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

Structure/class

·   Synthetic opioid

·   Phenylpiperidine derivative

·   Ester linkage

Presentation

·   Lyophillised white powder remifentanil HCl

·   Reconstituted with saline

·   Glycine additive (hence not for intrathecal use)

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, t_1/2ke0 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 V_DSS 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 + ↓V_DSS = short t_1/2β 10 mins

·   Carboxylic acid metabolite 1/1000 as active

Excretion

·   Metabolites -> urine

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 V_T

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)