Penezil

Uses

Penezil hydrochloride is used for the treatment of mild to moderate dementia of the Alzheimer’s type.

Penezil is also used to associated treatment for these conditions: Alzheimer's Disease (AD), Dementia due to Parkinson's disease, Dementia of the Alzheimer's Type, Dementia, Vascular, Diffuse Lewy Body Disease, Mild Dementia of the Alzheimer's Type, Moderate Alzheimer's Type Dementia, Severe Alzheimer's Type Dementia

How Penezil works

The commonly accepted cholinergic hypothesis proposes that a portion of the cognitive and behavioral decline associated with Alzheimer's are the result of decreased cholinergic transmission in the central nervous system. Penezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine. The main pharmacological actions of this drug are believed to occur as the result of this enzyme inhibition, enhancing cholinergic transmission, which relieves the symptoms of Alzheimer's dementia. In addition to the above, other mechanisms of action of donepezil are possible, including the opposition of glutamate-induced excitatory transmission via downregulation of NMDA receptors and the regulation of amyloid proteins, which have demonstrated significant effects on the disease process of Alzheimer's. Other possible targets for donepezil may also include the inhibition various inflammatory signaling pathways, exerting neuroprotective effects.

Dosage

Penezil dosage

Adult: Initially, 5 mg daily at bedtime, increase if necessary up to 10 mg once daily at bedtime after 4-6 wk.

Elderly: Initially, 5 mg daily at bedtime, increase if necessary up to 10 mg once daily at bedtime after 4-6 wk.

Since food does not affect the rate or extent of absorption of donepezil, it can be administered with or without food.

Side Effects

Generally well tolerated but some patients may experience nausea, vomiting & diarrhoea. These adverse events are of mild intensity and transient, resolving during continued treatment without the need for dose modification. Less frequent side effects are insomnia, fatigue, anorexia, muscle cramps, generalized seizure etc.

Toxicity

LD50

The rat oral LD50 of donepezil is 32.6 mg/kg.

Overdose information

Signs and symptoms of overdose with cholinesterase inhibitors such as donepezil can include severe nausea and vomiting, bradycardia, hypotension, perspiration, seizures, muscle weakness respiratory depression, and collapse. Significant muscle weakness may result in death if the respiratory muscles are affected by donepezil overdose. To manage an overdose, anticholinergics can be employed as antidotes. Atropine at intravenous doses of 1.0 - 2.0 mg can be administered and titrated according to the clinical response. Consult the local poison control center for the most updated guidelines on the management of a donepezil overdose. Whether donepezil can be removed from the body with dialysis is unknown at this time.

Precaution

Caution should be taken in sick sinus syndrome or other supraventricular conduction abnormalities, patients at risk of developing peptic ulcers, asthma, obstructive airway disease and during anaesthetic procedure.

Interaction

May increase the neurotoxic effect of antipsychotics. Concurrent use with systemic corticosteroids may increase the adverse effects of donepezil. May increase the neuromuscular-blocking effect of succinylcholine. May increase the adverse effects of cholinergic agonists. May increase the bradycardic effect of β-blockers.

Food Interaction

• Avoid alcohol.
• Take with or without food. The absorption is unaffected by food.

Penezil Drug Interaction

Moderate: metoprolol, metoprolol, metoprolol, metoprololMinor: aspirin, aspirin, aspirin, aspirinUnknown: apixaban, apixaban, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, memantine, memantine, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Penezil Disease Interaction

Major: bradycardia, bronchospasm, coronary artery disease, parkinsonism, PUD, seizuresModerate: hyperthyroidism, hepatic dysfunction

Volume of Distribution

The volume of distribution of donepezil is 11.8 ± 1.7 L/kg for a 5-mg dose and 11.6 ± 1.91 L/kg for a 10-mg dose. It is largely distributed in the extravascular compartments. Penezil crosses the blood-brain barrier and cerebrospinal fluid concentrations at the above doses have been measured at 15.7%. The volume of distribution at steady-state according to the FDA label for donepezil ranges from 12 - 16 L/kg.

Elimination Route

Penezil is slowly absorbed via the gastrointestinal tract after oral administration. Tmax is 3 to 4 hours with a bioavailability of 100% and steady-state concentrations are attained within 15 to 21 days of administration. The Tmax in one pharmacokinetic study determined a Tmax of 4.1 ± 1.5 hours. The Cmax of 5 mg donepezil tablets is estimated to be 8.34 ng/mL, according to the Canadian monograph. The AUC of 5 mg donepezil tablets has been determined to be 221.90-225.36 ng.hr/mL.

Half Life

The average elimination half-life of donepezil is about 70 hours according to the results of various studies and the FDA label for donepezil.. One pharmacokinetic study determined the average terminal half-life to be 81.5±22.0 h

Clearance

According to the FDA label, the average apparent plasma clearance of this drug is 0.13 – 0.19 L/hr/kg. A 5 mg dose of donepezil in healthy patients was shown to have a plasma clearance of 0.110±0.02 L/h/kg. In 10 patients diagnosed with alcoholic cirrhosis, showed a mean decrease in clearance by 20% when compared to the clearance in 10 healthy subjects. In 4 patients with severe renal impairment compared to 4 healthy subjects, no significant change in clearance was noted.

Elimination Route

In a study of radiolabeled administration donepezil in healthy adults, 57% of measured radioactivity was identified in the urine, and 5% was identified in the feces.

Pregnancy & Breastfeeding use

Pregnancy: There are no adequate and well controlled studies in pregnant woman. Penezil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mother: It is not known whether Penezil Hydrochloride is secreted in human breast milk or not. Penezil is not indicated in nursing mother.

Contraindication

Penezil is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.

Special Warning

In case of renal & hepatic impairment: A similar dose schedule can be followed for patients with renal or mild to moderate hepatic impairment as clearance of donepezil hydrochloride is not affected by these conditions.

In case of children: There are no adequate and well controlled trials in document to safety and efficacy of donepezil hydrochloride in any illness occurring in children. Penezil is not recommended for use in children.

Acute Overdose

Overdose may result in cholinergic crisis; symptoms include severe nausea, vomiting, salivation, hypotension, bradycardia, resp depression, collapse and seizures. Muscle weakness may increase and death may occur if resp muscles are involved. Treatment includes supportive measures and use of tertiary anticholinergics (such as atropine).

Storage Condition

Store below 30°C

Innovators Monograph

You find simplified version here Penezil