Page 520 - Basic _ Clinical Pharmacology ( PDFDrive )

506 SECTION V Drugs That Act in the Central Nervous System

mentioned. Treatment is started at 1 mg/d, and the dosage is antimuscarinic drug such as benztropine (2 mg intravenously),
increased by 1 mg every 5 days; most patients require 7–16 mg/d. diphenhydramine (50 mg intravenously), or biperiden (2–5 mg
It has similar side effects to haloperidol but may cause irregulari- intravenously or intramuscularly) is helpful, whereas in other
ties of cardiac rhythm. Haloperidol has been used for many years instances diazepam (10 mg intravenously) alleviates the abnormal
to treat tic disorders. Patients are better able to tolerate this drug if movements.
treatment is started with a small dosage (eg, 0.25 or 0.5 mg daily) Tardive dyskinesia, a disorder characterized by a variety of
and then increased gradually (eg, by 0.25 mg every 4 or 5 days) abnormal movements, is a common complication of long-term
over the following weeks depending on response and tolerance. neuroleptic or metoclopramide drug treatment (see Chapter 29).
Most patients ultimately require a total daily dose of 3–8 mg. Its precise pharmacologic basis is unclear. A reduction in dose of
Adverse effects include extrapyramidal movement disorders, seda- the offending medication, a dopamine receptor blocker, com-
tion, dryness of the mouth, blurred vision, and gastrointestinal monly worsens the dyskinesia, whereas an increase in dose may
disturbances. Aripiprazole (see Chapter 29) has also been found suppress it. The drugs most likely to provide immediate symp-
effective in treating tics. tomatic benefit are those interfering with dopaminergic function,
Although not approved by the US Food and Drug Administra- either by depletion (eg, reserpine, tetrabenazine) or receptor
tion (FDA) for the treatment of tics or Tourette syndrome, certain blockade (eg, phenothiazines, butyrophenones). Paradoxically,
α -adrenergic agonists may be preferred as an initial treatment the receptor-blocking drugs are the ones that also cause the dys-
2
because they are less likely to cause extrapyramidal side effects kinesia. Deutetrabenazine and valbenazine are selective inhibitors
than neuroleptic agents. Clonidine reduces motor or vocal tics in of VMAT2, which modulates dopamine release. They both show
about 50% of children so treated. It may act by reducing activity great promise for ameliorating tardive dyskinesia. Deutetrabena-
in noradrenergic neurons in the locus coeruleus. It is introduced zine has been approved by the FDA for Huntington’s disease, and
at a dose of 2–3 mcg/kg/d, increasing after 2 weeks to 4 mcg/ valbenazine for tardive dyskinesia.
kg/d and then, if required, to 5 mcg/kg/d. It may cause an initial Tardive dystonia is usually segmental or focal; generalized dys-
transient fall in blood pressure. The most common adverse effect tonia is less common and occurs in younger patients. Treatment is
is sedation; other adverse effects include reduced or excessive sali- the same as for tardive dyskinesia, but anticholinergic drugs may
vation and diarrhea. Guanfacine, another α -adrenergic agonist, also be helpful; focal dystonias may also respond to local injection
2
has also been used. Both of these drugs may be particularly helpful of botulinum A toxin. Tardive akathisia is treated similarly to
for behavioral symptoms, such as impulse control disorders. drug-induced parkinsonism. Rabbit syndrome, another neuro-
Atypical antipsychotics, such as risperidone and aripiprazole, leptic-induced disorder, is manifested by rhythmic vertical move-
may be especially worthwhile in patients with significant behav- ments about the mouth; it may respond to anticholinergic drugs.
ioral problems. Clonazepam and carbamazepine have also been Because the tardive syndromes that develop in adults are often
used. The pharmacologic properties of these drugs are discussed irreversible and have no satisfactory treatment, care must be taken
elsewhere in this book. to reduce the likelihood of their occurrence. Antipsychotic medi-
Injection of botulinum toxin A at the site of problematic tics is cation should be prescribed only when necessary and should be
sometimes helpful when these are focal simple tics. Treatment of withheld periodically to assess the need for continued treatment
any associated attention deficit disorder (eg, with clonidine patch, and to unmask incipient dyskinesia. Thioridazine, a phenothi-
guanfacine, pemoline, methylphenidate, or dextroamphetamine) azine with a piperidine side chain, is an effective antipsychotic
or obsessive-compulsive disorder (with selective serotonin reup- agent that seems less likely than most to cause extrapyramidal
take inhibitors or clomipramine) may be required. reactions, perhaps because it has little effect on dopamine recep-
Deep brain stimulation is sometimes worthwhile in otherwise tors in the striatal system. Finally, antimuscarinic drugs should not
intractable cases. be prescribed routinely in patients receiving neuroleptics, because
the combination may increase the likelihood of dyskinesia.
Drug-Induced Dyskinesias Neuroleptic malignant syndrome, a rare complication of treat-
ment with neuroleptics, is characterized by rigidity, fever, changes in
Levodopa or dopamine agonists produce diverse dyskinesias as mental status, and autonomic dysfunction (see Table 16–4). Symp-
a dose-related phenomenon in patients with Parkinson’s disease; toms typically develop over 1–3 days (rather than minutes to hours
dose reduction reverses them. Chorea may also develop in patients as in malignant hyperthermia) and may occur at any time during
receiving phenytoin, carbamazepine, amphetamines, lithium, and treatment. Treatment includes withdrawal of antipsychotic drugs,
oral contraceptives, and it resolves with discontinuance of the lithium, and anticholinergics; reduction of body temperature; and
offending medication. Dystonia has resulted from administration rehydration. Dantrolene, dopamine agonists, levodopa, or amanta-
of dopaminergic agents, lithium, serotonin reuptake inhibitors, dine may be helpful, but there is a high mortality rate (up to 20%)
carbamazepine, and metoclopramide; and postural tremor from with neuroleptic malignant syndrome.
theophylline, caffeine, lithium, valproic acid, thyroid hormone,
tricyclic antidepressants, and isoproterenol. Restless Legs Syndrome
The pharmacologic basis of the acute dyskinesia or dystonia
sometimes precipitated by the first few doses of a phenothiazine Restless legs syndrome is characterized by an unpleasant creep-
is not clear. In most instances, parenteral administration of an ing discomfort that seems to arise deep within the legs and