An anxious patient who has not responded to initial doses of clozapine titration wants to know about the dose-dependent side-effects of clozapine.
Which one of the following is definitely not a dose-related risk?
D. Agranulocytosis is not dose dependent; it is idiosyncratic. A reduction in dose of clozapine cannot help a patient who has developed agranulocytosis. Clozapine-associated seizures are clearly dose related. When doses of clozapine below 300 mg/day are used, the seizure rate remains 1%; further doses between 300 and 600 mg/day increase the seizure rate to 2.7%, and doses above 600 mg/day have a rate of 4.4%. Slower dose titration, using a lower dose, and the addition of anticonvulsant agent such as valproic acid can reduce the frequency of seizures. Anticholinergic effects, such as tachycardia and constipation, may be dose dependent, and are often noted in overdoses. Similar to sialorrhoea, clozapine-related tachycardia is often seen in early phases of treatment, and tolerance develops in due course.
Reference:
Acetyl cholinesterase and butyryl cholinesterase are two enzymes metabolizing acetylcholine.
Which one of the following anti-dementia drugs has significant effects on both enzymes?
B. Donepezil and galantamine are selective inhibitors of acetylcholinesterase enzyme. Rivastigmine affects both butyryl and acetyl cholinesterase. Galantamine also affects nicotinic receptors. However, these differences do not translate into significant clinical differences in efficacy or tolerability. Memantine is an N-methyl-D-aspartic acid (NMDA) antagonist and hence is thought to be a neuroprotective agent. Tacrine was one of the foremost anticholinesterases introduced but is no longer used due to hepatotoxic effects. Tacrine inhibits both acetyl and butyrylcholinesterases. Ginkgo biloba is widely used in Germany as a cognitive enhancer. Its mechanism of action is unclear.
References:
A 66-year-old lady being treated for tremors by her neurologist develops insomnia, increased nocturnal myoclonus, and disruptive nightmares following the prescription of a particular medication.
The most likely causative agent is:
B. Levodopa is used to treat symptoms of Parkinson’s disease. Levodopa is associated with increase in libido; in some cases secondary mania is reported. It can cause disruptive nightmares and forced reminiscences. It is a stimulating medication and can produce initial insomnia and nocturnal myoclonus. It is also associated with belpharospasms. Bromocriptine and pramipexole are dopamine agonists while selegeline is a monoamine oxidase B (MAO-B) inhibitor used in treating Parkinson’s disease.
A patient treated for severe Parkinson’s disease develops troublesome psychotic symptoms attributed to levodopa. The neurologist is reluctant to reduce or stop levodopa given her deterioration in the past when this was attempted.
The most appropriate drug to treat her psychotic symptoms is:
C. Psychosis is common in patients with Parkinson’s disease. This may be due to the use of dopaminergic medications such as levodopa or unrelated to the pathology of Parkinson’s disease. Lewy body dementia can result in psychotic features and prominent parkinsonism, in which case antipsychotic treatment may be required. In such cases and in levodopa-induced psychosis, quetiapine has been used as the treatment of choice as it has a very low extrapyramidal side effects profile. Clozapine is also equally useful and generally regarded as the gold standard. In Parkinson’s disease-related psychosis even low doses of atypical antipsychotics can result in good efficacy.
Which one of the following drugs denatures the monoamine oxidase enzyme, rendering it ineffective to metabolize even low amounts of tyramine?
C. Tyramine is predominantly metabolized by MAO-A enzyme present in gut wall and liver, apart from brain and other tissues. Drugs which irreversibly inhibit MAO-A affect tyramine metabolism. These include tranylcypromine and phenelzine. Drugs such as selegiline are irreversible MAO-B selective inhibitors; they do not have the same effect on tyramine as MAO-A inhibitors. Moclobemide is a reversible, somewhat competitive MAO-A selective inhibitor. Thus, when the relative amount of tyramine in the vicinity increases, the moclobemide molecule makes way for tyramine from the MAO-A enzyme site. Reboxetine is not an MAO inhibitor.
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