A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

132 MOVEMENT DISORDERS AND DEGENERATIVE CNS DISEASE
Table 21.2: Pharmacokinetics of donepezil, galantamine and rivastigmine
Donepezil Galantamine (prolonged Rivastigmine
release preparation)
T max 4 hours 4 hours 1 hour
Protein binding 90% 18% 40%
CYP3A4 metabolites ✓ ✓ ✓
Plasma t 1/2 unknown 70 hours 8 hours 2 hours a
a Cholinesterase inhibition, duration 10 hours.
Adverse effects
With all three drugs, adverse effects are mainly a consequence
of the cholinomimetic mechanism of action and are usually mild
and transient. Nausea, vomiting and diarrhoea are common.
Fatigue, dizziness, dyspepsia, urinary problems and syncope
have been reported. Careful dose titration can improve tolerance.
In overdose, a cholinergic crisis may develop including
severe nausea, vomiting, abdominal pain, salivation, lacrimation,
urination, defaecation, sweating, bradycardia, hypotension,
collapse, convulsions and respiratory depression. In
addition to supportive treatment, atropine should be administered
which reverses most of the effects.
Drug interactions
Theoretically, donepezil might interact with a number of
other drugs that are metabolized by cytochrome P450, but at
present there is no clinical evidence that this is important.
MEMANTINE
Memantine is an NMDA receptor antagonist used in moderate
to severe dementia in AD and Parkinson’s disease. The
National Institute for Clinical Excellence (NICE) does not recommend
its use outside clinical trials.
Key points
Alzheimer’s disease
• The prevalence of Alzheimer’s disease is increasing in
ageing populations.
• Currently, the principal therapeutic target is reduced
cholinergic transmission.
• Placebo-controlled studies in patients with mild or
moderate Alzheimer’s disease of central cholinesterase
inhibitors showed that scores of cognitive function
were greater at three to six months in patients treated
with the active drug. The clinical importance of this
difference is uncertain.
• The therapeutic benefits of cholinesterase inhibitors
appear to be modest and have not yet been
demonstrated to be sustained. Such therapy does not
appear to affect underlying disease progression or
mortality.
Case history
A 21-year-old woman was treated with an anti-emetic
because of nausea and vomiting secondary to viral
labyrinthitis. She received an initial intramuscular dose of
10 mg of metoclopromide and then continued on oral
metoclopramide 10 mg three times a day, which relieved
her nausea and vomiting. Two days later she was brought
into the local Accident and Emergency Department
because her husband thought she was having an epileptic
fit. Her arms and feet were twitching, her eyes were deviated
to the left and her neck was twisted, but she opened
her mouth and tried to answer questions. Muscle tone in
the limbs was increased.
Question
What is the diagnosis here and what is the most appropriate
and diagnostic acute drug treatment
Answer
Her posture, dystonia and head and ocular problems all
point to a major dystonia with oculogyric crisis, almost certainly
caused by metoclopramide. This side effect is more
common in young women on high doses (a similar syndrome
can occur with neuroleptics, such as prochlorperazine,
used to treat nausea). It is probably due to excessive
dopamine blockade centrally in a sensitive patient. It usually
resolves within several hours of discontinuing the
offending drug, and in mild cases this is all that may be
needed. In more severe cases, the treatment of choice is
intravenous benztropine or procyclidine (anticholinergic
agents), and further doses may be required, given orally.
An alternative, equi-effective but less satisfactory therapy
because it is not diagnostic is intravenous diazepam.
FURTHER READING
Citron M. Strategies for disease modification in Alzheimer’s disease.
Nature Reviews. Neuroscience 2004; 5: 677–85.
Nutt JG, Wooten GF. Diagnosis and initial managements of
Parkinson’s disease. New England Journal of Medicine 2005; 353:
1021–7.
Richman D, Agius M. Treatment of autoimmune myasthenia gravis.
Neurology 2003; 61: 1652–61.