REMENTIA 10

Indications

• Moderate to severe Alzheimer's disease

Dosage

Adults: The recommended starting dose of memantine is 5 mg once daily, which can be increased to a maximum dose of 20 mg daily, administered in divided doses.

Mechanism of action

Memantine acts as an uncompetitive (open-channel) antagonist at the NMDA receptor, reducing the excitatory effects of glutamate that can lead to neurotoxicity. Additionally, it exhibits antagonist activity at the type 3 serotonergic (5-HT3) receptor and blocks nicotinic acetylcholine receptors. This mechanism helps to mitigate the detrimental effects of excessive glutamate release, thereby providing neuroprotection and improving cognitive function in Alzheimer’s disease.

Pharmacodynamics

Memantine inhibits calcium influx into cells triggered by chronic NMDA receptor activation. At therapeutic doses, it enhances synaptic plasticity, which is crucial for learning and memory, while also providing neuroprotective effects against excitotoxicity. However, at high doses, it may impair synaptic plasticity, indicating a delicate balance in its pharmacological effects.

Pharmacokinetics

Memantine is well-absorbed after oral administration, with peak plasma concentrations typically achieved within 3 to 7 hours. It has a bioavailability of approximately 100%. The drug is primarily excreted unchanged in the urine, with renal clearance being a significant route of elimination. The half-life of memantine is about 60 to 100 hours, allowing for once-daily dosing in clinical practice.

Adverse effects

• Dizziness
• Headache
• Constipation
• Confusion
• Somnolence
• Hypertension

Interactions

• memantine+ketamine: Severe (increases risk of CNS adverse effects)
• amantadine+memantine: Moderate (increases risk of CNS toxicity)
• memantine+dopamine receptor agonists: Unknown (increases effects)
• memantine+apomorphine: Unknown (increases effects)
• memantine+bromocriptine: Unknown (increases effects)
• memantine+cabergoline: Unknown (increases effects)
• memantine+pramipexole: Unknown (increases effects)
• memantine+quinagolide: Unknown (increases effects)
• memantine+ropinirole: Unknown (increases effects)
• memantine+rotigotine: Unknown (increases effects)

Pregnancy

Memantine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether memantine is excreted in human milk. Caution should be exercised when administering memantine to a nursing woman.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Oral solution
• Film-coated tablets

Indications

• Moderate to severe Alzheimer's disease
• Dementia associated with Alzheimer's disease

Dosage

Adults: Initially, 10 mg daily, with titration to a maximum of 20 mg daily based on clinical response and tolerability.

Mechanism of action

Memantine acts as a non-competitive antagonist of the NMDA receptor, preventing excessive activation by glutamate. This helps to protect neurons from excitotoxicity, which can lead to neurodegeneration associated with Alzheimer's disease. The modulation of glutamate transmission contributes to improved cognitive function and daily living activities in patients suffering from dementia.

Pharmacodynamics

Memantine's pharmacodynamics involve its ability to modulate synaptic transmission and neuronal survival through NMDA receptor antagonism. By blocking the receptor in a use-dependent manner, it allows for normal glutamate function while preventing pathological over-activation. This results in a stabilization of cognitive decline and may enhance quality of life for individuals with Alzheimer's disease.

Pharmacokinetics

Memantine is well-absorbed after oral administration, with peak plasma concentrations occurring approximately 3 to 7 hours post-dose. It has a bioavailability of about 100%. The drug is primarily eliminated via renal excretion, with a half-life of approximately 60 to 100 hours, allowing for once-daily dosing in most cases. Dosage adjustments may be necessary in patients with renal impairment, as reduced renal function can lead to increased plasma levels of the drug.

Contra-indications

• Hypersensitivity to memantine or any component of the formulation
• Severe renal impairment (eGFR less than 5 mL/min/1.73 m2)

Adverse effects

• Dizziness
• Drowsiness
• Headache
• Fatigue
• Constipation
• Dyspnoea
• Impaired balance

Interactions

• Caution with other NMDA antagonists
• Potential interactions with drugs that affect renal clearance

Precautions

• History of epilepsy or seizures
• Patients with mild to moderate renal impairment should have dose adjustments
• Monitor for worsening symptoms of dementia

Pregnancy

Manufacturer advises to avoid unless essential; no information available.

Breast-feeding

Manufacturer advises to avoid; no information available.

Storage

Store below 25°C, protect from light. Keep out of reach of children.

Formulations

• Oral solution
• Film-coated tablets

Mechanism of action

Continuous activation of the N-methyl-D-aspartate (NMDA) receptors in the central nervous system caused by _glutamate_ is thought to cause some of the Alzheimer's disease symptoms. This overactivation is thought to contribute to neurotoxicity due to the excitatory properties of glutamate. The pharmacological effect of memantine likely occurs via the drug's behavior as an uncompetitive (open-channel) NMDA receptor antagonist, preventing glutamate action on this receptor. Memantine has a preference for the NMDA receptor-operated cation channels. Despite these antagonist effects, memantine has not been proven to prevent or retard the neurodegeneration seen in patients diagnosed with Alzheimer’s disease. In addition to exhibiting antagonists activity at the NMDA receptor, memantine exhibits antagonist activity at the type 3 serotonergic (5-HT3) receptor with a potency that appears to be similar to that at the NMDA receptor. Memantine also blocks the nicotinic acetylcholine receptor with a potency of about one-sixth to one-tenth that at the NMDA receptor. Memantine exhibits little or no affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels. Memantine is a similar uncompetitive NMDA-receptor antagonist to MK-801 and phencyclidine (PCP), and it prevents nerve cell death induced by the ischemia which induces as excessive release of glutamate. These medicines act on an ion channel binding site similar to the magnesium ion binding site. However, MK-801 and PCP cause schizophrenic symptoms, so they are not being used as a therapeutic drug for Alzheimer's Disease. Memantine does not have those toxicities and does not stimulate acetylcholine release in the cerebral cortex. Although the mechanism of the difference from memantine and MK-801 has not been made clear yet, it seems that memantine is combined and released with the ion channel depending on electric potential in the same way as the magnesium ion. As an uncompetitive inhibitor of the NMDA receptor, memantine, as with MK-801, does not block the binding of the neurotransmitter ,glutamate, to the receptor but rather blocks the ion current through the receptor channel that is activated by glutamate. ... Unlike such high affinity antagonist (MK-80), memantine blocks the NMDA receptor with relatively strong voltage dependence and rapid blocking/unblocking kinetics, dissociating from the NMDA receptors in response to membrane depolarization more readily than MK-801. ... Memantine is able to dissociate from the receptor in response to the strong, transient depolarizations that trigger physiological NMDA receptor activity, while blocking the receptor channels during the chronic, low level excitation that is thought to occur in neurodegenerative diseases such as Alzheimer's disease. Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor, but the key binding interactions between drug and receptor are not fully elucidated. To determine key binding interactions of memantine, we made side-by-side comparisons of IC(50) for memantine and amantadine, a structurally related drug, in the GluN1/GluN2B NMDA receptor. We identified hydrophobic binding pockets for the two methyl groups on memantine formed by the residues A645 and A644 on the third transmembrane helices of GluN1 and GluN2B, respectively. Moreover, we found that while adding two methyl groups to amantadine to produce memantine greatly improves affinity, adding a third methyl group to produce the symmetrical trimethylamantadine diminished affinity. Our results provide a better understanding of chemical-scale interactions between memantine and the NMDA channel, which will potentially benefit the development of new drugs for neurodegenerative diseases involving NMDA receptors.

Pharmacodynamics

**General effects** This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate. This leads to the improvement of Alzheimer's dementia symptoms, demonstrated by increased cognition and other beneficial central nervous system effects. **Effects on neuroplasticity** Like other NMDA receptor antagonists, memantine at high doses can reduce neuronal synaptic plasticity that is involved in learning and memory processes. At lower concentrations, which are normally used in the clinical setting, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters. **Effect on various receptors** Memantine has demonstrated minimal activity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, as well as voltage-dependent Ca2+, Na+ or K+ channels. This drug has shown antagonist activity at the 5HT3 receptors. Laboratory studies suggest that memantine does not affect the reversible inhibition of the acetylcholinesterase normally caused by donepezil, galantamine, or tacrine.