Pholcodine is an opioid anti-tussive (ie. cough suppressant). It is a common component of over-the-counter cough medications. However it has a special significance to anesthesiologists in relation to anaphylaxis risk, particularly related to neuromuscular agents.
Florvaag et al's 2009 review covers this issue very comprehensively. Earlier 2006 research from Florvaag et al attempting to explain some of the regional variability in anaphylaxis rates showed that exposure to pholcodine causes an 60-105 times increase in IgE levels!
Countries where pholcodine use is common (eg Norway) seem to have experienced higher levels of anaphylaxis to neuromuscular blocking agents than countries where it is not common (eg Sweden). In fact, in Norway rocuronium anaphylaxis was such a problem that its use was restricted to modified rapid sequence inductions. A pholcodine containing cough syrup has been withdrawn from the market in Norway because of this (and levels of sensitisation seem to be dropping although it is still too early to draw conclusions). It will be interesting to see if there are other compounds that have a similar effect on IgE sensitisation and whether other countries will consider withdrawing pholcodine products.
In addition to the two articles from Florvaag that specifically look at Pholcodine and it's effects, there is also an interesting review looking at recent insights into anaphylaxis in the anaesthetic setting from Dewachter and team.
Also interesting is Lee et al.'s 2016 case report describing two patients with pholcodine anaphylaxis who then when tested also showed NMBD sensitivity.
Helen Crilly & Michael Rose's 2014 review in Australian Prescriber Anaphylaxis and anaesthesia – can treating a cough kill? is another great summary of the issue.summary
...and 2 more notes
Suxamethonium chloride (suxamethonium, succinylcholine or sux) is a depolarising muscle relaxant that produces rapid-onset, short-duration, deep muscle relaxation. First identified in 1906 and used medically in 1951, it is one of the oldest anaesthesia drugs still widely used. Due to its unique properties and low cost, it remains on the World Health Organisation's List of Essential Medicines
- pH 3.5
- Shelf life 3 years at 4°C, though only 'months' at 20°C.
- Dose - ED95 0.5 mg/kg, IV 1.5 mg/kg, IM 2.5-4 mg/kg.
- Absorption - IM, IV.
- Distribution - >0.2 L/kg; crosses placenta slightly but little effect on foetus.
- Protein binding ?
- Onset 30s IV, 2-3 min IM; Offset 3-5 min.
- Metabolism - PChE to succinylmonocholine (5% activity) & choline -> succinic acid & choline.
- tß½ 5 minutes
- Mechanism - binds to alpha subunit of nicotinic ACh receptor, producing persistent depolarisation (phase 1 & phase 2 blocks).
- CNS - ⇡ intra-ocular pressure (4-8 mmHg rise), ⇡ intra-celebral pressure (to 30 mmHg at 2-4 min).
- CVS - arrhythmias (both bradycardia & tachycardia possible), ⇡ systolic blood pressure, (both negative inotropic and chronotropic effects).
- Resp - 'sux apnoea' pharmacogenetic diversity (94% normal, 3.8% heterozyg (10 min duration of effect), <1% homozog (1-2h duration))
- Renal - hyperkalaemia due to K+ release from muscle; beware in neuromuscular conditions, denervation, and extensive burns.
- GIT - ⇡ intragastric pressure, ⇡ secretions, salivation.
- SEs - anaphylaxis, malignant hyperthermia, sux apnoea, muscle pains, masseter spasm.
Pethidine (Meperidine) is a phenylpiperidine synthetic opioid first synthesized in 1938. Although widely used in the 20th century, it has fallen out of favour over the past decade due to abuse potential, limited advantages over other opioids and the existence of toxic metabolites.
- pKa - 8.5 (9% nonionised @ 7.4)
- Octanol water coefficient - 39 (so 40x lipid solubility of morphine)
- phenylpiperidine opioid
- Dose - 25-100 mg (10% morphine potency). Limit 1000 mg 1st day, then 600 mg/day there after.
- Absorption - IV, IM, epidural, po (55% biov)
- Distribution - Vdss 4.5 L/kg. Crosses placenta - foetal 80% of maternal.
- Protein binding - 60%
- Onset 10 min ; Offset 2-3 h
- Metabolism - ß½ 3 h; N-demethylation to norpethidine and then hydrolysis to norpethidinic acid; also direct hydrolysis to pethidinic acid. Renal elimination.
- Norpethidine - ß½ 15 h; 50% analgesic properties, 2x convulsant effects.
- Clearance - 20 mL/kg/min (same as morph & fentanyl)
- Mech - mu and kappa agonist, causing potent spinal and supraspinal analgesia.
- CNS - more euphoria, less N/V than morphine. No miosis, but may cause mydriasis (pupil dilation -atropine-like kappa action). No EEG changes like morphine. ⇡ latency & amplitude of SSEPs.
- NB: has LA action, so can be used as sole agent for neuroaxial block.
- anti-shivering effect (kappa)
- CVS - ⇣ MAP (> than morphine) due to histamine release & alpha adrenergic blockade (vasodilation). Inc HR (atropine like effect). Large doses depress myocardial contractility. May cause hypertensive crisis in those on MAOIs.
- depress myocardial contractility
- Resp - potent resp depressant - greater effect on TV than RR. Histamine release. Chest wall rigidity.