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Donepezila, Galantamina, Rivastigmina, Memantina

Retardam o avanço da doença, regulando neurotransmissores

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1. Mecanismo de ação:

• Inibidor reversível da acetilcolinesterase (AChE).

• Aumenta a concentração de acetilcolina nas sinapses.

• Melhora a função colinérgica no cérebro.

• Não altera o curso da doença de Alzheimer.

2. Farmacocinética:

• Farmacocinética linear (1–10 mg/dia).

• Absorção não é afetada por alimentos.

• Pico plasmático:

• ~3h (comprimido 10 mg)

• ~8h (comprimido 23 mg)

• Alta ligação a proteínas plasmáticas (albumina e alfa-1-glicoproteína ácida).

• Metabolizado por CYP2D6 e CYP3A4 + glucuronidação.

• Eliminação renal e fecal.

• Meia-vida de eliminação: ~70 horas.

3. Farmacodinâmica:

• Inibidor misto (competitivo e não competitivo) da AChE.

• Múltiplos modos de ligação ao sítio ativo da enzima.

• Aumenta acetilcolina no cérebro (evidência em modelos animais).

4. Efeitos adversos:

• Pode afetar junções neuromusculares.

• Pode exigir doses maiores de bloqueadores neuromusculares não despolarizantes durante cirurgias.

5. Indicação e aprovação:

• Indicado para o tratamento da Doença de Alzheimer.

• Aprovado pelo FDA (Estados Unidos).

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Abstract Memantine (Ebixa®, Axura®, Namenda®, Akatinol®) is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer’s type. In well designed clinical trials, oral memantine, as monotherapy or in addition to a stable dose of acetylcholinesterase inhibitors, was well tolerated during the treatment of mild to severe Alzheimer’s disease for up to 52 weeks. Memantine generally modified the progressive symptomatic decline in global status, cognition, function and behaviour exhibited by patients with moderate to severe Alzheimer’s disease in four 12- to 28-week trials. In patients with mild to moderate Alzheimer’s disease, data from three 24-week trials are equivocal, although meta-analyses indicate beneficial effects on global status and cognition. Memantine is an effective pharmacotherapeutic agent, and currently the only approved option, for the treatment of moderate to severe Alzheimer’s disease. Pharmacological Properties Memantine is an uncompetitive antagonist that blocks the NMDA channel with higher affinity, but less voltage-dependency, than magnesium. It moderately inhibits excitatory activity while preserving learning behaviours in vivo when compared with more potent NMDA receptor channel blockers. During pathological activation of the NMDA receptor, memantine blocks excessive calcium entry through the channel and is neuroprotective in in vitro and in vivo models. Oral memantine is completely absorbed with an absolute bioavailability of ≈100%. Steady-state plasma concentrations, achieved after about 2 weeks of memantine 20 mg/day, range from 70 to 150 gmg/L, while the steady-state area under the plasma concentration-time curve from time 0 to 24 hours is ≈1800 gmg · h/L after 4 weeks of treatment. Memantine is excreted in urine mostly as unchanged parent drug with the remainder being metabolised by glucuronidation, hydroxylation and N-oxidation to form NMDA-inactive metabolites. Memantine and its metabolites are primarily eliminated by the kidneys with a terminal elimination half-life of 60–100 hours. Total renal clearance in healthy volunteers is 170 mL/min/1.73m2. Therapeutic Efficacy The efficasy of memantine 20 mg/day has been examined in seven randomised, double-blind, placebo-controlled, multicentre trials of 12–28 weeks’ duration in patients with mild to severe Alzheimer’s disease. In two of four trials in patients with moderate to severe Alzheimer’s disease, intent-to-treat analyses indicated that global status was significantly better with memantine than with placebo, either as monotherapy or in addition to a stable dose of donepezil. In a third trial, while global status did not differ significantly based on intent-to-treat analysis, observed-case analysis favoured memantine over placebo. However, preliminary data from a fourth trial indicate numerical differences between memantine and placebo treatment groups that were not significant. In patients with moderate to severe Alzheimer’s disease, memantine or donepezil plus memantine also maintained superior cognitive performance and function with respect to placebo or placebo plus donepezil in two of the three trials in which they were assessed, and superior behaviour in two of the four trials. In one published trial in patients with mild to moderate Alzheimer’s disease, memantine monotherapy significantly attenuated the decline in global status and cognition observed in placebo recipients; however, in preliminary data from another monotherapy trial, significantly greater effects with memantine seen at 12 and 18 weeks were lost at trial end, apparently as a result of an improvement in global status and cognition in placebo recipients in the last weeks of the trial. Initial results of a third study in this patient population, with memantine or placebo added to a stable dose of an acetylcholinesterase inhibitor, indicate a numerical difference that was not significant. Meta-analyses indicate significant effects of memantine on global status, cognition and function in patients with mild to severe Alzheimer’s disease, and on global status, cognition, function and behaviour in patients with moderate to severe Alzheimer’s disease. Tolerability Memantine was generally well tolerated with a good safety profile during clinical trials, most adverse events being of mild or moderate severity. Adverse events were reported by 70% of patients receiving either memantine or placebo, but most were not considered drug related. In pooled analyses, memantine was associated with a higher incidence of dizziness, headache, constipation and somnolence than placebo. Serious adverse events occurred in 12.7% of memantine and 13.8% of placebo recipients.

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https://pesquisa.bvsalud.org/portal/resource/pt/lil-306907

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A galantamina no tratamento da doença de Alzheimer’s: da pesquisa ao paciente | Rev. bras. neurol;37(2): 6-17, abr.-jun. 2001. ilus | LILACS

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A galantamina no tratamento da doença de Alzheimer’s: da pesquisa ao paciente / Galantamine in the treatment of Alzheimer disease: from research to the patient