Page 302 - Basic _ Clinical Pharmacology ( PDFDrive )

288 SECTION IV Drugs with Important Actions on Smooth Muscle

Serotonin Syndrome and Similar Syndromes

Excess synaptic serotonin causes a serious, potentially fatal syn- animal models, many of the signs of the syndrome can be
drome that is diagnosed on the basis of a history of administration reversed by administration of 5-HT 2 antagonists; however, other
of a serotonergic drug within recent weeks and physical findings. 5-HT receptors may be involved as well. Dantrolene is of no value,
It has some characteristics in common with neuroleptic malignant unlike the treatment of MH.
syndrome (NMS) and malignant hyperthermia (MH), but its patho- NMS is idiosyncratic rather than predictable and appears to
physiology and management are quite different (Table 16–4). be associated with hypersensitivity to the parkinsonism-inducing
As suggested by the drugs that precipitate it, serotonin effects of D 2 -blocking antipsychotics in certain individuals. MH is
syndrome occurs when overdose with a single drug, or concur- associated with a genetic defect in the RyR1 calcium channel of
rent use of several drugs, results in excess serotonergic activity in skeletal muscle sarcoplasmic reticulum that permits uncontrolled
the central nervous system. It is predictable and not idiosyncratic, calcium release from the sarcoplasmic reticulum when precipitat-
but milder forms may easily be misdiagnosed. In experimental ing drugs are given (see Chapter 27).

Serotonin also constricts veins, and venoconstriction with Serotonin has little effect on gastrointestinal secretions, and what
increased capillary filling appears to be responsible for the flush effects it has are generally inhibitory.
that is observed after serotonin administration or release from a
carcinoid tumor. Serotonin has small direct positive chronotropic 5. Skeletal muscle and the eye—5-HT receptors are pres-
2
and inotropic effects on the heart, which are probably of no clini- ent on skeletal muscle membranes, but their physiologic role is
cal significance. However, prolonged elevation of the blood level not understood. As discussed in the box, serotonin syndrome
of serotonin (which occurs in carcinoid syndrome) is associated is associated with skeletal muscle contractions and precipi-
with pathologic alterations in the endocardium (subendocardial tated when MAO inhibitors are given with serotonin agonists,
fibroplasia), which may result in valvular or electrical malfunction. especially antidepressants of the selective serotonin reuptake
inhibitor class (SSRIs; see Chapter 30). Although the hyper-
Serotonin causes blood platelets to aggregate by activating 5-HT 2
receptors. This response, in contrast to aggregation induced during thermia of serotonin syndrome results from excessive muscle
normal clot formation, is not accompanied by the release of serotonin contraction, serotonin syndrome is probably caused by a
stored in the platelets. The physiologic role of this effect is unclear. central nervous system effect of these drugs (Table 16–4 and Box:
Serotonin Syndrome and Similar Syndromes).
4. Gastrointestinal tract—Serotonin is a powerful stimulant Studies in animal models of glaucoma indicate that 5-HT
2A
of gastrointestinal smooth muscle, increasing tone and facili- agonists reduce intraocular pressure. This action can be blocked
tating peristalsis. This action is caused by the direct action of by ketanserin and similar 5-HT antagonists.
2
serotonin on 5-HT smooth muscle receptors plus a stimulating
2
action on ganglion cells located in the enteric nervous system (see CLINICAL PHARMACOLOGY OF
Chapter 6). 5-HT and 5-HT receptors may also be involved. SEROTONIN
1A
7
Activation of 5-HT receptors in the enteric nervous system causes
4
increased acetylcholine release and thereby mediates a motility- Serotonin Agonists
enhancing or “prokinetic” effect of selective serotonin agonists
such as cisapride. These agents are useful in several gastrointestinal Serotonin has no clinical applications as a drug. However,
disorders (see Chapter 62). Overproduction of serotonin (and other several receptor subtype-selective agonists have proved to be of
substances) in carcinoid tumor is associated with severe diarrhea. value. Buspirone, a 5-HT agonist, has received attention as an
1A

TABLE 16–4 Characteristics of serotonin syndrome and other hyperthermic syndromes.

Syndrome Precipitating Drugs Clinical Presentation Therapy 1
Serotonin SSRIs, second-generation antidepressants, Hypertension, hyperreflexia, tremor, Sedation (benzodiazepines),
syndrome MAOIs, linezolid, tramadol, meperidine, clonus, hyperthermia, hyperactive bowel paralysis, intubation, and ventilation;
fentanyl, ondansetron, sumatriptan, sounds, diarrhea, mydriasis, agitation, consider 5-HT 2 block with cyproheptadine
MDMA, LSD, St. John’s wort, ginseng coma; onset within hours or chlorpromazine
Neuroleptic D 2 -blocking antipsychotics Acute severe parkinsonism; hypertension, Diphenhydramine (parenteral),
malignant hyperthermia, normal or reduced bowel cooling if temperature is very high,
syndrome sounds; onset over 1–3 days sedation with benzodiazepines
Malignant Volatile anesthetics, succinylcholine Hyperthermia, muscle rigidity, hyperten- Dantrolene, cooling
hyperthermia sion, tachycardia; onset within minutes
1 Precipitating drugs should be discontinued immediately. First-line therapy is in boldface font.
LSD, lysergic acid diethylamide, MAOIs, monoamine oxidase inhibitors; MDMA, methylenedioxy-methamphetamine (ecstasy); SSRIs, selective serotonin reuptake inhibitors.