DESCRIPCION

La ciproheptadina es un antagonista H1 de la histamina, si bien, a diferencia de otros antagonistas H1, también anatagoniza los receptores serotoninérgicos. Esta propiedad hace que la ciproheptadina sea útil en condiciones como la enfermedad de Cushing, las cefaleas de origen vascular y la anorexia. También esw eficaz en la anorgasmia producida por los antidepresivos inhibidores selectivos de los receptores serotoninérgicos.

Mecanismo de action: la ciproheptadina no impide la libreación de histamina (como el cromoglicato, p. ej.) pero compite con esta sustancia en los receptores H1. La ciproheptadina antagoniza competitivamente los efectos de la histamina sobre los receptores H1 del tracto disgestivo, útero, grandes vasos y músculo liso bronquial. El bloqueo de los receptores H1 suprime la formación de edema, prurito y otras reacciones que resultan de una actividad histamínica. Los efectos sedantes de la ciproheptadina se explican por sus efectos antagonistas a nivel de los re

e does not prevent the release of histamine, as do cromolyn and nedocromil, but rather competes with free histamine for binding at H1-receptor sites. Cyproheptadine competitively antagonizes the effects of histamine on H1-receptors in the GI tract, uterus, large blood vessels, and bronchial smooth muscle. Blockade of H1-receptors also suppresses the formation of edema, flare, and pruritus that result from histaminic activity. H1-antagonists also possess anticholinergic properties in varying degrees. The anticholinergic activity of piperidine derivatives such as cyproheptadine is moderate. Sedative effects from cyproheptadine are a result of antagonism at central histaminergic receptors, although sedation is not as pronounced as with other H1-antagonists such as diphenhydramine. Following prolonged administration, tolerance may occur, but this may be beneficial because sedative effects may be reduced. Cyproheptadine also competes with serotonin at receptor sites in smooth muscle in the intestines and other locations. Antagonism of serotonin on the appetite center of the hypothalamus may account for cyproheptadine's ability to stimulate appetite. Cyproheptadine also has been used to counter vascular headaches, which many believe are caused by changes in serotonin activity. It is unclear how cyproheptadine, a serotonin-receptor antagonist, exerts a beneficial effect on this condition, since sumatriptan, a newer agent specifically indicated for treating migraine, acts as an agonist at serotonin receptors. Pharmacokinetics: Cyproheptadine is administered orally. In general, H1-blockers are well absorbed from the GI tract, but they vary in solubility, which ultimately affects the onset of action. Less soluble H1-antagonists have a slower onset of action and are less likely to cause toxicity; cyproheptadine has moderate solubility. Peak concentration of cyproheptadine occurs in about 6ïŋ―9 hours, and the duration of action is about 8 hours. Distribution of cyproheptadine has not been elucidated and it is unknown if the drug is distributed into milk. The parent compound is extensively metabolized in the liver to a number of conjugated metabolites. Plasma half-life ranges from 1ïŋ―4 hours. Excretion is mainly renal, with no apparent excretion of unchanged drug. Some unchanged drug and metabolites are excreted in feces.

Indications...Dosage For prevention and treatment of allergic conditions, such as allergic rhinitis, allergic conjunctivitis, pruritus, or cold urticaria: Oral dosage: Adults: 4 mg PO every 8ïŋ―12 hours. Dosage may be increased as necessary. Usual daily dosage is 4ïŋ―20 mg/day. Maximum daily dosage is 0.5 mg/kg/day or 32 mg/day PO, whichever is less. Elderly: Initially, 4 mg PO every 12 hours. Dosage may be increased slowly as necessary and administered in divided doses every 8 hours. Maximum daily dosage is 0.5 mg/kg/day or 32 mg/day PO, whichever is less. Children age 7ïŋ―14 years: 0.25 mg/kg/day in two or three divided doses or 4 mg PO every 8ïŋ―12 hours. Maximum daily dosage is 16 mg. Children age 2ïŋ―6 years: 0.25 mg/kg/day in two or three divided doses or 2 mg PO every 8ïŋ―12 hours. Maximum daily dosage is 12 mg. For the adjunct treatment of anorexiaïŋ― nervosa or non-psychogenic anorexiaïŋ― for stimulation of appetite: NOTE: Exclusion of organic causes of weight loss is important before treatment begins. Oral dosage: Adults: Initially, 2 mg PO two or three times per day with meals. May be increased over 3 weeks to a usual maintenance dose of 8ïŋ―12 mg/day PO given in two or three divided doses. Weight gain is usually noted during the first few weeks of therapy. In adults with anorexia nervosa, up to 8 mg PO four times per day has been administered Elderly: Initially, 2 mg PO two or three times per day with meals. May be increased over 3 weeks to a usual maintenance dose of 8ïŋ―12 mg/day PO given in two or three divided doses. Treatment period should not exceed 6 months. Weight gain is usually noted during the first few weeks of therapy. Children 7ïŋ―14 years: Initially, 2 mg PO two or three times per day with meals. Maintenance dose is usually 4 mg PO two or three times per day. Maximum daily dosage should not exceed 16 mg. Weight gain is usually noted during the first few weeks of therapy. Children 2ïŋ―6 years: Initially, 2 mg PO two or three times per day with meals. May be increased, but maximum daily dosage should not exceed 12 mg. Weight gain is usually noted during the first few weeks of therapy. For the treatment of male or female anorgasmyïŋ― secondary to antidepressant therapy: Oral dosage: Adults: 4ïŋ―12 mg PO given one to two hours before anticipated sexual activity or up to 16 mg/day in divided doses. For the treatment of Cushing's syndromeïŋ― secondary to pituitary disorders: Oral dosage: Adults: Initially, 8 mg PO per day in divided doses. May be increased gradually up to 24 mg/day in divided doses. For prophylaxis and treatment of vascular headacheïŋ― including migraineïŋ― (ie., migraine prophylaxisïŋ―): Oral dosage: Adults: At onset of attack, 4 mg PO. Repeat in 30 minutes, if necessary. Maintenance dose is 4 mg PO every 4ïŋ―6 hours.[351] Maximum Dosage Limits: ïŋ―Adults: 0.5 mg/kg/day PO or 32 mg/day PO, whichever is less. ïŋ―Elderly: 0.5 mg/kg/day PO or 32 mg/day PO, whichever is less. ïŋ―Adolescents 15ïŋ―18 years: 0.5 mg/kg/day PO or 32 mg/day PO, whichever is less. ïŋ―Adolescents 13ïŋ―14 years: 16 mg/day PO. ïŋ―Children >= 7 years: 16 mg/day PO. ïŋ―Children 2ïŋ―6 years: 12 mg/day PO. ïŋ―Children < 2 years: Safe and effective use not established. ïŋ―Infants: Safe and effective use not established. Patients with hepatic impairment: Dosage should be reduced for those patients with hepatic impairment; however, specific guidelines for dosage adjustments are not available. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. ïŋ―non-FDA-approved indication

Administration Oral Administration ïŋ―Cyproheptadine may be administered without regard to meals.

Contraindications The anticholinergic activity of H1-antagonists may result in thickened bronchial secretions in the respiratory tract thereby aggravating an acute asthmatic attack or COPD. Although H1-antagonists should be avoided during an acute asthmatic attack, these anticholinergic effects do not preclude the use of H1-antagonists in all asthmatic or COPD patients, particularly if the above respiratory symptom is not a primary component of the illness. Cyproheptadine exhibits only a moderate amount of anticholinergic activity; although, the use of an H1-antagonist with less anticholinergic effects may be preferable in some instances. Cyproheptadine is classified as pregnancy category B. H1-antagonists generally are not recommended for use in pregnancy, especially during the third trimester, because of a seizure risk to the fetus. Cyproheptadine should be considered during pregnancy only when the benefits of therapy outweigh the risks to the fetus. H1-antagonists are not recommended for use during breast-feeding because they can induce a paridoxical CNS stimulation in neonates or seizures in premature infants. Inhibition of lactation may also occur. Alternative methods of feeding should be used if cyproheptadine therapy is necessary. Cyproheptadine should be used with caution in children since a paradoxical CNS stimulation can occur. There have been a number of cases of respiratory depression, sleep apnea, and SIDS in children receiving phenothiazine antihistamines. The mechanism of this reaction is not yet known; therefore, antihistamines should be used with extreme caution in children with a family history of SIDS or sleep apnea. H1-antagonists should not be used in neonates due to the possibility of paradoxical CNS stimulation or seizures. Cyproheptadine should be used conservatively in patients with closed-angle glaucoma. An increase in intraocular pressure may occur from the anticholinergic actions of the drug, precipitating an acute attack of glaucoma. Elderly patients are more susceptible to the anticholinergic effects of cyproheptadine, including possible precipitation of undiagnosed glaucoma. Other ocular effects resulting from the anticholinergic effects of cyproheptadine include dry eyes or blurred vision. This may be of significance in the elderly and wearers of contact lenses. Although cyproheptadine has only moderate anticholinergic effects, a worsening of symptoms may be seen in patients with bladder obstruction, GI obstruction or ileus, benign prostatic hypertrophy, or urinary retention. These precautions are most significant when using antihistamines from the ethanolamine and phenothiazine groups. The elderly are more susceptible to the anticholinergic effects of drugs since there is a decline in endogenous cholinergic activity that occurs with age. Cyproheptadine is extensively metabolized in the liver. The metabolism of cyproheptadine may be reduced in the presence of hepatic impairment. Those with significant hepatic disease receiving cyproheptadine should be monitored for liver function and side effects. Dosage adjustments may be required in these patients. The quinidine-like local anesthetic and anticholinergic effects of antihistamines are responsible for the adverse cardiac effects which have been observed including tachycardia, ECG changes, hypotension, and arrhythmias. Although these cardiovascular effects are uncommon, H1-antagonists should be used conservatively in patients with cardiac disease. Cyproheptadine can cause drowsiness. Patients receiving cyproheptadine should be advised to avoid driving or operating machinery until the effects of the drug are known.

Interactions The anticholinergic activity of MAOIs is minimal; however, anticholinergic effects sometimes occur. It is recommended that the concurrent use of MAOIs with drugs possessing anticholinergic activity be avoided, especially atropine and scopolamine, since their effects and those of other anticholinergic drugs are potentiated and may become severe. Most manufacturers recommend that H1-antagonists not be used within two weeks of therapy with an MAOI. The anticholinergic effects of cyproheptadine may be enhanced when combined with other antimuscarinics. Drugs with significant antimuscarinic effects include most tricyclic antidepressants (e.g., amitriptyline, amoxapine, clomipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), phenothiazines (e.g., chlorpromazine, mesoridazine, promazine, thioridazine, triflupromazine), ethanolamine-derivative H1-blockers (e.g., clemastine, diphenhydramine), and benztropine. Although the anticholinergic effects of cyproheptadine are only moderate, the use of an H1-antagonist with less anticholinergic effects may be preferable when an H1-blocker must be used with any of the above agents. Although cyproheptadine is only moderately sedating, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including ethanol, entacapone, barbiturates, anxiolytics, sedatives, and hypnotics, antipsychotics, opiate agonists, butorphanol, nalbuphine, pentazocine, tricyclic antidepressants, or other H1-blockers. H1-antagonists which do not appear to potentiate the effects of CNS depressants include astemizole, loratadine, and terfenadine. Cyproheptadine has been used for the management of inhibited male or female orgasm caused by antidepressants such as the SSRIs; however, a reversal of antidepressant effects may occur when these agents are combined due to the serotonin antagonistic effects of cyproheptadine. PRN administration of cyproheptadine may be preferable to routine use if the combination is indicated.

CNS depression, manifested as sedation, drowsiness, and/or dizziness, can occur during therapy with cyproheptadine. There is considerable individual patient response to sedative effects, so patients should be warned of the possible impairment of mental acuity. These side effects may disappear after a few days of medication. Geriatric patients may be more predisposed to developing adverse CNS depressant effects, and alcohol intake will increase sedation. If symptoms persist or are severe, a dose reduction or change to another H1-antagonists may be advisable. Other possible CNS effects include headache and muscular weakness. H1-antagonists can cause CNS stimulation; although, this is more likely to occur in children. Symptoms may include restlessness, insomnia, palpitations, and in severe cases, seizures. Cyproheptadine possesses a moderate degree of anticholinergic activity. Anticholinergic effects that can occur during therapy include thickening of bronchial secretions, xerostomia, urinary retention, insomnia, nervousness, and/or blurred vision. Geriatric patients are more susceptible to these adverse reactions, since endogenous cholinergic activity declines with age. H1-antagonists can cause adverse GI effects including nausea/vomiting, diarrhea, constipation, and/or abdominal pain. Some of these adverse reactions may be relieved by taking the drug with meals or milk. Adverse cardiovascular responses are likely to be associated with the anticholinergic properties or the quinidine-like anesthetic effects of antihistamines. These responses may include sinus tachycardia, extrasystoles, palpitations, and/or cardiac arrhythmias. Alpha-adrenergic blockade may lead to hypotension. Hypertension may also occur, but is usually not of clinical significance.

REFERENCIAS139. Coutts A, Greaves MW. Evaluation of six antihistamines in vitro and in patients with urticaria. Clin Exp Dermatol 1982;7:529ïŋ―36.

351. Schulman EA, Silberstein SD. Symptomatic and prophylactic treatment of migraine and tension-type headache. Neurology 1992;42(suppl 2):16ïŋ―21.