Doxapram

Doxapram is an analeptic agent (a stimulant of the central nervous system).

It is also used to prevent and treat pulmonary complications of premature birth.

Doxapram is rapidly distributed into the tissues and gets extensively metabolised in the liver via ring hydroxylation to active metabolite, keto-doxapram.The Metabolites and a small amount of unchanged drug are excreted via bile to the faeces.

The onset of action of Doxapram is Resp stimulation: 20-40 seconds.

The Duration of Action of Doxapram is 5-12 min.

Doxapram shows common side effects like Dysrrhythmias, seizure, HTN or hypotension, dyspnoea. Nervous: Confusion, convulsions, dizziness, hallucinations, headache, hyperactivity.

Doxapram is available in the form of Solutions

Doxapram is available in India, Germany, Canada, Italy.

Doxapram stimulates respiration through action on peripheral carotid chemoreceptors. It also directly stimulates the central respiratory center in medulla w/ progressive stimulation of other parts of the brain and spinal cord at higher doses.

Doxapram is indicated for use as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease.

Doxapram is approved for use in the following clinical indications

Respiratory stimulant for respiratory depression secondary to anesthesia, mild-to-moderate drug-induced respiratory and CNS depression; acute hypercapnia secondary to COPD.

Intravenous

• Postoperative respiratory depression

Adult: 1-1.5 mg/kg via inj over at least 30 seconds, repeated at hrly intervals, as necessary. Alternatively, an initial dose of 2-5 mg/min via infusion, reduced to 1-3 mg/min according to response. Max total: 4 mg/kg.

Incompatibility: Incompatible w/ ascorbic acid, cefoperazone, cefotaxime, cefotetan, cefuroxime, clindamycin, folic acid, dexamethasone, diazepam, hydrocortisone, methylprednisolone. May form precipitate or gas w/ alkaline soln (e.g. thiopental Na, Na bicarbonate, furosemide, or aminophylline.

Intravenous

• Acute respiratory failure

Adult: 1.5-4 mg/min via infusion, adjusted according to response.

Incompatibility: Incompatible w/ ascorbic acid, cefoperazone, cefotaxime, cefotetan, cefuroxime, clindamycin, folic acid, dexamethasone, diazepam, hydrocortisone, methylprednisolone. May form precipitate or gas w/ alkaline soln (e.g. thiopental Na, Na bicarbonate, furosemide, or aminophylline.

Doxapram is available in 20 mg/ml

Doxapram is available in the form of solutions.

Dosage Adjustment in Kidney Patient

● There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, use caution in severe impairment due to the potential for altered pharmacokinetics.

Dosage Adjustment in Hepatic impairment Patient

• There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, use caution in severe impairment due to the potential for altered pharmacokinetics.

Dosage Adjustment for Pediatric Patients

Drug-induced CNS depression:

Children ≥12 years and Adolescents: IV:

● Intermittent injection: Initial: Priming dose of 1 to 2 mg/kg; repeat after 5 minutes; may repeat at 1 to 2 hour intervals until sustained consciousness; if relapse occurs may resume repeat doses at 1 to 2 hour intervals until sustained consciousness or maximum dose reached; maximum daily dose: 3,000 mg/day. May repeat in 24 hours if necessary; repeat doses should only be given to patient who demonstrated a response to initial dose.

● IV infusion: Initial: Priming dose of 1 to 2 mg/kg; repeat after 5 minutes. If no response, wait 1 to 2 hours and repeat priming dose. If some respiratory stimulation is noted, initiate infusion at 1 to 3 mg/minute (depending on size of patient/depth of CNS depression); suspend infusion if patient begins to awaken. Infusion should not be continued for >2 hours. May reinstitute infusion as described above, including bolus, after rest interval of 30 minutes to 2 hours; maximum daily dose: 3,000 mg/day.

Respiratory depression following anesthesia:

Children ≥12 years and Adolescents: IV:

● Intermittent injection: Initial: 0.5 to 1 mg/kg; may repeat at 5-minute intervals; maximum single injection dose: 1.5 mg/kg; maximum total dose: 2 mg/kg.

● Continuous IV infusion: Initial: 5 mg/minute until adequate response or adverse effects seen; decrease to 1 to 3 mg/minute; maximum total dose: 4 mg/kg (in an average adult, ~300 mg total dose).

Hypersensitivity to doxapram or any component of the formulation; significant cardiovascular impairment (eg, uncompensated heart failure, severe coronary artery disease); severe hypertension (including severe hypertension associated with hyperthyroidism or pheochromocytoma); cerebral edema, cerebral vascular accident, epilepsy or other convulsive disorders, head injury; mechanical disorders of ventilation (eg, mechanical obstruction, muscle paresis, neuromuscular blockade, flail chest, pneumothorax, acute asthma, pulmonary fibrosis), pulmonary embolism (proven or suspected).

Concerns related to adverse effects:

• Cardiovascular effects: May cause dysrhythmias; monitor for disturbances of cardiac rhythm. If sudden hypotension develops during use, discontinue. Increases in blood pressure are generally modest; use is contraindicated in patients with severe hypertension.

• CNS stimulation: May cause severe CNS stimulation, including seizures; antiseizure medications (as well as oxygen and resuscitative equipment) should be available to manage potential excessive CNS stimulation.

Disease-related concerns:

• Cerebrovascular disease: Use with caution in patients with cerebrovascular disease; lowered pCO₂ induced by hyperventilation produces cerebral vasoconstriction and decreased circulation.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Do not use in patients on mechanical ventilation. Use with caution in treating pulmonary disease; a pressor effect on pulmonary circulation may result in a fall in arterial pO₂. If sudden dyspnea develops during use, discontinue. Doxapram causes patients to increase the work of breathing; therefore, do not increase the rate of infusion in an attempt to lower the pCO₂ in severely-ill COPD patients.

Concurrent drug therapy issues:

• MAO inhibitors (MAOIs): Use caution with coadministration; additive pressor effect may occur.

• Sympathomimetics: Use caution with coadministration; additive pressor effect may occur.

• Volatile anesthetics: If patient has received anesthesia with a volatile agent known to sensitize the myocardium to catecholamines, avoid use of doxapram until anesthetic has been eliminated to decrease the risk of ventricular tachycardia or ventricular fibrillation.

Doxapram should not be used in conjunction with mechanical ventilation. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants.

High-fat meal may decrease the rate but not the extent of absorption. Management: May administer with meals.

Significant

Increased left ventricular output, and stroke volume, tachycardia, hyper- or hypoglycaemia, diuresis, electrolyte loss, withdrawal symptoms (e.g. tiredness, decreased alertness), increased metabolism.

Cardiac disorders: Arrhythmia.

Gastrointestinal disorders: Gastrointestinal disturbances.

Nervous system disorders: Convulsion, tremor, headache.

Additive pressor effect when concurrently used with MAOIs or sympathomimetics. May temporarily mask the residual effect when used with neuromuscular blocking agents. May cause increased CNS stimulation, agitation, muscle fasciculation and hyperactivity with concurrent use of aminophylline/theophylline. Cardiac arrhythmias may occur when given with anaesthetics that are known to sensitise the myocardium to catecholamines (e.g. enflurane, halothane, isoflurane), delay initiation of doxapram for at least 10 min after discontinuance of anaesthesia.

The common side effects of Doxapram include the following Psychiatric disorders: Insomnia, nervousness, irritability, anxiety.

Respiratory, thoracic and mediastinal disorders: Elevated respiration.

Potentially Fatal: Necrotising enterocolitis.

Symptoms: HTN, tachycardia and other arrhythmias, skeletal muscle hyperactivity including enhanced deep tendon reflexes, dyspnoea, cough, confusion, agitation, sweating; clonic and generalised seizure may occur.

Management: Symptomatic treatment. IV diazepam, phenytoin, and short-acting barbiturates may be given, along with oxygen and resuscitative equipment.

Pharmacodynamic

Doxapram is an analeptic agent (a stimulant of the central nervous system). The respiratory stimulant action is manifested by an increase in tidal volume associated with a slight increase in respiratory rate. A pressor response may result following doxapram administration. Provided there is no impairment of cardiac function, the pressor effect is more marked in hypovolemic than in normovolemic states. The pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following doxapram administration, an increased release of catecholamines has been noted

Pharmacokinetics

• Distribution: Rapidly distributed into the tissues.
• Metabolism: Extensively metabolised in the liver via ring hydroxylation to active metabolite, keto-doxapram.
• Excretion: Metabolites and a small amount of unchanged drug are excreted via bile to the faeces.

• https://www.rxlist.com/dopram-drug.htm
• https://www.mims.com/india/drug/info/doxapram?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00561
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003846/