic pain
Abuse potential is high
Synthetic opioid agonist
Highly effective by PO route
Low abuse potential
Some action on NMDA receptor
Centrally acting analgesic
Moderate affinity for mu receptor
Weak affinity for kappa and delta receptors
5 to 10 times less potent than morphine as an analgesic
Absence of depression of ventilation
Low potential for development of tolerance, dependence, and abuse
Treatment of moderate to severe pain
* 3 mg/kg PO,IV, IM
Synthetic opioid
Acetylation of morphine
--> Diacetylmorphine
Rapid penetration into CNS
--> (Hydrolysis)
--> Monoacetylmorphine and morphine (both active)