memantine

**Mechanism of action:** Memantine is an uncompetitive, voltage-dependent, open-channel blocker of the NMDA-type glutamate receptor (binds within the channel at the Mg2+ site/PCP site). In Alzheimer disease, chronic low-level glutamate activation causes excessive Ca2+ influx and excitotoxic neuronal injury. Memantine blocks this tonic pathologic activation (a "noise" reduction) but, because of its fast off-rate and low affinity, still allows transient physiologic glutamate signaling (needed for learning/memory/LTP). This contrasts with high-affinity blockers (ketamine, PCP, MK-801), which cause psychotomimetic effects.

**Indication:** Moderate-to-severe Alzheimer dementia (FDA-approved). Used as monotherapy or add-on to cholinesterase inhibitors (donepezil, rivastigmine, galantamine). Combination product: memantine/donepezil (Namzaric). Benefit is modest (slows functional/cognitive decline; not disease-modifying). Mild AD is typically treated first with an AChE inhibitor.

**Pharmacokinetics:** Oral; ~100% bioavailability; mostly excreted unchanged in urine (renal elimination, urine pH-dependent—alkaline urine reduces clearance). Dose-adjust in severe renal impairment (CrCl <30 mL/min). Long half-life (60-80 h). Titrated gradually.

**Adverse effects:** Generally well tolerated. Dizziness, headache, confusion, constipation, somnolence, hypertension. Less GI/cholinergic toxicity than AChE inhibitors (no nausea, bradycardia, vomiting, vivid dreams as prominent features). Rarely seizures, agitation/hallucinations.

**Comparison with AChE inhibitors (high-yield):** - Donepezil, rivastigmine, galantamine: increase ACh; side effects = nausea, diarrhea, bradycardia/syncope, vivid dreams, bronchospasm; used for mild-moderate AD. - Memantine: NMDA antagonist; used for moderate-severe AD; fewer cholinergic effects.

**Other associations/pearls:** - Related NMDA antagonists: amantadine (also anti-Parkinson/antiviral), dextromethorphan, ketamine, PCP. - Esketamine (intranasal) for treatment-resistant depression is also NMDA-based. - Off-label/investigational: vascular dementia, Lewy body dementia, neuropathic pain, OCD augmentation—not board-testable as indications. - Excitotoxicity concept: glutamate → NMDA receptor → Ca2+ overload → neuronal death (also in stroke, Huntington, ALS—riluzole reduces glutamate release in ALS). - Newer AD therapies (anti-amyloid monoclonal antibodies like lecanemab, donanemab) are disease-modifying for early AD and carry ARIA risk—differentiate from memantine.

**Exam buzz:** "Moderate-to-severe Alzheimer disease + NMDA receptor antagonist + prevents excitotoxicity" = memantine.