5-Hydroxytryptamine (5-HT) Antagonists

5-Hydroxytryptamine (5-HT) Antagonists

Cyproheptadine

Uses

·      Anti-allergic.

·      Appetite stimulant.

·      Treatment of migraine, hyperlactinaemia, and Cushing’s syndrome.

Clinical (Toxic) Features

·      Toxicity results in hallucinations, ataxia, seizures, tachy-cardia, mydriasis, and staggering gait. Fatalities can occur.

·      Cyproheptadine has been reported to cause toxic psychosis following overdose ingestions in children. Toxic psychosis is characterised by agitation, disorientation, and hallucina-tions.

·      Acute hepatitis has also occurred after therapeutic admin-istration of cyproheptadine.

·      Weight gain has been reported as a side effect of cyprohep-tadine therapy. The increase in weight is directly propor-tional to the amount of cyproheptadine ingested.

·      Cyproheptadine has also been reported to interact with fluoxetine in two patients being treated for bulimia nervosa. The bulimia was in remission after fluoxetine therapy and reappeared after cyproheptadine was added.

Treatment

·      Stomach wash.

·      Control of seizures with diazepam or phenytoin.

·      Supportive measures.

Ketanserin

Uses

·      Hypertension.

·      Peripheral vascular disease, Raynaud’s disease.

Clinical Features

Hypotension, bradycardia, drowsiness, vertigo, nausea.

Treatment

Symptomatic measures: stomach wash, elevation of legs, pressor amines, IV normal saline.

Ondansetron and Related Drugs

Ondansetron is a selective serotonin 5-HT₃ receptor antagonist. Newer derivatives include alosetron, dolasetron, granisetron, and tropisetron

Uses

·      Prevention of emesis during cytotoxic chemotherapy.

·      Reduction in the severity of radiation-induced emesis, and terminal cancer emesis.

·              Ondansetron and dolasetron are indicated also for the treatment or prevention of post-operative nausea and vomiting.

Clinical (Toxic) Features

·      Adverse effects of therapeutic doses include constipa-tion or diarrhoea, headache, dry mouth, and hiccup, and asymptomatic elevation of liver enzymes. Rash and injection site reactions have occurred; ondansetron is not a vesicant. Injection site reactions include redness, swelling, burning. Burning sensations and hot flashes have been reported. There is also a report of shock with cardiac arrest and apnoea, a few minutes following ondansetron injection.

·      Toxicity has so far been rarely reported. Accidental intra-venous administration of ondansetron at 10 times the normal dose has occurred with no serious adverse reaction. However, one patient who received 72 mg of ondansetron as a single intravenous dose developed sudden blindness of 2 to 3 minutes duration. Some studies mention the following manifestations in overdose : fever, rash, rest-lessness, diarrhoea, seizures. Mild transient elevation of serum lactate dehydrogenase has been reported. Headache, dizziness, sedation, and extrapyramidal reactions have occurred.

·      Overdose of intravenous administration of dolasetron has resulted in hypotension, dizziness and abnormal ECG inter-vals. Co-administration of dolasetron with anti-arrhythmic drugs may increase the chances for QT prolongation.

·      Glaxo Wellcome voluntarily withdrew alosetron from the United States market on November 28, 2000. Several deaths and many cases of serious adverse events, including ischaemic colitis and severely obstructed or ruptured bowels due to complications of severe constipation, were reported in patients taking alosetron. In June 2002, the US Food and Drug Administration has decided to allow alos-etron back on to the US market under heavy restrictions for use only in women with refractory, diarrhoea-predominant irritable bowel syndrome.

Treatment

·      Supportive and symptomatic.

·      Activated charcoal is beneficial.

·      Haemodialysis/haemoperfusion is not expected to be of benefit due to the large volume of distribution (160 L for ondansetron).

Decongestants

Uses

■■  Decongestants reduce nasal congestion by stimulating the alpha-adrenergic receptor sites on vascular smooth muscles which causes the dilated arterioles to constrict and thereby reduce the blood flow to engorged nasal vascular beds.

■■  Pseudoephedrine is the d- isomer of ephedrine and has only 25% of the adrenergic receptor activity of ephedrine. While both ephedrine and pseudoephedrine are stimulants of alpha as well as beta adrenergic receptors, phelylpro-panolamine is devoid of beta-adrenergic receptor activity. Phenylpropanolamine is a sympathomimetic agent with primarily direct alpha-adrenergic agonist effects, but also indirect stimulation of noradrenaline release. It also has weak beta-1 agonist effects but lacks beta-2 agonist prop-erties. It is used as an oral and topical decongestant and an anorexiant.

■■Locally instilled nasal decongestants comprise imidazoline compounds such as naphazoline, oxymetazoline, tetrahy-drozoline, and xylometazoline, which are powerful alpha₂-adrenergic receptor stimulants.

Clinical (Toxic) Features

·              Toxicity usually manifests as CNS stimulation, hyperten-sion, and tachycardia (bradycardia with phenylpropa- nolamine). Headache is common. Serious manifestations include seizures, dysrhythmias, cerebral haemorrhage, and psychosis.

·              Imidazoline decongestants cause CNS depression, hypoten-sion, bradycardia, and respiratory depression. Imidazolinesmay also be used in combination with other sympa-thomimetics (e.g. phenylephrine or ephedrine), in whichcase, hypertension may be seen. Miosis may be present.Mydriasis has also occurred.

·              Imidazolines have presynaptic alpha-2 stimulant effects,like clonidine. Overdose or intoxication from oral inges-tion or excessive topical administration can result in severedrowsiness with diaphoresis, hypotension or shock, brady-cardia, respiratory depression, and coma. These manifesta-tions may occur in both adults and children; however, youngchildren (especially infants) are more susceptible to toxicity.Recovery may be expected in 12 to 36 hours. CNS depres-sion ranging from sleepiness, hypotonia, and hyporeflexiato coma is common in children. Lucidity upon arousal froma depressed mental state by vigorous verbal or tactile stimulifollowing imidazoline overdose is an important differentialdiagnostic finding. Headache, nervousness, tremors, andinsomnia are frequently reported.

·              Chronic overuse may result in reactive vasodilation of thenasal mucosa. Acute psychosis and hypertension have beenreported with chronic abuse.

·              Signs and symptoms of phenylpropanolamine overdosecomprise hypertension, mydriasis, arrhythmias, anxiety,chest pain, auditory and visual hallucinations, paranoidideation, occasionally delirium and psychosis, seizures,haemorrhagic and non-haemorrhagic cerebral infarctions,rhabdomyolysis, urinary retention, and renal failure. In fact,phenylpropanolamine has a propensity to cause significanthypertension, and may result in reflex bradycardia, exten-sive myocardial ischaemia, cerebral haemorrhage, or renaltoxicity. Tachycardia can also occur. Peak blood pressureeffects of phenylpropanolamine occur at about 2.5 hoursafter PPA ingestion with individual times ranging from 0.5to 4.5 hours.

·              Psychiatric disturbances, particularly in children, have been reported after ingestion of phenylpropanolamine includingrestlessness, irritability, aggressiveness, sleep disturbances,psychotic episodes, confusion, acute mania and hallucina-tions.

Treatment

Because drowsiness and coma may occur rapidly, emesis is not indicated even when nasal decongestants have been ingested. Emesis is contraindicated in patients with hypertension, since protracted vomiting may increase intracranial pressure. Activated charcoal and gastric lavage are also not routinely recommended, though they may be of value in phenylpropa-nolamine ingestions. Monitor serum CPK and renal function in severely symptomatic patients, and those with prolonged seizures or coma. A CT scan is indicated in patients with severe headache, neurologic deficits, or abnormal mental status (espe-cially in the case of phenylpropanolamine).

·      Seizures, agitation, and psychosis should be treated with IV diazepam. Refractory cases should be managed with barbiturates or neuromuscular blocking agents. Monitor for respiratory depression, hypotension, arrhythmias, and the need for endotracheal intubation. Evaluate for hypoxia, electrolyte disturbances and hypoglycaemia.

·      Severe symptomatic palpitations, tremor, and associated anxiety may respond to propranolol, particularly in patients with combination overdose of phenylpropanolamine and other sympathomimetic agents. However, propranolol may worsen hypertension in patients with single-ingredient phenylpropanolamine overdose.

·      Persistent or highly elevated hypertension should be treated with nitroprusside or nifedipine. Nitroglycerin and phen-tolamine are possible alternatives.

·      Hypotension can be managed with isotonic fluids, Trendelenberg position, and dopamine infusions.

·      Dysrhythmias usually respond to standard doses of lignocaine or bretylium. Propranolol can also be used. Lignocaine and amiodarone are generally first line agents for stable mono-morphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Sotalol is an alternative for stable monomorphic ventricular tachycardia. Sinus tachycardia does not generally require treatment unless haemodynamic compromise develops. If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred. Bradycardia generally does not require treatment. Since the bradycardia is a reflex response, atropine should theoretically be avoided as it may worsen hypertension.

·      Because the imidazoline decongestants produce sedation, hypotension, and bradycardia via a central alpha-adrenore-ceptor stimulation, similar to clonidine, the administration of naloxone may theoretically be beneficial.

·      Dialysis may be beneficial in phenylpropanolamine overdose.

Forensic Issues

■■   Caffeine was formerly available in combination with phenylpropanolamine and ephedrine in formulations designed to mimic controlled stimulants. This combina-tion was declared irrational by the FDA (USA) in August 1982, and removed from the market. Combinations of caffeine with phenylpropanolamine are illegal regardless of labelling. In fact in 2000, the FDA has requested the discontinuation of phenylpropanolamine from all pharma-ceutical products and has issued a public health warning concerning the risk of haemorrhagic stroke associated with phenylpropanolamine use, particularly among women. The dose of PPA used for appetite suppression is greater than the dose used in cough and cold preparations. The association between use of PPA in cough and cold preparations and increased risk of haemorrhagic stroke is less clear.

■■  Some patients developed acute hepatitis, characterised by abdominal pain, jaundice, and elevated liver enzyme levels, within 2 to 12 weeks after beginning daily use of a dietary supplement containing 25 mg norephedrine (phenylpropa-nolamine), 100 mg sodium usniate, 100 mcg 3,5-diiodothy-ronine, 3 mg yohimbine, and 100 mg caffeine. One of the patients developed fulminant hepatic failure with cerebral oedema despite discontinuation of the product. However, with supportive care, all patients gradually recovered without sequelae.

■■  Phenylpropanolamine is an FDA Pregnancy Category C drug. There is a recognised association between 1st trimester use and foetal malformations (hypospadias, gastroschisis, polydactyly, cataract, pectus escavatum, congenital dislocation of the hip, etc.).