2011A06 Write a brief outline on the pharmacology of remifentanil.

List:

· PC

· PK

· PD

Physicochemical:

Structure/class	· Synthetic opioid · Phenylpiperidine derivative · Ester linkage
Presentation	· Lyophillised white powder remifentanil HCl · Reconstituted with saline · Glycine additive (hence not for intrathecal use)

Pharmacokinetic:

Administration	· Bolus 0.5-1mcg/kg for induction or intubation · Infusion 0.025-0.2mcg/kg/min · Infusion TCI Ce 2-6ng/mL (e.g. Minto model)
Time course	· Onset: <1 min · Peak: 1.8 mins · Duration: 3-5mins (rapid metabolism)
Absorption	· Oral bioav low
Distribution	· Rapid effect site equilibration, t1/2ke0 1.5 mins o Moderate lipid solubility 20x morphine o Weak base pKa 7.1, 68% unionised at pH 7.4, plasma protein binding 70% · Very small VDSS 0.3L/kg
Metabolism	· Hydrolyis by non-specific esterases in plasma and muscle · i.e. multicompartment and organ-independent · Fast Cl 40mL/kg/min · ↑Cl + ↓VDSS = short t1/2β 10 mins · Carboxylic acid metabolite 1/1000 as active
Excretion	· Metabolites -> urine

Dynamics:

Mechanism	· Pure μ opioid receptor agonist
Analgesic effect	· Supraspinal (e.g. PAG): inhibit OFF cell -> disinhibit ON cell -> ↑descending modulation via noradrenaline and serotonin -> pre-synaptic inhibition at dorsal horn · Spinal (dorsal horn): pre-synaptic inhibition of nociceptors · Risk of severe pain when infusion ceased · Risk of hyperalgaesia and tolerance if prolonged, high dose infusion
Other CNS effects	· Sedation (M receptors in the medulla) +/- unconsciousness · Miosis: (M receptor in CNIII EW nucleus) · Euphoria, dysphoria, hallucination
CVS effects	· ↓SNS output from medulla, ↑PSNS output via CNX · ↓HR, +/- arrest if bolus (Rx atropine) · ↓SVR, ↓mAP
Respiratory effects	· Respiratory centre depression: o Decreased RR more than VT o Apnoea if bolused · Airway reflex depression, anti-tussive · Chest wall rigidity if bolused o M receptor on GABA-ergic neurons in basal ganglia o May herald unconsciousness o Rx: paralysis
Other	· Most other opioid side effects uncommon due to o Used primarily under GA o Rapid offset · ↓GIT motility · Urinary retention · ↓Immune function · ↓Hypothalamic/pituitary function -> hypogonadism, osteoporosis
Indications/use	· TIVA with propofol · Synergistic adjunct to propofol or volatile anaesthetic o Reduces nociceptive activation of reticular activating system o Hence ↓MAC, ↓Cp50 propofol · ETT tolerance: o Facilitate intubation without paralysis (e.g. neuromuscular disorder) o Cough free emergence (if high risk of secondary bleeding) · Reduce bleeding in sinus surgery · Facilitate rapid emergence up for neurological assessment (e.g. with desflurane) · PCA for labour analgesia (rapid onset and offset, minimal effect on foetus)