Caffeine

Caffeine is a stimulant belonging to the methyl xanthine class.

Caffeine is indicated for the short-term treatment of apnea of prematurity in infants and off-label for the prevention and treatment of bronchopulmonary dysplasia caused by premature birth.

Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, the onset of action takes place within 45 mins to 1 hour. Food may delay caffeine absorption. Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat-soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population. Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2)

Caffeine shows common side effects like Insomnia, nervousness, irritability, and anxiety. Respiratory, thoracic, and mediastinal disorders: Elevated respiration.

Caffeine is available in the form of Oral solutions, Tablets, Capsules, lozenges, and Injections.

Caffeine is available in India, Germany, Canada, and Italy.

Caffeine exerts several actions on cells, but its clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participation in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP.This causes lipolysis through the activation of hormone-sensitive lipases, releasing fatty acids and glycerol.

Caffeine is indicated for the short-term treatment of apnea of prematurity in infants.

Caffeine is approved for use in the following clinical indications

It is used to treatment of apnea of prematurity.

Although not approved there have been certain off label use documented for Caffeine which includes:-

It is also used for the treatment Of Augmentation of seizure induction during electroconvulsive therapy (caffeine and sodium benzoate); Postdural puncture headache (caffeine and sodium benzoate); Reversal of dipyridamole- or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing (alternative agent)

Caffeine is available in various strengths as

• Tablets (175 and 200mg)
• Capsules (175mg)
• Injection (20mg/ml )

Caffeine is available in the form of Oral solutions, Tablets, Capsules, lozenges, and Injections.

Dosage Adjustment in Kidney Patient

● Short-term treatment of neonatal apnoea of prematurity:

● Reduced maintenance daily dose may be necessary and must be guided by blood caffeine measurements.

Dosage Adjustment in Hepatic impairment Patient

• Mild impairment: No dosage adjustment necessary.
• Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling

Dosage Adjustment for Pediatric Patients

Neonates As caffeine citrate oral solution: Loading dose: 20 mg/kg (10 mg/kg caffeine). If there is no adequate response within 4 hours, a 2nd loading dose may be given. If there is continued inadequate response, measure caffeine blood levels before giving further doses. Maintenance: 5-10 mg/kg (2.5-5 mg/kg caffeine) daily, starting 24 hours after the loading dose(s). Dosage adjustments and further monitoring may be required according to clinical judgment in at-risk situations (refer to detailed product guidelines).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Studies to assess the potential carcinogenic effects of Caffeine have not been conducted.

Caffeine was negative for genotoxicity in the following assays: bacterial reverse mutation assay (Ames test), gene mutation assay in Chinese hamster V79 cells, chromosomal aberration assay in Chinese hamster ovary cells, unscheduled DNA synthesis in HELA S3 cells, and in vivo mouse micronucleus assay.

A 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 hypoglycemia, diuresis, electrolyte loss, withdrawal symptoms (e.g. tiredness, decreased alertness), and increased metabolism.

• Cardiac disorders: Arrhythmia.
• Gastrointestinal disorders: Gastrointestinal disturbances.
• Nervous system disorders: Convulsion, tremor, headache.

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

Respiratory, thoracic, and mediastinal disorders: Elevated respiration.

Potentially Fatal: Necrotising enterocolitis.

Pediatric Use

Caffeine is indicated for rescue treatment, including the reduction of mortality and pneumothorax, of Respiratory Distress Syndrome (RDS) in premature infants

Symptoms: Seizure, jitteriness, tachypnoea, tachycardia, opisthotonos, rigidity, tonic-clonic movements, hypokalaemia, fine tremor of extremities, gastric irritation, restlessness, gastrointestinal hemorrhage, involuntary jaw, and lip movements, increased WBC count, compromised circulation, vomiting, fever, agitation, hypertonia, gastric residues, hyperexcitability, distended abdomen, metabolic acidosis, hyperglycemia, increased urea levels, pallor, dilated pupils, insomnia, headache, rapid speech, diuresis, tinnitus, and elevated respiration. Management: Supportive and symptomatic treatment. Monitor blood levels of caffeine and electrolyte (e.g. plasma K). Correct hypokalaemia and hyperglycemia. Consider exchange transfusion for severe cases. Administer IV anticonvulsants (e.g. diazepam, phenobarbital) to treat convulsion. May administer activated charcoal (adult: 50 g; children: 10-15 g) or perform gastric lavage (in adults) within 1 hour of ingestion; correct electrolyte imbalances if needed. Monitor pulse, cardiac rhythm, and blood pressure. Administer amiodarone or disopyramide for ventricular arrhythmias occurring in patients having convulsions. May give β-blocker for persistent hypertension.

Pharmacodynamic

Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic.

Pharmacokinetics

• Absorption

Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, the onset of action takes place within 45 to 1 hour.15 Food may delay caffeine absorption.

• Distribution

Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat-soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population.

• Metabolism

Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2)

• https://go.drugbank.com/drugs/DB00201
• https://www.mims.com/philippines/drug/info/caffeine?mtype=generic
• https://www.uptodate.com/contents/benefits-and-risks-of-caffeine-and-caffeinated-beverages
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462044/