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PHARMACOLOGICAL COMPATIBILITY*

Donepezil Metabolization (applicable to Galantamine)

Donepezil (in the form of hydrochloride) is a reversible inhibitor of cholinesterase (ChEI). Donepezil shows a very high affinity towards cholinesterase and is devoid of hepatotoxity. The long plasma life of donepezil allows treatments of a single dose per day.

Donepezil is used to treat dementia (a brain disorder that affects the ability to remember, think clearly, communicate and perform daily activities, and can cause changes in mood and personality) in people who have Alzheimer’s disease (AD), a brain disease that slowly destroys memory and the ability to think, learn, communicate and perform daily activities. Donepezil improves mental functions (such as memory, attention, the ability to interact with others, speaking, clearly thinking and performing regular daily activity) by increasing the amount of certain substances that naturally occur in the brain. Donepezil can improve the ability to think and remember, or delay the loss of the referred capacities in people with Alzheimer’s disease. However, donepezil does not cure this disease or prevent the loss of mental abilities at some time in the future.

Donepezil has shown the same clinical efficacy as other cholinesterase inhibitors in the treatment of Alzheimer’s disease. Although donepezil does not alter the long-term prognosis of Alzheimer’s disease, it seems to slow its settlement.

CONTRAINDICATIONS AND CAUTIONS

The treatment must be initiated and supervised by a doctor with experience in the diagnosis and treatment of Alzheimer’s dementia. Treatment with donepezil should only be initiated if a caregiver is available to regularly monitor the intake of the drug by the patient. Maintenance treatment can be continued as long as there is a therapeutic benefit for the patient. Therefore, the clinical benefit of donepezil should be re-evaluated on a regular basis. The abrupt interruption of the treatment should be avoided to avoid a sudden decline of the cognitive function or an increase of the alterations on the behavior.

When prescribing donepezil the following precautions must be taken. Caution in anesthesia due to succinylcholine type increased muscle relaxation. Precautions should be taken in patients with abnormal supraventricular cardiac conduction, with a history of asthma, with a history of obstructive pulmonary disease or with a history of ulcerative disease.

Precautions should be taken when prescribing donepezil in concomitance with NSAIDs (non-steroidal anti-inflammatory drugs) since may exacerbate or induce extrapyramidal symptoms. There is a risk of developing neuroleptic malignant syndrome during treatment with donepezil: if indicative symptoms develop stop treatment immediately. There is also a risk of rhabdomyolysis, more frequent at the beginning of treatment or when increasing the dose. Caution should also be exercised when prescribing to patients with gastrointestinal disorders, such as, for example, patients with a history of ulcerative disease or gastrointestinal hemorrhage.

Extreme caution should be exercised since donepezil can generate adverse neurological processes such as seizures: It is believed that cholinomimetics have some potential to cause generalized seizures.

However, seizures can also be a manifestation of Alzheimer’s disease. Although seizures have rarely been observed with donezepil, caution is advised when administering this drug to predisposed patients (patients with traumatic brain injuries, intracranial pressure or other unstable metabolic conditions). Cholinergic effects increased by donepezil may increase the symptoms of Parkinson’s disease.

Pulmonary processes: due to their cholinomimetic actions, cholinesterase inhibitors should be prescribed with caution to patients with a history of asthma or obstructive pulmonary disease. The administration of donepezil concomitantly with other acetylcholinesterase inhibitors, agonists or antagonists of the cholinergic system should be avoided.

Liver processes: donepezil should be used with caution in patients with hepatic impairment. Clearance of donepezil was shown to be reduced by 20% in 10 patients with alcoholic cirrhosis compared to normal subjects.

Donepezil is classified as category C risk for pregnancy. The risk to the fetus is not known. It is also not known if the drug is excreted in breast milk and therefore if its administration during lactation is not recommended.

SIDE EFFECTS

Donepezil can cause side effects such as: nausea, vomiting, diarrhea, loss of appetite, weight loss, need to urinate more often, difficulty controlling urination, muscle cramps, pain, swelling or stiffness of joints, pain, excessive tiredness, difficulty to sleep or to staying asleep), headache, dizziness, nervousness, depression, confusion, changes in mood behavior, hallucinations (seeing things or hearing voices that do not exist), abnormal dreams, redness, peeling or itching on the skin…

In patients treated with acetylcholinesterase inhibitors, weight losses of 1 to 1.5 kg are usually observed.

Some side effects can be serious: fainting, heartbeat slower than normal, chest pain, new or worsening respiratory problems, heartburn, black or tarry stools, red blood in the stools, vomiting with blood, vomiting of a material similar to coffee beans, inability to control urine, difficulty or pain when urinating, low back pain, fever, seizures, discoloration or bruising of the skin

Donepezil is generally well tolerated at doses of 5 mg/day. With doses of 10 mg/day, the percentage of patients who had to discontinue treatment due to severe side effects amounted to 13%. Most of the side effects are of cholinergic nature and are dose-dependent.

PHARMACOLOGICAL INTERACTIONS

Other cholinesterase inhibitors (eg, rivastigmine, tacrine, galantamine) can produce additive pharmacological effects when administered concomitantly with donepezil. This is also true for sympathomimetics such as betanecol.

The clearance of donepezil can increase with the concomitant administration of some inducers of hepatic isoenzymes such as CYP2D6 and CYP3A4. The inducers of one or both isoenzymes include: antiretroviral protease inhibitors, barbiturates (eg, phenobarbital), carbamazepine, dexamethasone, fosphenytoin, modafinil, phenytoin, pioglitazone, rifamycins (eg, rifabutin, rifapentine, rifampin), St. John’s wort (Hypericum perforatum) and troglitazone. The clinical effects of these interactions on the effectiveness of donepezil have not been determined. Patients receiving these drugs should be monitored for loss of effectiveness of donepezil.

It has been shown, in vitro, that quinidine inhibits the metabolism of donepezil by inhibiting the hepatic isoenzyme CYP2D6. Other inhibitors of CYP2D6 metabolism are amiodarone, desipramine, propafenone, and some selective serotonin reuptake antidepressants. The clinical consequences of this interaction have not been yet determined.

Fluoxetine, paroxetine, and sertraline are potent inhibitors of the hepatic CYP2D6 isoenzyme and its concomitant administration with donepezil may cause significant increases in plasma levels of the drug, increasing the incidence of cholinergic side effects. At least two cases of interactions between paroxetine and donepezil have been reported: gastrointestinal adverse reactions, insomnia, confusion and agitation were observed when paroxetine was added to a donepezil therapy. The side effects disappeared by reducing the doses of donepezil or by discontinuing treatment with both drugs. Both fluoxetine and fluvoxamine, two antidepressants of the same family, inhibit the hepatic CYP3A4 isoenzyme and can interact with donepezil metabolism.

BRAND NAME

  • Aricept®

GENE OR REGION STUDIED


  • CYP2D6

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