[Ref: SH(H)2:p81]
Levorotatory isomers are more active
Acts on stereospecific opioid receptors
* Only levorotatory forms have agonist activity
--> Increased K+ conductance and/or Ca2+ channel inactivation
--> Decreased neurotransmitter release
--> Decreased neurotransmission
NB:
Opioids need to be in ionized state to bind strongly to (anionic) opioid receptor site
Classified into mu, delta, and kappa receptors
* All G-protein coupled
Mu receptors are responsible for supraspinal and spinal anaesthesia
Administration of opioids by spinal or epidural (compared with IV administration)
* No sympathetic nervous system depression
* No skeletal muscle weakness
* No loss of proprioception
* More specific for visceral pain than somatic pain
Analgesia is produced by
* Diffusion across the dura, and
* Systemic absorption of the opioid
Penetration of the dura is dependent on the lipid solubility
* Fentanyl CSF level peak in 20min
* Sufentanil CSF level peak in 6 min
* Morphine CSF level peak in 1-4 hours
NB:
CSF ascends from lumbar region in cephalad direction
--> Reaching cisterna magna in 1-2 hours
--> Reaching 4th and lateral ventricle by 3-6 hours
Cough and straining affects CSF movement
Body position does not affect CSF movement
Often localized to face, neck, and upper thorax
Precede the onset of analgesia
In the case of neuraxial opioids, pruritis is not due to histamine release
--> Caused by interaction with opioid receptors in the trigeminal nucleus
Can be relieved by opioid antagonist (e.g. naloxone)
Antihistamine can help due to sedation effect
More common with neuraxial opioid administration
Interaction with opioid receptors in the sacral spinal cord
--> Inhibition of sacral parasympathetic nervous system outflow
--> Detrusor muscle relaxation
--> Increased maximum bladder capacity
--> Urinary retention
Early depression of ventilation occurs within 2 hours of neuraxial injection of opioid (fentanyl or sufentanil)
* Most likely from systemic absorption of opioid
* Cephalad migration of opioid in the CSF is also a possible cause
Clinically significant early depression of ventilation after intrathecal injection of morphine is unlikely
Delayed depression of ventilation after neuraxial opioid
--> Cephalad migration of opioid in CSF
--> Interaction with opioid receptors in the ventral medulla
After neuraxial administration of morphine (intrathecal or epidural)
--> Delayed depression of ventilation occurs 6-12 hours afterwards
Most reliable clinical sign of ventilation depression is
* Depressed level of consciousness
* Possibly caused by hypercapnia
Sedation
* Most commonly associated with sufentanil
CNS excitation
* Tonic skeletal muscle rigidity
* Common after large IV dose, but rare with neuraxial opioids
Viral reactivation
* Possible link between epidural morphine in obstetric patients and reactivation of herpes simplex labialis virus
Neonatal morbidity
* Systemic absorption leads to opioid build-up in neonates
GIT dysfunction
* Cause delayed gastric emptying
Thermoregulatory dysfunction
* Inhibition of shivering
--> Decreased body temperature
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Separate subtype
mu1, mu2, kappa 1,2,3, deta1,2
Possible from post-translational modification
Spinal opioids
Act preferentially on receptors in the dorsal horn
Analgesic effect through modulation of afferent sensory input via A-delta and C fibres
Some effect by rostral spread and action on supraspinal opioid receptors
Adverse effects
Pruritis (80%) but most do not complain
N&V
Resp depression
Pethidine has sodium channel blocking properties (like LA)
When used in spinal, creates acceptable block alone but can also cause hypotension
Tolerance - exposure to a drug results in the dimunution of effect or the need for a higher dose to maintain an effect
--> A shift to the right of the dose-response curve
Have a comparative overview of the opioid agonists in pharmacokinetics
Pethidine - high pKa
Fentanil - faster redistribution but slower elimination halftime than morphine
Sufentanil - very lipid soluble, very fast redistribution, accumulates, slow elimination half-time
Alfentanil - low pKa, very fast effect-site equilibration time, redistribution not significant, small Vd (context-sensitive halftime hits ceiling earlier than sufentanil), CSHT more variable due to P450 enzyme activity variance (CYP3A4)
Remifentanil - low pKa (not as low as alfentanil), rapid clearance, tight-concentration-effect relationship,
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volume of epidural space is reduced in elderly
compensatory mechanism are limited in elderly