G. Doxapram hydrochloride
Doxapram hydrochloride (DopramŽ) is a central nervous system stimulant (analeptic agent). It is used as a respiratory stimulant but has only a limited role in the management of respiratory failure. Formerly, nikethamide and ethamivan were used as respiratory stimulants but are no longer recommended because the effective doses were close to toxic levels.
When given intravenously to normal subjects, it causes a increase in tidal volume and respiratory rate, thereby increasing minute volume with a concomitant fall in PaCO2 and rise in PaO2. This effect in animals is dependent upon an intact respiratory centre and is mediated by increased neuromuscular drive in a dose dependent fashion. The main mode of action is thought to be due to specific stimulation of peripheral chemoreceptors, especially in the carotid body. Doxapram can antagonise the blunted ventilatory response to carbon dioxide caused by opiates and can also antagonise respiratory depression caused ethanol. Doxapram also has effects on the cardiovascular system including an increase in stroke volume and an increase in blood pressure. In higher dosages, there is non-specific stimulation of the central nervous system which may lead to convulsions.
Doxapram is given intravenously and has a half life of about 3 hours and has a mean volume of distribution of about 1.5l/kg in adults. It is mainly metabolised by the liver and one of its main metabolites, keto-doxapram has slight pharmacological activity and accumulates during continuous intravenous infusion.
The use of doxapram in the management of acute hypercapnic respiratory failure is limited to those patients who are unsuitable for intubation and ventilation (i.e., patients with acute on chronic respiratory failure). When doxapram is used, it should be in conjunction with other supportive measures such as controlled oxygen therapy, nebulised bronchodilators, physiotherapy and more recently, nasal ventilatory support. Its short half life requires that it is given as a continuous intravenous infusion and there is some evidence that the may be tachyphylaxis as the infusion rate may need to be increased with time to give an equivalent therapeutic effect, but this may just represent worsening of the underlying condition. The usual infusion rate is 1-4mg/min according to clinical response and blood gas measurements. It should only be used where facilities for close patient monitoring are available. The use of doxapram is absolutely contraindicated in the treatment of respiratory failure secondary to acute severe asthma, pulmonary embolism, pulmonary oedema, pneumothorax and other causes of non hypercapnic respiratory failure. Doxapram is also used in the treatment of respiratory depression following general anaesthesia. It can antagonise the respiratory depressant effects of opiate analgesics without inhibition of their analgesic properties. It is usually given as an intravenous injection of 1-1.5mg/kg repeated after one hour. If further injections are required, a continuous infusion may be necessary. The short duration of action after a single dose is due to redistribution of the drug rather than metabolism. Doxapram is also contraindicated in patients with epilepsy, severe hypertension, hyperthyroidism and ischaemic heart disease. It should not be used in respiratory depression due to intracranial pathology.
General stimulation of the central nervous system may occur even within the therapeutic range. There may be muscle fasciculation or spasm and a risk of generalised seizures. There is often a slight rise in blood pressure and an increased incidence of dysrhythmias. Non specific side effects include headache, dizziness, agitation, confusion, nausea, vomiting and perineal warmth on intravenous injection. Side effects may be more common if there is concomitant use of theophyllines as is often the case. It should also be noted that doxapram cannot be given in the same infusion line as aminophylline as the two are incompatible. Because patients become more aroused with doxapram, they may become more aware of their dyspnoea and the increased respiratory drive may make bronchospasm more obvious and increase coughing. Toxic side effects should be treated symptomatically.
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