Galantamine

Indications

• FDA-approved only for mild to moderate dementia of the Alzheimer type, as immediate-release tablets or solution twice daily or extended-release capsules once daily.
• Efficacy is comparable to donepezil and rivastigmine, giving roughly a 2-3 point ADAS-cog advantage over placebo across 6-month trials.
• Should not be used for mild cognitive impairment, where two randomized trials found an unexplained excess of deaths in treated patients.
• Not approved for severe Alzheimer disease, vascular dementia, Parkinson disease dementia or dementia with Lewy bodies.
• Sometimes used off-label in mixed Alzheimer and vascular dementia, where trial results have been inconsistent and benefit is uncertain.
• May be combined with memantine in moderate disease, although the combination evidence is stronger for donepezil than for galantamine.

Mechanism of action

• Competitive and reversible inhibitor of acetylcholinesterase, raising synaptic acetylcholine in cortical and hippocampal circuits.
• Uniquely acts as an allosteric potentiating modulator at nicotinic acetylcholine receptors, which may amplify presynaptic acetylcholine release.
• Has little effect on butyrylcholinesterase, in contrast to rivastigmine, and the clinical significance of that difference is unsettled.
• The cholinergic boost improves attention, working memory and functional performance modestly without altering underlying pathology.
• Peripheral muscarinic stimulation drives nausea, vomiting, diarrhea, bradycardia and increased gastric acid secretion.

Pharmacokinetics

• Absorption is rapid and essentially complete with about 90% bioavailability; food slows absorption but dosing with meals limits nausea.
• Elimination half-life is roughly 7 h, which supports twice-daily immediate-release dosing or once-daily extended-release capsules.
• Metabolized by CYP2D6 and CYP3A4 with additional glucuronidation, and about 20% of a dose is excreted unchanged in the urine.
• CYP2D6 poor metabolizers have around 25% higher exposure, but no dose adjustment is recommended on genotype alone.
• Both renal and hepatic impairment raise exposure meaningfully, which is why each carries a specific dose cap in the label.

Dosing

• Immediate release: 4 mg twice daily for 4 weeks, then 8 mg twice daily for at least 4 weeks, then 12 mg twice daily if needed and tolerated.
• Extended release: 8 mg once every morning for 4 weeks, then 16 mg daily for at least 4 weeks, then 24 mg daily as the maximum dose.
• The effective maintenance range is 16-24 mg/day; do not shorten the 4-week interval between steps, since that is what generates nausea.
• Take with food and adequate fluid, and if treatment is interrupted for several days, restart at the lowest dose and re-titrate upward.
• Moderate hepatic impairment (Child-Pugh 7-9) or creatinine clearance of 9-59 mL/min caps the dose at 16 mg/day.
• Avoid entirely in severe hepatic impairment (Child-Pugh 10-15) or when creatinine clearance is below 9 mL/min.

Adverse effects

• Nausea in about 17%, vomiting in 10% and diarrhea in 12% are dose-related, concentrated during titration, and often transient.
• Anorexia and weight loss are common and clinically important in frail patients, so weight is the practical tolerability measure.
• Bradycardia, syncope and atrioventricular block occur through vagotonic effects and contribute to falls and hip fracture.
• Serious skin reactions including Stevens-Johnson syndrome and acute generalized exanthematous pustulosis warrant immediate discontinuation of any rash.
• Increased gastric acid secretion raises the risk of peptic ulceration and gastrointestinal bleeding, especially with NSAIDs.
• Seizures, bladder outflow obstruction and worsening asthma or COPD are uncommon but should be anticipated in susceptible patients.

Monitoring

• Weight and appetite at every visit, since gastrointestinal intolerance and weight loss are the main reasons treatment is stopped.
• Pulse and orthostatic blood pressure at baseline and after each dose increase, with an ECG when syncope or conduction disease is present.
• Baseline and periodic renal and hepatic function, because both determine the maximum permissible dose.
• Ask about rash at every contact and stop the drug immediately if a rash appears, given the risk of severe skin reactions.
• Cognitive and functional measures every 6 months, alongside a review of total anticholinergic burden.

Interactions

• Strong CYP2D6 inhibitors such as paroxetine, fluoxetine, quinidine and bupropion raise galantamine exposure by roughly 40%.
• Strong CYP3A4 inhibitors including ketoconazole, erythromycin and ritonavir increase exposure by about 30-40% and may require dose reduction.
• Anticholinergic drugs directly oppose the therapeutic effect and should be reviewed and stopped wherever possible.
• Additive bradycardia with beta blockers, digoxin, diltiazem, verapamil and amiodarone can produce syncope, heart block and falls.
• Succinylcholine-type neuromuscular blockade is exaggerated during anesthesia, and NSAIDs compound gastrointestinal bleeding risk.

Special populations

• Pregnancy and lactation: there are no human data, and no plausible indication exists in patients of childbearing age.
• Pediatric safety and effectiveness have not been established and there is no approved dose for patients under 18 years.
• Geriatric patients are the intended population; the limiting factors are weight loss, bradycardia, syncope and drug burden.
• Renal impairment: cap at 16 mg/day when creatinine clearance is 9-59 mL/min and avoid the drug entirely below 9 mL/min.
• Hepatic impairment: cap at 16 mg/day at Child-Pugh 7-9 and do not use at Child-Pugh 10-15.

Clinical pearls

• Hold each step for a full 4 weeks; nearly all the nausea comes from titrating too quickly.
• Do not use it for mild cognitive impairment: trials showed unexplained excess mortality.
• Any rash means stop; Stevens-Johnson syndrome and AGEP are labeled risks.