Caffeine

Usage

• Medical Conditions: Caffeine is primarily used to treat apnea of prematurity in infants. It is also used to treat fatigue and drowsiness and as a respiratory stimulant, though its use as a respiratory stimulant is strongly discouraged. Off-label, caffeine can be used as a stimulant diuretic.
• Pharmacological Classification: Central nervous system stimulant, adenosine receptor antagonist.
• Mechanism of Action: Caffeine primarily acts as a nonselective competitive antagonist of adenosine receptors, particularly A₁ and A_2A receptors. It also inhibits phosphodiesterase and increases cytosolic calcium concentrations, leading to increased cardiac conduction and activity.

Alternate Names

• Trimethylxanthine
• 1,3,7-Trimethylpurine-2,6-dione
• Methyltheobromine
• Guaranine
• Theine
• Mateine

Brand Names: Numerous brand names exist depending on the formulation (e.g., Vivarin, NoDoz, and various generic caffeine tablets, as well as combination products). Caffeine is also present in many beverages and foods (coffee, tea, energy drinks, chocolate).

How It Works

• Pharmacodynamics: Caffeine stimulates the central nervous system, increasing alertness, reducing fatigue, and improving cognitive function (especially in tasks requiring sustained attention). It can also increase heart rate and blood pressure, act as a mild diuretic, and stimulate gastric acid secretion.
• Pharmacokinetics:
  • Absorption: Rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations occur within 30-60 minutes.
  • Metabolism: Primarily metabolized in the liver by the cytochrome P450 enzyme CYP1A2, resulting in paraxanthine, theobromine, and theophylline.
  • Elimination: Metabolites are excreted primarily in the urine. The elimination half-life varies considerably (2.5-10 hours), depending on factors like age, genetics, liver function, and smoking status. Pregnancy can significantly prolong the half-life.
• Mode of Action: Caffeine competitively blocks adenosine receptors in the brain. Adenosine typically promotes sleep and reduces neuronal excitability. By blocking these receptors, caffeine increases neuronal firing, leading to its stimulant effects. Caffeine also inhibits phosphodiesterase, leading to increased cyclic AMP levels.
• Receptor Binding, Enzyme Inhibition, Neurotransmitter Modulation: Caffeine is a nonselective adenosine receptor antagonist (A₁, A_2A, A_2B, A₃), with higher affinity for A₁ and A_2A. Inhibits phosphodiesterase. Modulates dopamine and glutamate release.
• Elimination Pathways: Primarily renal excretion of metabolites. Metabolism by CYP1A2 is a key step in caffeine clearance.

Dosage

Standard Dosage

Adults: Up to 400 mg daily for healthy adults. This is equivalent to approximately four cups of brewed coffee.

Children: Less than 3 mg/kg of body weight per day for children under 18. Limit caffeine intake to avoid potential negative effects on sleep, mood, and behavior.

Special Cases:

• Elderly Patients: 50 to 100 mg of caffeine is generally well-tolerated. Consider lower doses if caffeine sensitivity is present.
• Patients with Renal Impairment: Reduce dosage and monitor serum caffeine levels due to the potential for accumulation.
• Patients with Hepatic Dysfunction: Reduce dosage and monitor serum caffeine levels due to impaired metabolism.
• Patients with Comorbid Conditions: Caution is advised in patients with anxiety disorders, diabetes, cardiovascular disease, and insomnia. Caffeine can exacerbate these conditions. For diabetes patients, consider limiting caffeine intake to less than 200 mg per day. For those with cardiovascular disease, moderate caffeine intake (up to 400 mg/day) appears generally safe for most individuals, but individual responses can vary significantly. Monitor blood pressure for those with hypertension.

Clinical Use Cases

• Apnea of Prematurity: Caffeine citrate is used in neonates. A loading dose of 20 mg/kg (IV) is followed by a maintenance dose of 5 mg/kg/day (orally or IV).
• Intubation: Caffeine is not routinely used during intubation.
• Surgical Procedures: Not typically administered during surgical procedures.
• Mechanical Ventilation: Not routinely used with mechanical ventilation.
• Intensive Care Unit (ICU) Use: May be used cautiously for apnea of prematurity or off-label as a respiratory stimulant in select cases.
• Emergency Situations: May be used in specific cases, such as assisting in reversing respiratory depression caused by certain medications.

Dosage Adjustments:

Adjustments are necessary based on renal and hepatic function, and in other special populations as described above. Consider pharmacogenomic factors, especially CYP1A2 polymorphisms, which can influence caffeine metabolism.

Side Effects

Common Side Effects:

Anxiety, insomnia, restlessness, tremors, headache, nausea, increased heart rate, diuresis.

Rare but Serious Side Effects:

Cardiac arrhythmias, seizures, psychosis (at very high doses).

Long-Term Effects:

Potential for caffeine dependence, anxiety disorders exacerbation, and sleep disturbances with chronic excessive use.

Adverse Drug Reactions (ADR):

Severe anxiety, cardiac arrhythmias, seizures.

Contraindications:

No absolute contraindications, but use cautiously in patients with anxiety disorders, insomnia, cardiac arrhythmias, uncontrolled hypertension, peptic ulcer disease, and seizure disorders. Genetic polymorphisms affecting caffeine metabolism should be considered when appropriate.

Drug Interactions

• CYP450 Interactions: Caffeine is metabolized by CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) can increase caffeine levels. Inducers of CYP1A2 (e.g., smoking) can decrease caffeine levels.
• Other Drug Interactions: Caffeine can interact with medications like adenosine, theophylline, some antibiotics, and certain antidepressants. It may increase the effects of stimulants and reduce the effects of sedatives.
• OTC Drugs and Supplements: Interactions with ephedrine and other stimulants can increase the risk of adverse effects.
• Food and Lifestyle Factors: Smoking induces CYP1A2, reducing caffeine levels. Alcohol and grapefruit juice may inhibit caffeine metabolism.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Moderate caffeine intake during pregnancy (up to 300 mg/day) appears generally safe, though some sources recommend limiting it to 200 mg/day. Caffeine readily crosses the placenta, and excessive intake can increase the risk of miscarriage and other complications.
• Breastfeeding: Caffeine is excreted in breast milk and can cause irritability and sleep disturbances in infants. Limit caffeine intake during breastfeeding to 200 to 300 mg/day.

Drug Profile Summary

• Mechanism of Action: Adenosine receptor antagonist, phosphodiesterase inhibitor.
• Side Effects: Anxiety, insomnia, tremors, headache, nausea, increased heart rate.
• Contraindications: Use cautiously in patients with anxiety, insomnia, cardiac arrhythmias, uncontrolled hypertension, peptic ulcer disease, seizure disorders.
• Drug Interactions: CYP1A2 inhibitors and inducers, adenosine, theophylline, stimulants, sedatives.
• Pregnancy & Breastfeeding: Moderate intake is generally safe; limit to 200-300 mg/day.
• Dosage: Up to 400 mg/day for adults, less than 3 mg/kg/day for children. Special adjustments required for renal/hepatic impairment and other conditions.
• Monitoring Parameters: Heart rate, blood pressure, serum caffeine levels (in specific clinical situations).

Popular Combinations:

• Caffeine is often combined with ergotamine for migraine treatment.
• It may be combined with analgesics (e.g., acetaminophen, aspirin) for enhanced pain relief.

Precautions

• Evaluate patients for caffeine sensitivity, anxiety disorders, cardiac conditions, hypertension, peptic ulcer disease, and seizure disorders.
• Specific Populations: See details above regarding pregnant women, breastfeeding mothers, children, and the elderly.
• Lifestyle Considerations: Advise patients about potential interactions with alcohol, smoking, and other dietary factors. Caffeine can impair sleep; therefore, caution patients against consuming it close to bedtime.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Caffeine?

A: Up to 400 mg/day for healthy adults, less than 3 mg/kg/day for children under 18. Pregnant and breastfeeding women should limit intake to 200-300 mg/day.

Q2: How does caffeine affect patients with diabetes?

A: Caffeine can impact insulin sensitivity and may lead to fluctuations in blood sugar levels. Monitor blood sugar closely, and consider limiting intake to under 200 mg/day for patients struggling to control their diabetes.

Q3: Can caffeine be used in patients with cardiovascular disease?

A: Moderate caffeine intake is generally safe for most people with cardiovascular disease. Individual responses to caffeine can vary substantially, especially concerning blood pressure and heart rate. Carefully monitor patients with hypertension and consider advising them to limit or avoid caffeine.

Q4: Does caffeine interact with any medications?

A: Yes, caffeine can interact with several medications, including CYP1A2 inhibitors (e.g., fluvoxamine), CYP1A2 inducers (e.g., smoking), adenosine, theophylline, some antibiotics, and certain antidepressants.

Q5: What are the signs of caffeine overdose?

A: Symptoms include anxiety, restlessness, insomnia, tremors, rapid heart rate, nausea, vomiting, and in severe cases, seizures and cardiac arrhythmias.

Q6: Can caffeine trigger seizures?

A: High doses of caffeine can potentially lower the seizure threshold and might trigger seizures in susceptible individuals, particularly those with epilepsy. However, moderate doses may even have a slight protective effect. Monitor patients with epilepsy closely.

Q7: How does caffeine affect sleep?

A: Caffeine can disrupt sleep patterns by blocking adenosine, a neurotransmitter that promotes sleep. Advise patients to avoid caffeine close to bedtime.

Q8: Is caffeine addictive?

A: Caffeine can lead to dependence, and withdrawal symptoms (headache, fatigue, irritability) can occur upon cessation. Advise patients to reduce intake gradually if discontinuing caffeine.

Q9: How does caffeine affect athletic performance?

A: Caffeine can enhance athletic performance by increasing alertness, reducing perceived exertion, and improving endurance. However, individual responses can vary depending on genetic and other factors.

Q10: What is the role of caffeine in apnea of prematurity?

A: Caffeine citrate is used to stimulate respiration in premature infants experiencing apnea. It is effective in reducing the frequency and severity of apnea episodes.