indication

For management of fatigue, orthostatic hypotension, and for the short term treatment of apnea of prematurity in infants.

pharmacology

Caffeine, a naturally occurring xanthine derivative like theobromine and the bronchodilator theophylline, is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of prematurity). Often combined with analgesics or with ergot alkaloids, caffeine is used to treat migraine and other headache types. Over the counter, caffeine is available to treat drowsiness or mild water-weight gain.

mechanism of action

Caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine act as antagonists at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of caffeine. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.

toxicity

LD₅₀=127 mg/kg (orally in mice)

biotransformation

Hepatic cytochrome P450 1A2 (CYP 1A2) is involved in caffeine biotransformation. About 80% of a dose of caffeine is metabolized to paraxanthine (1,7-dimethylxanthine), 10% to theobromine (3,7-dimethylxanthine), and 4% to theophylline (1,3-dimethylxanthine).

absorption

Readily absorbed after oral or parenteral administration. The peak plasma level for caffeine range from 6-10mg/L and the mean time to reach peak concentration ranged from 30 minutes to 2 hours.

half life

3 to 7 hours in adults, 65 to 130 hours in neonates

route of elimination

In young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function.

drug interactions

Adenosine: Caffeine may diminish the therapeutic effect of adenosine. Specific management recommendations vary slightly depending on specific adenosine product used (i.e., therapeutic vs. diagnostic use of adenosine). Significantly higher adenosine doses, or alternative agents, may be required. Monitor for decreased therapeutic effects of adenosine if the patient is already receiving caffeine. Discontinue caffeine in advance (5 half-lives, or approximately 24 hours, is specifically recommended) of scheduled diagnostic use of adenosine (e.g., for radionuclide imaging studies) whenever possible.

Ciprofloxacin: Ciprofloxacin may increase the effect and toxicity of caffeine.

Clozapine: Caffeine increases the effect and toxicity of clozapine

Conivaptan: Conivaptan may increase the serum concentration of CYP3A4 substrates such as caffeine. Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates.

Grepafloxacin: Grepafloxacin may increase the effect and toxicity of caffeine.

Lithium: Caffeine decreases serum levels of lithium

Norfloxacin: Norfloxacin may increase the effect and toxicity of caffeine.

Tamsulosin: Caffeine, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Caffeine is initiated, discontinued, or dose changed.

Terbinafine: Terbinafine may increase the plasma concentration of Caffeine.

Thiabendazole: The strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Caffeine by decreasing Caffeine metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Caffeine if Thiabendazole is initiated, discontinued or dose changed.

Tolterodine: Caffeine may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.