Specific drug therapies, such as dantrolene, amantadine, and bromocriptine, have an uncertain role in the treatment of neuroleptic malignant syndrome. Recommendations for the use of these drugs are from noncontrolled prospective and retrospective studies and case reports; no controlled studies exist. While the drugs generally are felt to be helpful, they have been found to have deleterious effects in some studies.
Skeletal Muscle Relaxants
These agents stimulate muscle relaxation by modulating skeletal muscle contractions at sites beyond the myoneural junction and by acting directly on muscle itself. Benzodiazepines are used in a small number of patients with neuroleptic malignant syndrome unresponsive to other measures. In most cases, a continuous IV infusion of diazepam or lorazepam has been utilized.
Dantrolene interferes with the release of calcium from sarcoplasmic reticulum, thus directly inhibiting muscle contraction. It also prevents or reduces the increase in myoplasmic calcium ion concentration that activates acute catabolic process associated with malignant hyperthermia. It is used to treat muscular rigidity and hyperthermia associated with neuroleptic malignant syndrome.
Dantrolene is available as a sodium salt in 25-mg, 50-mg, and 100-mg capsules and in 20-mg vial for intravenous (IV) administration. The IV form is much more expensive and should be reserved for patients unable to take oral medications.
By binding to specific receptor sites, benzodiazepines appear to potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and the action of other inhibitory transmitters.
Diazepam modulates postsynaptic effects of gamma amino-butyric acid A (GABA-A) transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, as well as on the thalamus and hypothalamus, to induce a calming effect. Individualize dosage and increase cautiously to avoid adverse effects.
Lorazepam is a benzodiazepine with short onset of effects and intermediate-long half-life.
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it might depress all levels of CNS, including the limbic and reticular formation.
A dopamine agonist must stimulate D2 receptors if it is to offer clinical benefit in neuroleptic malignant syndrome. D2 receptor blockade might cause neuroleptic malignant syndrome by removing tonic inhibition from the sympathetic nervous system or more directly by neuroleptic agents (eg, phenothiazines).
Bromocriptine is a semisynthetic, ergot alkaloid derivative that is a strong dopamine D2-receptor agonist and a partial dopamine, D1-receptor agonist. It stimulates dopamine receptors in the corpus striatum. Bromocriptine may relieve akinesia, rigidity, and tremor associated with Parkinson disease. Initiate at low dosage. Slowly increase dosage to individualize therapy. Assess dosage titration every 2 weeks. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.
Amantadine has been used to treat Parkinson disease and has been tried in neuroleptic malignant syndrome because it increases synaptic dopamine activity. Its antiparkinsonian activity results from blocking reuptake of dopamine into presynaptic neurons and causing direct stimulation of postsynaptic receptors.
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