Drugs for Dementia, MS, Myasthenia & Migraine

Alzheimer disease and Huntington chorea

Cholinesterase inhibitors. Alzheimer disease depletes cortical acetylcholine as cholinergic neurons of the nucleus basalis of Meynert degenerate. Donepezil, rivastigmine, and galantamine inhibit acetylcholinesterase so released ACh persists in the synapse. Benefit is modest and symptomatic; none slows neurodegeneration. Rivastigmine also inhibits butyrylcholinesterase, comes as a transdermal patch, and is approved for Parkinson disease dementia; galantamine also enhances nicotinic receptor signaling.

Cholinergic adverse effects. Nausea, diarrhea, anorexia, weight loss, and vivid dreams are common. Extra ACh at cardiac M2 receptors raises vagal tone, causing bradycardia, AV block, and syncope, a cause of falls in older adults. Anticholinergic drugs (oxybutynin, diphenhydramine) oppose these agents and worsen cognition.

Memantine. A low-affinity, uncompetitive (open-channel) NMDA receptor antagonist that limits Ca²⁺-driven excitotoxicity from excess glutamate while sparing normal signaling. It is used for moderate to severe disease, often added to donepezil. Side effects are mild (dizziness, headache, confusion, constipation); lower the dose in severe renal impairment.

Anti-amyloid antibodies. Lecanemab binds soluble amyloid-β protofibrils (IV every 2 weeks); donanemab binds pyroglutamate amyloid-β in established plaques (IV monthly). Both clear amyloid and modestly slow decline in early symptomatic disease (mild cognitive impairment or mild dementia) when amyloid is confirmed by PET or CSF.

ARIA is the defining toxicity: ARIA-E is vasogenic edema or sulcal effusion on FLAIR MRI; ARIA-H is microhemorrhage or superficial siderosis on GRE/SWI. Most episodes are silent and early, so surveillance MRIs are scheduled; symptomatic cases bring headache, confusion, or seizures. Risk peaks in APOE ε4 homozygotes (genotype before treatment), and anticoagulants raise the risk of serious intracerebral bleeding.

VMAT2 inhibitors. Tetrabenazine, deutetrabenazine, and valbenazine reversibly block vesicular monoamine transporter 2. Unpackaged cytosolic dopamine is degraded by MAO, so less reaches striatal targets and Huntington chorea lessens (D2 blockers such as haloperidol act postsynaptically instead). Monoamine depletion causes depression and suicidality (boxed warning in Huntington disease), plus parkinsonism, akathisia, somnolence, and QT prolongation. Deuterium slows CYP2D6 metabolism of deutetrabenazine, allowing less frequent dosing. Reserpine blocks VMAT irreversibly, an old antihypertensive infamous for depression.

Multiple sclerosis

Relapses. IV methylprednisolone 1 g daily for 3–5 days speeds recovery from relapses such as optic neuritis but does not change long-term disability; plasma exchange rescues severe steroid-refractory attacks.

Platform therapies. Injected interferon-β causes flu-like symptoms, depression, elevated transaminases, and leukopenia. Glatiramer acetate, a random amino-acid polymer mimicking myelin basic protein, causes injection-site lipoatrophy and a brief post-injection flush with chest tightness. Oral dimethyl fumarate activates the Nrf2 antioxidant pathway and causes flushing, GI upset, and lymphopenia (rare PML); aspirin 30 minutes beforehand blunts the prostaglandin-mediated flush, as with niacin. Teriflunomide, another oral agent, inhibits dihydroorotate dehydrogenase.

Natalizumab. This α4 integrin (VLA-4) antibody stops lymphocytes binding VCAM-1 and crossing the blood–brain barrier; it is highly effective and is also used for Crohn disease. It permits reactivation of JC polyomavirus, which lyses oligodendrocytes to cause progressive multifocal leukoencephalopathy; risk rises with anti-JCV antibody positivity, more than 2 years of therapy, and prior immunosuppressants. Vedolizumab blocks only gut-homing α4β7, so PML is far rarer.

S1P receptor modulators. Fingolimod (phosphorylated by sphingosine kinase), siponimod, ozanimod, and ponesimod internalize lymphocyte S1P1 receptors, so lymphocytes cannot follow the S1P gradient out of lymph nodes; blood counts fall and fewer autoreactive cells reach the CNS. Risks: first-dose bradycardia and AV block (6-hour monitoring), macular edema (eye exams), VZV and other infections (confirm VZV immunity), elevated transaminases, and teratogenicity.

Anti-CD20 therapy. Ocrelizumab depletes CD20⁺ B cells by antibody- and complement-mediated killing, sharply reducing relapses, and was the first drug approved for primary progressive MS; ofatumumab is a subcutaneous anti-CD20 for relapsing disease. Risks: infusion reactions, infections, hypogammaglobulinemia, blunted vaccine responses, and hepatitis B reactivation (screen HBsAg and anti-HBc first).

Dalfampridine. This 4-aminopyridine blocks voltage-gated K⁺ channels exposed on demyelinated axons, prolonging the action potential to restore conduction and improve walking without modifying disease. It lowers the seizure threshold and is renally cleared, so avoid it with prior seizures or CrCl ≤50 mL/min.

Myasthenia gravis

Pyridostigmine. A quaternary cholinesterase inhibitor that does not cross the blood–brain barrier; it raises ACh at the neuromuscular junction to outcompete anti-AChR antibodies, each dose lasting about 3–4 hours. It treats symptoms only. Muscarinic effects (cramps, diarrhea, salivation, sweating, bradycardia) are countered with glycopyrrolate, which spares nicotinic NMJ receptors.

Excess pyridostigmine causes cholinergic crisis: weakness from depolarizing blockade plus SLUDGE and miosis. Myasthenic crisis is weakness from the disease itself.

Complement and FcRn blockers. Eculizumab and ravulizumab bind C5 and prevent membrane attack complex injury to the postsynaptic membrane; like terminal complement deficiency, this invites Neisseria meningitidis sepsis, so MenACWY and MenB vaccines are given at least 2 weeks before dosing. Efgartigimod blocks the neonatal Fc receptor (FcRn), which normally rescues IgG from lysosomal breakdown, so IgG and its pathogenic autoantibodies fall.

Migraine

Triptans. Sumatriptan and rizatriptan are 5-HT1B/1D agonists: 5-HT1B constricts dilated meningeal vessels, and 5-HT1D blocks trigeminal release of CGRP and substance P. Take them early in an attack.

Avoid triptans in coronary artery disease, Prinzmetal angina, prior stroke or TIA, peripheral vascular disease, uncontrolled hypertension, hemiplegic migraine, and within 24 hours of an ergot. Ergotamine and dihydroergotamine vasoconstrict even more and are avoided in pregnancy and with CYP3A4 inhibitors.

CGRP-targeted drugs. Trigeminal CGRP drives meningeal vasodilation and pain. Gepants are oral CGRP-receptor antagonists: ubrogepant and rimegepant abort attacks, while atogepant and rimegepant prevent them. Preventive antibodies bind the CGRP receptor (erenumab) or CGRP itself (fremanezumab, galcanezumab, eptinezumab). None constrict vessels, so gepants are the acute choice when vascular disease rules out triptans. Lasmiditan, a 5-HT1F agonist, also avoids vasoconstriction but causes dizziness and sedation (no driving for 8 hours).

Prevention. Offer a preventive for frequent (≥4 headache days per month) or disabling attacks; onabotulinumtoxinA is reserved for chronic migraine.