Pharmacology of Drugs for Myasthenia Gravis

1. Introduction/Overview

Myasthenia gravis is a chronic autoimmune neuromuscular disorder characterized by fluctuating, fatigable weakness of skeletal muscles. The condition results from an antibody-mediated attack on postsynaptic nicotinic acetylcholine receptors at the neuromuscular junction, impairing synaptic transmission and leading to muscle weakness. The pharmacological management of myasthenia gravis represents a cornerstone of treatment, aimed at symptomatic relief, immunomodulation, and induction of remission. This chapter provides a systematic examination of the drugs used in its management, detailing their mechanisms, pharmacokinetic profiles, clinical applications, and associated adverse effects. A thorough understanding of this pharmacology is essential for optimizing therapeutic outcomes and minimizing treatment-related morbidity.

Learning Objectives

• Describe the pathophysiological basis of myasthenia gravis and the corresponding pharmacological targets for intervention.
• Classify the primary drug classes used in the management of myasthenia gravis, distinguishing between symptomatic and immunomodulatory agents.
• Explain the detailed mechanism of action, including molecular and cellular pharmacodynamics, for acetylcholinesterase inhibitors and immunosuppressive agents.
• Analyze the pharmacokinetic properties, therapeutic uses, major adverse effects, and significant drug interactions for each key medication.
• Evaluate special considerations in pharmacotherapy, including use in specific populations and during clinical crises.

2. Classification

The pharmacological agents used in myasthenia gravis are broadly classified into two categories based on their primary therapeutic goal: symptomatic treatment and immunomodulatory or immunosuppressive treatment. A third category encompasses agents used for acute crisis management and procedures.

Symptomatic Pharmacotherapy

This class aims to enhance neuromuscular transmission by increasing the concentration of acetylcholine in the synaptic cleft, providing rapid but temporary relief of weakness.

• Acetylcholinesterase Inhibitors (Cholinesterase Inhibitors): Reversible inhibitors of the enzyme acetylcholinesterase.
  • Pyridostigmine bromide
  • Neostigmine bromide
  • Ambenonium chloride (less commonly used)

Immunomodulatory and Immunosuppressive Pharmacotherapy

These agents modify the underlying autoimmune process, aiming to reduce antibody production and induce long-term remission or disease control.

• Corticosteroids: Potent anti-inflammatory and immunosuppressive agents.
  • Prednisone
  • Prednisolone
  • Methylprednisolone (often for pulse therapy)
• Non-steroidal Immunosuppressants:
  • Antimetabolites: Azathioprine, Mycophenolate mofetil, Methotrexate
  • Calcineurin Inhibitors: Cyclosporine, Tacrolimus
  • mTOR Inhibitor: Sirolimus (emerging use)
• Biologic Immunomodulators:
  • Monoclonal Antibodies: Rituximab (anti-CD20), Eculizumab (anti-C5 complement), Efgartigimod (FcRn antagonist)

Agents for Crisis Management and Adjuncts

• Therapeutic Plasma Exchange (Plasmapheresis): A procedure, not a drug, but a critical acute intervention.
• Intravenous Immunoglobulin (IVIG): A pooled blood product used for immunomodulation.
• Agents for Anesthesia and Surgery: Specific considerations for medications used during thymectomy or other procedures.

3. Mechanism of Action

Acetylcholinesterase Inhibitors

The primary mechanism involves reversible inhibition of the enzyme acetylcholinesterase (AChE), which is responsible for the rapid hydrolysis of the neurotransmitter acetylcholine (ACh) in the synaptic cleft. Under normal physiological conditions, ACh released from the presynaptic motor neuron binds to nicotinic ACh receptors on the muscle endplate, generating an endplate potential. AChE terminates this signal within milliseconds. In myasthenia gravis, autoantibodies reduce the number of functional receptors. By inhibiting AChE, these drugs prolong the presence and action of ACh in the synaptic cleft, increasing the probability of receptor activation and improving the safety factor of neuromuscular transmission. This action is purely symptomatic and does not alter the underlying autoimmune pathology.

At a molecular level, these agents contain a quaternary ammonium group that binds to the anionic site of AChE, similar to acetylcholine. They form a carbamylated or phosphorylated enzyme intermediate (depending on the drug class; for reversible inhibitors like pyridostigmine, it is a carbamyl-enzyme complex) that hydrolyzes much more slowly than the acetylated enzyme. The duration of action is directly related to the stability of this intermediate.

Corticosteroids

The immunosuppressive effects are multifactorial and involve genomic and non-genomic pathways. The primary mechanism is mediated by binding to cytosolic glucocorticoid receptors, which translocate to the nucleus and modulate gene transcription. This leads to:

• Downregulation of Pro-inflammatory Genes: Inhibition of transcription factors like NF-κB and AP-1, reducing the production of cytokines (e.g., IL-1, IL-2, IL-6, TNF-α), chemokines, and adhesion molecules.
• Induction of Anti-inflammatory Proteins: Upregulation of proteins like annexin-1 (lipocortin-1), which inhibits phospholipase A2, thereby reducing arachidonic acid metabolites.
• Immunosuppression: Reduction in T-cell and B-cell proliferation and function, decreased antibody production, and inhibition of dendritic cell maturation. In myasthenia gravis, this results in a gradual reduction in anti-acetylcholine receptor antibody titers.

High-dose pulse therapy may also involve rapid, non-genomic effects on cell membranes and signaling.

Non-steroidal Immunosuppressants

Azathioprine: A purine analogue prodrug metabolized to 6-mercaptopurine, which is subsequently converted to thioguanine nucleotides. These false nucleotides are incorporated into DNA and RNA, inhibiting purine synthesis and disrupting the proliferation of rapidly dividing cells, particularly lymphocytes. This leads to a reduction in the number of circulating B-cells and T-cells and a decrease in autoantibody production.

Mycophenolate Mofetil: A prodrug hydrolyzed to mycophenolic acid, which selectively and reversibly inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of guanosine nucleotide synthesis. Lymphocytes are highly dependent on this pathway, whereas other cell types can use salvage pathways. Inhibition preferentially suppresses T- and B-lymphocyte proliferation and antibody formation.

Cyclosporine and Tacrolimus: These calcineurin inhibitors form complexes with intracellular immunophilins (cyclophilin and FK-binding protein, respectively). The drug-immunophilin complex binds to and inhibits calcineurin, a calcium/calmodulin-dependent phosphatase. This prevents the dephosphorylation and nuclear translocation of the transcription factor NFAT (Nuclear Factor of Activated T-cells), thereby inhibiting the transcription of interleukin-2 (IL-2) and other cytokines crucial for T-cell activation and clonal expansion.

Biologic Agents

Rituximab: A chimeric monoclonal antibody directed against the CD20 antigen expressed on the surface of pre-B and mature B lymphocytes, but not on plasma cells or stem cells. Binding leads to B-cell depletion via complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. This reduces the population of B-cells that can differentiate into antibody-producing plasma cells, potentially lowering pathogenic autoantibody levels.

Eculizumab: A humanized monoclonal antibody that binds to the complement protein C5, preventing its cleavage into C5a and C5b. This inhibits the formation of the membrane attack complex (C5b-9), a terminal component of the complement cascade implicated in the destruction of the postsynaptic membrane in anti-acetylcholine receptor antibody-positive myasthenia gravis.

Efgartigimod: A human IgG1 antibody Fc fragment engineered to have high affinity for the neonatal Fc receptor (FcRn). FcRn normally protects IgG from lysosomal degradation, recycling it back into circulation. By competitively binding FcRn, efgartigimod accelerates the catabolism of all IgG antibodies, including pathogenic autoantibodies, leading to a rapid reduction in their serum levels.

Intravenous Immunoglobulin (IVIG)

The mechanism in autoimmune diseases is not fully elucidated but is believed to be multifactorial, involving:

• Modulation of Fc receptor expression and function on macrophages and other immune cells.
• Provision of anti-idiotypic antibodies that neutralize pathogenic autoantibodies.
• Inhibition of complement activation and deposition.
• Effects on cytokine production and dendritic cell function.

4. Pharmacokinetics

Acetylcholinesterase Inhibitors

Pyridostigmine: Oral bioavailability is low and variable (≈10-20%), due to significant first-pass metabolism. It is primarily metabolized in the liver, with only a minor fraction (15-25%) excreted unchanged in the urine. The onset of action after oral administration is 30-45 minutes, with a peak effect at 1-2 hours. The plasma elimination half-life (t_1/2) is short, approximately 3-4 hours, necessitating dosing every 4-6 hours. A sustained-release formulation is available, with a duration of action up to 6-12 hours, but its absorption is erratic and it is typically reserved for overnight use. The volume of distribution is limited, as the quaternary ammonium structure confines it largely to the extracellular space.

Neostigmine: Oral bioavailability is even lower (1-2%). It is hydrolyzed by plasma cholinesterases and metabolized in the liver. Its t_1/2 is about 50-90 minutes. It is more commonly used parenterally (subcutaneous or intramuscular) for acute settings or in patients unable to take oral medication.

Corticosteroids

Prednisone/Prednisolone: Prednisone is a prodrug converted to the active prednisolone in the liver. Oral bioavailability is high (>80%). Prednisolone is approximately 90% protein-bound, primarily to transcortin (corticosteroid-binding globulin) and albumin. It is metabolized extensively in the liver via CYP3A4 and other pathways to inactive metabolites, which are excreted in the urine. The plasma t_1/2 is 2-4 hours, but the biological half-life (duration of pharmacological effect) is 18-36 hours, allowing for once-daily dosing. The relationship between dose and effect is log-linear, meaning small dose changes can have significant clinical effects.

Non-steroidal Immunosuppressants

Azathioprine: Well absorbed orally (≈47%), with extensive metabolism. It is non-enzymatically cleaved to 6-mercaptopurine, which undergoes complex metabolism via three competing pathways involving thiopurine methyltransferase (TPMT), xanthine oxidase, and hypoxanthine-guanine phosphoribosyltransferase. Genetic polymorphisms in TPMT activity significantly influence toxicity risk. The elimination t_1/2 of azathioprine is short (≈1-2 hours), but the active metabolites have longer intracellular persistence.

Mycophenolate Mofetil (MMF): Rapidly and almost completely absorbed after oral administration and hydrolyzed to mycophenolic acid (MPA). MPA undergoes enterohepatic recirculation, contributing to a secondary peak in plasma concentration 6-12 hours post-dose. It is highly protein-bound (97-99%) and metabolized in the liver to the inactive glucuronide metabolite (MPAG), which is excreted in urine. The t_1/2 of MPA is approximately 17 hours.

Cyclosporine: Absorption is variable and incomplete (20-50%), influenced by bile, food, and gastrointestinal motility. It is highly lipophilic and extensively distributed, with high concentration in erythrocytes and leukocytes. Metabolism is primarily hepatic via CYP3A4, producing numerous metabolites. The t_1/2 is biphasic, with a terminal t_1/2 of 5-18 hours. Therapeutic drug monitoring is essential due to narrow therapeutic index and pharmacokinetic variability.

Biologic Agents

Rituximab: Administered intravenously. It follows nonlinear pharmacokinetics due to target-mediated drug disposition; B-cell depletion reduces clearance. The terminal t_1/2 is approximately 20 days after the first infusion but increases with subsequent doses as B-cells are depleted. Distribution is primarily within the vascular compartment.

Eculizumab: Administered intravenously or subcutaneously. It exhibits linear pharmacokinetics at the recommended doses, with a terminal t_1/2 of approximately 11-13 days.

Efgartigimod: Administered intravenously. Its pharmacokinetics are influenced by FcRn binding. It causes a rapid reduction in total IgG levels, with a t_1/2 of the drug itself being several days, but the pharmacodynamic effect on IgG lasts for weeks.

5. Therapeutic Uses/Clinical Applications

First-line Symptomatic Therapy

Acetylcholinesterase inhibitors, primarily pyridostigmine, are initiated in nearly all patients at diagnosis for immediate symptomatic control. Dosing is individualized based on symptom severity and tolerability, starting low and titrating upward. The goal is to achieve adequate strength for daily activities without causing cholinergic adverse effects. They are often used as monotherapy in ocular myasthenia or as an adjunct to immunosuppressants in generalized disease.

Immunosuppressive Therapy

Immunosuppressive agents are indicated for patients with generalized myasthenia gravis who do not achieve sufficient control with pyridostigmine alone, or for those with progressive disease.

• Corticosteroids: Often the first-choice immunosuppressant due to rapid onset (benefit seen within weeks). Used for induction of remission, especially in moderate to severe disease. A common regimen starts with a high dose (e.g., prednisone 1 mg/kg/day) followed by a slow taper over months to a maintenance dose.
• Azathioprine and Mycophenolate Mofetil: Used as steroid-sparing agents to allow reduction of corticosteroid dose and for long-term maintenance therapy. Their onset of action is slow (3-12 months). Mycophenolate is often preferred due to a more favorable side effect profile, though evidence of superior efficacy is debated.
• Calcineurin Inhibitors: Typically considered second-line steroid-sparing agents or for refractory cases due to their toxicity profile.

Biologic and Acute Therapies

• Rituximab: Generally reserved for patients with refractory disease, particularly those with MuSK antibody-positive myasthenia gravis, where it appears to be especially effective.
• Eculizumab: Approved for anti-AChR antibody-positive generalized myasthenia gravis in patients who remain symptomatic despite immunosuppressive therapy. It is used as add-on therapy.
• Efgartigimod: Approved for generalized myasthenia gravis in adult patients who are anti-AChR antibody positive, providing a rapid reduction in symptom burden.
• IVIG and Plasma Exchange: Used for rapid immunomodulation in myasthenic crisis, preoperative optimization before thymectomy, or as a bridge therapy while awaiting the onset of action of slower oral immunosuppressants.

Thymectomy

Thymectomy is a surgical procedure, not a pharmacotherapy, but it is a key component of management for patients with thymoma and for selected patients with generalized, anti-AChR antibody-positive myasthenia gravis under the age of 60. Pharmacological management is crucial for stabilizing the patient preoperatively and during postoperative recovery.

6. Adverse Effects

Acetylcholinesterase Inhibitors

Adverse effects are primarily extensions of their pharmacological action (cholinergic excess) and are dose-dependent.

• Muscarinic Effects: Abdominal cramps, diarrhea, nausea, vomiting, increased salivation and bronchial secretions, bradycardia, miosis, diaphoresis.
• Nicotinic Effects: Muscle fasciculations, cramping, and, at high doses, depolarizing blockade leading to increased weakness (cholinergic crisis).
• CNS Effects: Rare with quaternary amines like pyridostigmine due to poor blood-brain barrier penetration, but headache, dizziness, and drowsiness may occur.

Corticosteroids

Adverse effects are numerous, dose-related, and duration-dependent.

• Metabolic: Hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, central obesity, fluid retention.
• Musculoskeletal: Osteoporosis, avascular necrosis, myopathy, growth suppression in children.
• Dermatological: Skin thinning, easy bruising, impaired wound healing.
• Neuropsychiatric: Insomnia, mood changes, psychosis, cognitive impairment.
• Immunological: Increased susceptibility to infections, masking of infection signs.
• Ophthalmic: Cataracts, glaucoma.
• Gastrointestinal: Peptic ulcer disease, pancreatitis.
• Cardiovascular: Hypertension.
• Adrenal Suppression: With prolonged use, requiring slow tapering for withdrawal.

Non-steroidal Immunosuppressants

Azathioprine: Bone marrow suppression (leukopenia, thrombocytopenia, macrocytic anemia), hepatotoxicity (elevated transaminases), pancreatitis, gastrointestinal intolerance (nausea), increased risk of infections and malignancies (lymphoma, skin cancer). TPMT deficiency increases toxicity risk.

Mycophenolate Mofetil: Gastrointestinal effects (diarrhea, nausea, abdominal pain) are most common. Bone marrow suppression (leukopenia, anemia), increased risk of infections (including opportunistic infections), and potential teratogenicity are significant concerns.

Cyclosporine/Tacrolimus: Nephrotoxicity (acute and chronic), hypertension, neurotoxicity (tremor, headache, paresthesia), hyperglycemia (tacrolimus more so), hyperkalemia, hypomagnesemia, gingival hyperplasia (cyclosporine), hirsutism, and increased risk of malignancies.

Biologic Agents

Rituximab: Infusion reactions (fever, chills, rigors), increased risk of infections (including reactivation of hepatitis B and JC virus leading to PML), prolonged hypogammaglobulinemia, and rare but severe mucocutaneous reactions.

Eculizumab: The most serious adverse effect is a markedly increased risk of life-threatening meningococcal infections due to terminal complement blockade. Vaccination against Neisseria meningitidis is mandatory at least 2 weeks prior to initiation, and antibiotic prophylaxis is often recommended. Headache, upper respiratory infections, and nausea are common.

Efgartigimod: As it lowers all IgG, there is a theoretical increased risk of infection. Upper respiratory tract infections are commonly reported. Hypersensitivity reactions may occur.

IVIG

Headache, flu-like symptoms, fever, chills, and nausea are common infusion-related reactions. More serious effects include aseptic meningitis, thromboembolic events, acute renal failure (with sucrose-containing products), hemolytic anemia, and anaphylaxis in IgA-deficient patients.

7. Drug Interactions

Acetylcholinesterase Inhibitors

• Cholinergic Agonists/Other AChE Inhibitors: Additive effects and toxicity.
• Anticholinergic Agents (e.g., atropine, propantheline, tricyclic antidepressants): May be used to counteract muscarinic side effects but can mask early signs of cholinergic overdose.
• Aminoglycoside Antibiotics, Polymyxins, Clindamycin, Magnesium, Beta-blockers, Procainamide, Quinidine: These agents can impair neuromuscular transmission and may antagonize the effects of AChE inhibitors or precipitate weakness.
• Succinylcholine: AChE inhibitors prolong the action of this depolarizing neuromuscular blocker.

Corticosteroids

• CYP3A4 Inducers (e.g., phenytoin, rifampin, carbamazepine): Increase metabolism of corticosteroids, potentially reducing efficacy.
• CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole): Decrease metabolism, increasing the risk of corticosteroid toxicity.
• NSAIDs: Increased risk of gastrointestinal ulceration.
• Diuretics (especially thiazides and loop diuretics): Enhanced hypokalemia.
• Antidiabetic Agents: Corticosteroid-induced hyperglycemia may necessitate dose adjustments.
• Live Vaccines: Contraindicated due to immunosuppression.

Non-steroidal Immunosuppressants

Azathioprine:

• Allopurinol, Febuxostat: Potent inhibitors of xanthine oxidase, the enzyme that metabolizes 6-mercaptopurine. Concurrent use leads to profound, potentially fatal bone marrow suppression. Azathioprine dose must be reduced by 75% or more if allopurinol is essential.
• Angiotensin-Converting Enzyme (ACE) Inhibitors: Concurrent use may increase risk of anemia and severe leukopenia.
• Warfarin: Azathioprine may reduce anticoagulant effect.

Mycophenolate Mofetil:

• Antacids, Cholestyramine, Sevelamer: Reduce absorption of MMF by binding.
• Acyclovir, Ganciclovir, Valganciclovir: Additive bone marrow suppression.
• Live Vaccines: Contraindicated.

Cyclosporine/Tacrolimus:

• CYP3A4/P-glycoprotein Inhibitors (e.g., ketoconazole, clarithromycin, verapamil, diltiazem, grapefruit juice): Increase plasma levels, risk of nephrotoxicity and neurotoxicity.
• CYP3A4/P-glycoprotein Inducers (e.g., rifampin, phenytoin, St. John’s wort): Decrease plasma levels, risk of therapeutic failure.
• Nephrotoxic Drugs (e.g., aminoglycosides, amphotericin B, NSAIDs): Additive nephrotoxicity.
• Potassium-sparing diuretics, ACE inhibitors, ARBs: Increased risk of hyperkalemia.

8. Special Considerations

Pregnancy and Lactation

Myasthenia gravis management during pregnancy requires careful balancing of maternal disease control and fetal safety.

• Acetylcholinesterase Inhibitors: Pyridostigmine is generally considered safe and is the mainstay of symptomatic control. Dosing frequency may need adjustment due to altered pharmacokinetics (increased renal clearance, expanded plasma volume).
• Corticosteroids: Prednisone and prednisolone are preferred, as they are inactivated by placental 11-beta-hydroxysteroid dehydrogenase, limiting fetal exposure. High doses may be associated with a small increased risk of cleft palate.
• Azathioprine: Often continued in pregnancy if needed for disease control, as data suggest a relatively low risk of major malformations, though it crosses the placenta.
• Mycophenolate Mofetil, Methotrexate, Cyclophosphamide: Contraindicated due to teratogenicity.
• Biologics: Data are limited. Use is generally avoided unless the benefit outweighs the risk. Immunoglobulins may cross the placenta, especially in the third trimester.
• Lactation: Pyridostigmine and prednisolone are considered compatible with breastfeeding in usual doses. Azathioprine metabolites are found in very low concentrations in breast milk; its use is often considered acceptable. For other immunosuppressants and biologics, caution is advised.

Neonates may develop transient myasthenia due to placental transfer of maternal antibodies, requiring monitoring and possible treatment.

Pediatric Considerations

Juvenile myasthenia gravis is managed similarly to adults, with dose adjustments based on weight or body surface area. Corticosteroids can cause growth suppression, making steroid-sparing agents particularly important for long-term management. Live vaccines should be avoided in immunosuppressed children.

Geriatric Considerations

Elderly patients may have increased susceptibility to adverse effects of medications. Cholinergic side effects of AChE inhibitors may exacerbate conditions like bradycardia, COPD, or benign prostatic hyperplasia. The risks of corticosteroids (osteoporosis, diabetes, hypertension) and immunosuppressants (infections, myelosuppression) are heightened. Renal and hepatic function must be carefully assessed for dose adjustments.

Renal and Hepatic Impairment

Renal Impairment: Pyridostigmine and its metabolites are renally excreted; dose reduction may be necessary in severe renal failure to avoid accumulation. Mycophenolate dose may need adjustment as its metabolite (MPAG) accumulates. IVIG requires caution in patients with renal dysfunction, especially with sucrose-containing formulations.

Hepatic Impairment: Metabolism of pyridostigmine, corticosteroids, azathioprine, calcineurin inhibitors, and many other agents is hepatic. Dose reductions or increased monitoring may be required. Azathioprine is contraindicated in severe hepatic impairment.

Myasthenic Crisis vs. Cholinergic Crisis

This is a critical clinical distinction. A myasthenic crisis is a severe exacerbation of the disease with respiratory failure due to insufficient treatment or a triggering factor (infection, surgery). It is treated with increased immunomodulation (IVIG, plasma exchange) and supportive care. A cholinergic crisis results from overtreatment with AChE inhibitors, leading to depolarizing blockade and weakness plus severe muscarinic symptoms. It is treated by withholding AChE inhibitors and providing supportive care, including atropine for muscarinic effects. The edrophonium (Tensilon) test was historically used to differentiate but is now rarely used due to safety concerns.

9. Summary/Key Points

• Pharmacotherapy for myasthenia gravis is dichotomized into symptomatic treatment with acetylcholinesterase inhibitors (e.g., pyridostigmine) and long-term immunomodulation with agents like corticosteroids, azathioprine, and mycophenolate mofetil.
• The mechanism of acetylcholinesterase inhibitors is reversible inhibition of AChE, increasing synaptic ACh to overcome receptor deficiency. Immunosuppressants work via diverse pathways to reduce autoantibody production and the inflammatory response.
• Pyridostigmine has variable oral bioavailability and a short half-life, necessitating frequent dosing. Immunosuppressants often have delayed onsets of action (weeks to months).
• Adverse effect profiles are class-specific: cholinergic excess for AChE inhibitors; broad metabolic, infectious, and organ toxicities for immunosuppressants. Eculizumab carries a high risk of meningococcal infection.
• Significant drug interactions exist, particularly for azathioprine with allopurinol and for calcineurin inhibitors with CYP3A4 modulators.
• Management in pregnancy prioritizes pyridostigmine and prednisone. Many immunosuppressants are teratogenic. Special caution is required in renal/hepatic impairment and in the elderly.
• Acute exacerbations (crisis) require rapid immunomodulation with IVIG or plasma exchange and intensive supportive care, distinguishing them from cholinergic toxicity.

Clinical Pearls

• Initiate pyridostigmine at a low dose (e.g., 30-60 mg every 4-6 hours) and titrate based on symptom response and cholinergic side effects.
• When starting corticosteroids, anticipate an initial potential worsening of weakness and discuss this with the patient. Slow tapering is essential to avoid adrenal crisis and disease flare.
• Monitor for bone marrow suppression and hepatotoxicity with azathioprine and mycophenolate. Consider checking TPMT activity before starting azathioprine.
• For patients on eculizumab, confirm meningococcal vaccination and consider antibiotic prophylaxis.
• In any patient with myasthenia gravis presenting with acute respiratory distress, differentiate between myasthenic and cholinergic crisis, as management is fundamentally different.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.