Neuromuscular Pharmacology

What You'll Learn

MG pharmacotherapy — pyridostigmine (symptomatic), prednisone (may initially worsen), steroid-sparing agents, complement inhibitors (eculizumab), FcRn inhibitors (efgartigimod)
Myasthenic crisis — ICU monitoring, IVIG or PLEX; 20/30/40 rule: FVC <20 mL/kg, NIF |<30| cmH₂O (i.e., not more negative than −30), MEP <40 cmH₂O — intubate; avoid aminoglycosides/fluoroquinolones/magnesium
Drugs that worsen MG — aminoglycosides, fluoroquinolones, magnesium, beta-blockers, checkpoint inhibitors, telithromycin, D-penicillamine
Lambert-Eaton — 3,4-DAP (amifampridine) first-line; pyridostigmine less effective; treat underlying malignancy
Botulinum toxin — cleaves SNARE/SNAP-25, onset 3–7 days, duration ~3 months; used for dystonia, spasticity, chronic migraine, sialorrhea
NMJ blockers — succinylcholine (depolarizing, hyperkalemia risk) vs rocuronium/vecuronium (nondepolarizing, reversed by sugammadex)
Inflammatory myopathy Rx — prednisone first-line, steroid-sparing agents, IVIG (especially dermatomyositis); IBM has limited treatment response
Neuropathy treatments — CIDP (IVIG/PLEX/steroids), GBS (IVIG or PLEX — steroids NOT effective), neuropathic pain (duloxetine, pregabalin)

HighYield Pearls

Pyridostigmine in MuSK MG: often poorly tolerated / less effective — cholinergic hypersensitivity is the classic clue; immunotherapy (rituximab) is the actual workhorse.
Cholinergic crisis vs myasthenic crisis: excess pyridostigmine produces SLUDGE-M + fasciculations + miosis; edrophonium worsens cholinergic crisis — clinical context (recent dose, secretions) distinguishes.
Steroid-induced MG worsening: high-dose prednisone can transiently worsen MG in ~10–20% — bridge with IVIG or PLEX before starting in moderate-severe disease.
Eculizumab / ravulizumab / zilucoplan: meningococcal vaccination is MANDATORY ≥2 weeks before initiation — failure to vaccinate is a board-favorite error.
Azathioprine + TPMT: check TPMT activity BEFORE starting — deficient patients develop life-threatening myelosuppression.
Mycophenolate & methotrexate: both teratogenic — pregnancy is an absolute contraindication; counsel on contraception.
Drugs to AVOID in MG: aminoglycosides, fluoroquinolones, telithromycin (black-box), IV magnesium, β-blockers, immune checkpoint inhibitors (ICI-induced myasthenia/myocarditis/myositis overlap carries high mortality).
3,4-DAP (amifampridine) for LEMS: first-line — blocks presynaptic voltage-gated K⁺ channels → prolongs AP → ↑ Ca²⁺ influx → ↑ ACh release.
Tofersen: ONLY for SOD1-mutant ALS — intrathecal antisense oligonucleotide; not for sporadic ALS.
Deflazacort vs prednisone in DMD — less weight gain and behavioral effects, but MORE cataracts (monitor eyes); standard of care alongside exon-skipping ASOs (eteplirsen-51, golodirsen/viltolarsen-53, casimersen-45).
IVIG in IgA-deficient patients: risk of anaphylaxis — use IgA-depleted product; also watch for thromboembolism, aseptic meningitis, headache.

🔍 Quick ReferenceMechanism · Adverse effects · Use / monitoring

Mechanism

Pyridostigmine / neostigmine / edrophonium → reversible AChE inhibitor — ↑ ACh at NMJ
Azathioprine → purine synthesis inhibitor (6-MP prodrug)
Mycophenolate mofetil → IMPDH inhibitor — blocks de novo purine synthesis in lymphocytes
Methotrexate → dihydrofolate reductase inhibitor (folate antagonist)
Cyclosporine / tacrolimus → calcineurin inhibitors — block IL-2 transcription
Rituximab → anti-CD20 mAb — B-cell depletion
Eculizumab / ravulizumab / zilucoplan → terminal complement (C5) inhibitors — block MAC assembly
Efgartigimod / rozanolixizumab → FcRn antagonists — accelerate IgG catabolism
3,4-DAP (amifampridine / Firdapse) → presynaptic voltage-gated K⁺ channel blocker → ↑ ACh release
Riluzole → glutamate release inhibitor / Na⁺ channel blocker
Edaravone → free-radical scavenger (oxidative stress in ALS)
Tofersen → SOD1 antisense oligonucleotide (intrathecal)
Nusinersen / risdiplam → SMN2 splicing modifiers (SMA); onasemnogene abeparvovec (Zolgensma) → AAV9 SMN1 gene replacement
Eteplirsen / golodirsen / viltolarsen / casimersen → exon-skipping ASOs (DMD exons 51, 53, 53, 45); delandistrogene moxeparvovec (Elevidys) → AAV micro-dystrophin gene therapy for AMBULATORY DMD only; 2025 FDA boxed warning for acute serious liver injury / acute liver failure; ataluren → nonsense-mutation readthrough — NOT FDA-approved; EU conditional marketing authorization NOT renewed in March 2025 (historical / non-US)

Adverse effects

SLUDGE-M + fasciculations + miosis → cholinergic crisis (pyridostigmine excess)
Myelosuppression in TPMT-deficient patient → azathioprine
Teratogenicity / pregnancy contraindication → mycophenolate, methotrexate
Pulmonary fibrosis + hepatotoxicity → methotrexate (give folic acid; leucovorin rescue)
PRES + nephrotoxicity + HTN + tremor + gingival hyperplasia / hirsutism → cyclosporine / tacrolimus (calcineurin inhibitors)
Meningococcal sepsis risk → eculizumab / ravulizumab / zilucoplan (vaccinate first)
Hepatitis B reactivation + PML (rare) → rituximab
Anaphylaxis in IgA deficiency + thromboembolism + aseptic meningitis → IVIG
Hypotension + coagulopathy + citrate-related hypocalcemia → PLEX
LFT elevation → riluzole (monitor transaminases)
Chronic corticosteroids in DMD → weight gain (less with deflazacort vs prednisone) but MORE cataracts with deflazacort — monitor eyes
Myasthenia + myocarditis + myositis overlap (high mortality) → immune checkpoint inhibitor irAE

Use / monitoring / drug-to-avoid

First-line symptomatic MG → pyridostigmine (less useful in MuSK MG)
First-line LEMS → 3,4-DAP / amifampridine (Firdapse)
Refractory AChR-positive generalized MG → eculizumab / ravulizumab / zilucoplan or efgartigimod / rozanolixizumab
MuSK-positive MG, refractory AChR MG, NMOSD, PCNSV → rituximab
MG crisis → IVIG or PLEX (steroids may transiently worsen; bridge first)
GBS → IVIG or PLEX (steroids NOT effective)
CIDP → IVIG, PLEX, or steroids (efgartigimod SC now approved)
Drugs that worsen MG (AVOID): aminoglycosides, fluoroquinolones, telithromycin (black-box), macrolides (caution), IV magnesium, β-blockers, CCBs, lithium, procainamide, quinine/quinidine, D-penicillamine, ICIs
Pre-azathioprine → check TPMT activity; monitor CBC + LFTs
Pre-eculizumab → meningococcal vaccine ≥2 weeks prior (± prophylactic antibiotics)
SOD1-mutant familial ALS → tofersen (intrathecal) — not for sporadic ALS
ALS disease-modifying → riluzole (oral) + edaravone (IV/oral cycles)
DMD standard of care → deflazacort (preferred) ± mutation-specific exon-skipping ASO ± AAV gene therapy
SMA infants <2 yr → onasemnogene abeparvovec (single IV dose); nusinersen (intrathecal) or risdiplam (oral) for ongoing therapy
Inflammatory myopathies (DM/PM/IMNM) → steroids first-line + IVIG (esp. dermatomyositis) + MTX/AZA/MMF steroid-sparing; rituximab refractory; IBM → poor response to immunotherapy
Neonatal transient MG → supportive care ± temporary AChEI / PLEX

Myasthenia Gravis Pharmacology

Overview of MG Treatments

Drug	Class / Mechanism	Role	Key Considerations
Pyridostigmine	AChE inhibitor — increases ACh at NMJ	First-line symptomatic therapy	Cholinergic side effects (diarrhea, cramping, salivation); less effective in MuSK-positive MG
Prednisone	Corticosteroid	First-line immunotherapy for moderate–severe MG	Initial worsening in ~10–20% (higher with rapid high-dose initiation); start low, go slow; long-term side effects require steroid-sparing agents
Azathioprine	Purine synthesis inhibitor	Steroid-sparing; onset 6–12 months	Check TPMT before starting; risk of myelosuppression
Mycophenolate	IMPDH inhibitor	Steroid-sparing; onset 6–12 months	GI side effects; teratogenic; RCTs negative but widely used
Rituximab	Anti-CD20 — B-cell depletion	Refractory MG; especially effective in MuSK-positive MG	Screen for hepatitis B; risk of PML (rare)
Eculizumab / Ravulizumab	Terminal complement (C5) inhibitor	Refractory generalized AChR-positive MG	Must vaccinate against Neisseria meningitidis before starting
Efgartigimod	FcRn inhibitor — accelerates IgG degradation; lowers IgG but does NOT affect IgM or IgA (selective class effect)	Generalized AChR-positive MG	Reduces total IgG levels; cyclic dosing (4 weekly infusions per cycle)
Efgartigimod SC (Vyvgart Hytrulo)	FcRn inhibitor — SC formulation with hyaluronidase	Generalized AChR-positive MG; also CIDP indication (FDA 2024)	SC alternative to IV efgartigimod; same MOA
Rozanolixizumab (Rystiggo)	FcRn inhibitor — SC	AChR+ AND MuSK+ generalized MG (FDA 2023)	First FcRn inhibitor approved for MuSK-positive disease
Zilucoplan (Zilbrysq)	SC daily anti-C5 peptide (complement inhibitor)	AChR-positive generalized MG (FDA 2023)	Self-administered SC daily; meningococcal vaccination required
IVIG	Pooled immunoglobulins	Acute exacerbations, crisis, pre-thymectomy	Check IgA level (anaphylaxis risk in IgA deficiency)
Plasmapheresis (PLEX)	Removes circulating antibodies	Myasthenic crisis, rapid stabilization	Requires central access; effects are temporary

Thymectomy

Indicated for: thymoma (regardless of MG severity) and non-thymomatous generalized AChR-positive MG (MGTX trial)
Less beneficial in: MuSK-positive MG, late-onset MG (>50 years), purely ocular MG

Board Pearl

Eculizumab requires meningococcal vaccination before initiation. It blocks terminal complement (C5), which is also the defense against Neisseria. Efgartigimod works by blocking FcRn, which normally recycles IgG — blocking it accelerates IgG catabolism, lowering pathogenic antibody levels. FcRn inhibitors selectively lower IgG; they do NOT affect IgM or IgA — an increasingly board-relevant distinction.

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