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NMBs & anticholinesterases

Where every drug acts along the acetylcholine pathway, the relaxants themselves, reversal agents, and the anticholinergics that must accompany them.

The acetylcholine pathway — and what blocks each step

Choline + acetyl CoA → (choline acetyltransferase) → ACh → released → acts on receptor → broken down by acetylcholinesterase in the synaptic cleft into choline and acetic acid.

Step	Drugs acting here	Effect
1. Preventing ACh synthesis	Hemicholinium	Blocks choline uptake into the nerve terminal
2. Preventing ACh release	Magnesium ions · aminoglycosides · botulinum toxin	Mg and aminoglycosides inhibit presynaptic calcium entry. Botulinum irreversibly binds the nerve terminal
3. Depleting ACh stores	Tetanus toxin	Depletes vesicular stores
4. Blocking the ACh receptor	Non-depolarising NMBAs (competitive) Depolarising NMBA — suxamethonium	Non-depolarisers compete; suxamethonium binds and persistently depolarises
5. Inhibiting acetylcholinesterase	Neostigmine, edrophonium, pyridostigmine, physostigmine, organophosphates	↑ ACh levels by reducing breakdown — the basis of reversal

Suxamethonium

The only depolarising agent in use. It binds the ACh receptor as a non-competitive agonist, causing persistent depolarisation.
Broken down by plasma cholinesterase — NOT by junctional acetylcholinesterase.
Because anticholinesterases raise ACh levels, giving neostigmine during a suxamethonium block prolongs it rather than reversing it.
Suxamethonium duration is prolonged by: magnesium, echothiophate, neostigmine and organophosphates — all of which inhibit plasma cholinesterase or raise ACh.
It is a malignant hyperthermia trigger, along with all volatile agents.

Dibucaine number	Genotype	Block duration	Frequency
~80 (70–80)	Normal homozygote (Eu Eu)	2–5 min	Normal population
50–60 (30–70)	Heterozygote (Eu Ea)	20–30 min	~1 in 25
<30 (~20)	Atypical homozygote (Ea Ea)	2–3 hours	~1 in 3000

The dibucaine number measures enzyme QUALITY, not quantity — it is the percentage inhibition of the enzyme by dibucaine.

Non-depolarising relaxants

All are water soluble, and all are competitive antagonists at the NMJ, binding the α subunit of the nicotinic receptor on the post-junctional membrane.

	Aminosteroids	Benzylisoquinoliniums
Members	Vecuronium (intermediate) Rocuronium (intermediate) Pancuronium (long)	Atracurium (intermediate) Mivacurium (short) Tubocurarine (long)
Histamine release	No histamine release	Atracurium and mivacurium release histamine; cisatracurium does not
Metabolism	Hepatic / biliary (vecuronium, rocuronium); pancuronium largely renal	Atracurium: Hofmann elimination + ester hydrolysis. Mivacurium: plasma cholinesterase
Reversed by sugammadex	Yes	No

Rocuronium doses

Standard intubating dose 0.6 mg/kg — onset about 3 minutes.
RSI dose 1.2 mg/kg — onset comparable to suxamethonium.
The 1.2 mg/kg RSI dose is only a safe strategy because it can be rapidly reversed with sugammadex 16 mg/kg.

Factors potentiating non-depolarising block

Magnesium and aminoglycosides (both reduce presynaptic ACh release), volatile agents, hypothermia, acidosis, hypokalaemia, lithium, calcium channel blockers, and myasthenia gravis.

Anticholinesterases

They antagonise the acetylcholinesterase enzyme at the NMJ, raising ACh levels by reducing its breakdown — so more ACh competes with the non-depolariser at the receptor.

Type of bond	Drug	Use	Crosses BBB?
Competitive / reversible	Edrophonium	Diagnosis of myasthenia (Tensilon test)	No — quaternary
Carbamylated complex	Neostigmine	Reversal of neuromuscular block	No — quaternary
	Pyridostigmine	Maintenance treatment of myasthenia	No — quaternary
	Physostigmine	Central anticholinergic syndrome	YES — tertiary amine
Irreversible	Rivastigmine, galantamine	Treatment of Alzheimer's disease	Yes
Irreversible	Organophosphates	Poisoning — treated with pralidoxime	Yes

Why an antimuscarinic must always accompany them

Anticholinesterases raise ACh at muscarinic receptors too, producing bradycardia, bronchospasm, arrhythmias, nausea and vomiting, ↑salivation, ↑gut motility, abdominal cramps and miosis.
So always give an anticholinergic with them — glycopyrrolate with neostigmine, atropine with edrophonium.
Neostigmine has a ceiling effect: once all the enzyme is inhibited, no further reversal is possible. It cannot reverse a profound block.

Sugammadex doses and speed

2 mg/kg — shallow block (reappearance of T2) — reversal in about 2 minutes.
4 mg/kg — deep block (post-tetanic count 1–2) — about 3 minutes.
16 mg/kg — immediate reversal after 1.2 mg/kg rocuronium — about 1.5 minutes.
It is a modified γ-cyclodextrin that encapsulates the drug. It works on aminosteroids only.

Anticholinergics

Atropine, glycopyrrolate, hyoscine (scopolamine) and ipratropium. All block muscarinic ACh receptors — they are parasympatholytic and vagolytic. Note they do NOT raise ACh levels; they block its effect.

Effect	Anticholinergic (blocks ACh)	Anticholinesterase (raises ACh)
Secretions	Dry	Wet
Heart rate	Fast	Slow
Pupils	Dilated (mydriasis)	Constricted (miosis)
Airway	Bronchodilation	Bronchospasm

Getting the terminology straight

Vagolytic = blocks the vagus = ↑heart rate → atropine.
Parasympathomimetic = ↑parasympathetic = ↑ACh → neostigmine.
Parasympatholytic = ↓ACh effect = blockade → atropine.
Sympathomimetic = adrenergic agonists.
Sympatholytic = β blockers, α blockers, α₂ agonists.

Other anticholinergic effects

Mydriasis and cycloplegia · bronchodilation · reduced secretions · urinary retention · reduced gut motility.
Atropine is a tertiary amine and crosses the blood–brain barrier — hence central anticholinergic syndrome, treated with physostigmine.
Glycopyrrolate is quaternary and does not cross — making it the safer choice in the elderly, and the better antisialogogue.

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