Acetylcholinesterase Inhibitors
Examples
- Galantamine
- Rivastigmine
- Donepezil
Indications
All 3 Acetylcholinesterase Inhibitors are currently only licensed in the UK for the treatment of Mild-Moderate Alzheimer's Disease. There is insufficient evidence to justify their use in more severe Alzheimer's disease. Rivastigmine is also licensed to treat mild-moderate dementia in Parkinson's disease.
All 3 drugs are reversible inhibitors of acetylcholinesterase.
Contraindications
Contraindications
Caution
- Cardiac Disease (especially those with supraventricular conduction abnormalities) - see "Adverse Reactions" for reasoning
- Asthma
- COPD
- Hepatic and renal impairment
- GI Ulcers
- History of seizures
Mechanism
Acetylcholine (ACh) is a neurotransmitter released by cholinergic neurones which has roles in both the Peripheral and Central Nervous Systems. In the CNS it is involved in language, perception and short term memory. Research has shown that in Alzheimer's disease there is degeneration of cholinergic neurones, which results in a reduction of levels of ACh in certain parts of the brains of sufferers. This reduction in ACh is thought to be central to the symptoms experienced in Alzheimer's disease.
Acetylcholinesterase is an enzyme which breaks down ACh to two metabolites: acetate and choline. This terminates the action of ACh. By inhibiting this enzyme, Galantamine, Rivastigmine and Donepezil all prevent ACh from being metabolised, and therefore prolong its lifetime. The theory of using the drug in Alzheimer's is that preventing the breakdown of ACh will help to maintain levels of the compound in patients' brains - preventing the symptoms which are associated with ACh loss.
Administration
All 3 drugs can be taken orally and in addition, Rivastigmine can be administered as a transdermal patch.
Adverse Reactions
Cholinergic neurones are found in many other glands and organs throughout the body, not just the brain. In particular, ACh has important parasympathetic effects on the heart, by decreasing both heart rate and contractility. As discussed, Acetylcholinesterase Inhibitors cause an accumulation of ACh by preventing its breakdown. As a result, cardiac side effects caused by excess ACh are not uncommon. These parasympathetic effects on the heart can present in many ways, including dizziness, syncope, headache and bradycardia. Other common side effects of Acetylcholinesterase Inhibitors include:
- Nausea and vomiting
- Diarrhoea
- Fatigue
- Insomnia
- Muscle cramps
- Agitation and aggression
- Depression
- Weight loss and anorexia
- Urinary incontinence
- Rash
- Pruritus
- Hallucinations
Less common, but important side effects include:
- GI Haemorrhage
- Hepatitis
- Pancreatitis
- Exacerbation of Parkinson's disease
- Seizures
Interactions
Ketoconazole and Quinidine both inhibit the metabolism of Donepezil (See "Pharmacokinetics")
Phenytoin, Carbamazepine, Dexamethasone, Rifampacin and Phenobarbitol all increase the metabolism of Donepezil (See "Pharmacokinetics").
Ketoconazole, Paroxetine and Erythromycin all inhibit metabolism of Galantamine, whilst Amitriptyline, Fluoxetine and Quinidine all increase its metabolism
Be aware of the 2 most common enzyme inducers of all - alcohol and smoking!
Education
Patients and relatives should be strongly reminded that although Acetylcholinesterase Inhibitors can help to alleviate symptoms of Alzheimer's disease, they are in no way a "cure" and there is still no drug which has been shown conclusively to halt the progression of the disease.
Pharmacokinetics
Both Donepezil and Galantamine are primarily metabolised through the Cytochrome P450 system in the liver. Therefore, drugs which either induce or inhibit enzymes in this system will increase or decrease the metabolism of Acetylcholinesterase Inhibitors respectively. This is important, as it may necessitate an increase or decrease in the dose of Acetylcholinesterase Inhibitor prescribed.
Obviously, those with hepatic impairment may well require dose adjustments too.
As Rivastigmine metabolism effectively avoids the Cytochrome P450 system entirely, there are no similar problems with prescribing it.
Interestingly, around 7% of the normal population have reduced levels of CYP2D6 (the particular enzyme which metabolises Galantamine). This is an important group of potential patients for whom the dose of Galantamine prescribed would need to be decreased.
