カフェイン

Biological Agents -> Plant Toxins

Stimulant

Waste-water effluent contaminant

DEA NFLIS-Drug Category -> Stimulants

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Analgesics

Pharmaceuticals -> Metabolite of Theophylline

Cosmetics ingredient -> Conditioning/Emollient; Moisturizing/Humectant; Other (Specify)

Cosmetic ingredients (Caffeine) -> CIR (Cosmetic Ingredient Review)

Skin conditioning

Other Treatment

Active substance -> EU Pesticides database: Not approved

log Kow = -0.07

-0.07

-0.07

1.23 at 64 °F (NTP, 1992) - Denser than water; will sink

1.23 at 18 °C/4 °C

1.23 g/cm³

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

This chemical does not meet GHS hazard criteria for 0.6% (13 of 2217) of reports.

Warning

H302 (98.9%): Harmful if swallowed [Warning Acute toxicity, oral]

Chemical: 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-

Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012)

Reg. (EU) 2024/2766

Status: Active Update: 20-09-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/10085

Caffeine: Does not have an individual approval but may be used under an appropriate group standard

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

Combustible. Gives off irritating or toxic fumes (or gases) in a fire.

SYMPTOMS: Symptoms of exposure to this compound may include central nervous system stimulation, less drowsiness, less fatigue, more rapid and clearer flow of thought, decreased reaction time, affects on muscular coordination, accurate timing and arithmetic skills, nervousness, restlessness, insomnia, tremors and hyperesthesia. At higher doses, symptoms include focal and generalized convulsions, Cheyne-Stokes respiration, apnea of preterm infants, vomiting, nausea, effects on circulatory system, small decreases in heart rate, tachycardia, arrhythmias, premature ventricular contractions and vasodilation. Overdosage may cause death, emesis, convulsions, excitement, mild delirium, sensory disturbances such as ringing in the ears and flashes of light, tense and tremulous muscles, extrasystoles and quickened respiration. Continued excessive use may lead to digestive disturbances, constipation, palpitations, shortness of breath and depressed mental states. Other symptoms may include pulmonary edema, myocardial infarction, ventricular fibrillation, stomach cramps, chills, cerebral edema and hypokalemia. It may also cause rapid pulse, hallucinations, photophobia, gastroenteric distress and diuresis. Anxiety and irritability may occur. Gastric irritation, headache, fever, agitation, hyperventilation and respiratory failure may also occur. Dizziness has been reported. It may also cause irritation of the skin, eyes, mucous membranes and respiratory tract.

A diuretic and CNS and heart stimulant; [ICSC] Repeated intraperitoneal doses are toxic to liver in mice; Subcutaneous dose causes convulsions in mice with LD50 of 81 mg/kg; [RTECS] Ingestion of 35 mg/kg is moderately toxic in children. Coffee contains 50-200 mg and tea 40-100 mg of caffeine per cup. Acute caffeine poisoning can cause nausea, vomiting, delirium, seizures, hypokalemia, and fatal arrhythmias. [Olson, p. 170]

(a) Product: Caffeine. (b) Tolerance: 0.02 percent. (c) Limitations, restrictions, or explanation: This substance is generally recognized as safe when used in cola-type beverages in accordance with good manufacturing practice.

Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: caffeine and caffeine citrate are is included in weight control products.

Stimulant drug products for over-the-counter human use. Stimulant active ingredient. The active ingredient of the product consists of caffeine when used within the dosage limits established in section 340.50(d).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl caffeine citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Caffeine citrate/

CAFFEINE may be hygroscopic. Aqueous solutions (1.12 mg/mL) are stable for three weeks at 41 °F if protected from light. In normal room lighting and at room temperature, solutions are stable for 3 days. Solutions of this chemical in water, DMSO, 95% ethanol or acetone should be stable for 24 hours under normal lab conditions. REACTIVITY: This compound may react with strong oxidizing agents. It is also incompatible with iodine, silver salts and tannins. This compound is a very weak base. It is decomposed by strong solutions of caustic alkalis. (NTP, 1992)

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)

Use water spray, dry powder.

Fresh air, rest. Refer for medical attention.

Remove contaminated clothes. Rinse skin with plenty of water or shower.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth. Refer for medical attention .

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Separated from food and feedstuffs. Well closed.

Commercially available caffeine and sodium benzoate and caffeine citrate injection and oral solution should be stored at 15-30 °C. /Caffeine and sodium benzoate; Caffeine citrate/

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Sweep spilled substance into covered sealable containers. If appropriate, moisten first to prevent dusting. Carefully collect remainder. Then store and dispose of according to local regulations.

Caffeine was detected in 6 of 28 human breast milk samples from France and Canada at concentations ranging from <0.5 ng/L to 4.5 ng/L(1). Caffeine was detected in the blood from an umbilical cord (0-11 ug/ml), human blood samples (0.36-270 ug/mL), and brain, kidney, lung, heart, saliva (2.6-42.6 ug/mL), semen (0.42-8.54 ug/mL), and urine (mean concentration ranging from 0.8-24 ug/mL) samples(2).

When caffeine and disulfiram are administered concomitantly...the total blood clearance of caffeine is substantially decreased and its elimination half-life is increased.

... Cocaine and caffeine's independent effects on cardiodynamics are documented but to our knowledge combined effects of both on complete cardiovascular hemodynamics remains to be examined. Eighteen dogs were instrumented to pass cardiac catheters into right and left heart. The experiments were performed after they recovered from the effects of anesthesia. In phase I (30 experiments on 8 dogs), the doses were established by dose-response curve. In phases II and III, another 10 dogs were subjected to 28 experiments. They were given i.v. cocaine followed by caffeine and vice versa to study their effects on hemodynamics and coronary flow reserve. Phase 1: The doses of cocaine (2 mg/kg) and caffeine (5 mg/kg) were established. Phase II: Cocaine increased heart rate, blood pressure and dP/dt but coronary flow reserve (CFR) decreased significantly. Caffeine administered after cocaine attenuated these effects (dP/dt decreased to 4910 + or -104 from 5066 + or - 110 mm Hg s; p<NS). Phase III: Caffeine mildly increased hemodynamic parameters but reduced dP/dt. Cocaine's administration as the second drug had synergistic excitatory effects (dP/dt increased to 6166 + or - 160 from 5055 + or - 142 mm Hg/s; p<0.04). CFR decreased significantly. Cocaine increased heart rate, blood pressure and dP/dt but reduced CFR. Caffeine mildly increased the hemodynamic variables but decreased CFR. Combined cocaine+caffeine attenuated the excitatory effects of cocaine significantly. A reversed drug combination i.e., caffeine+cocaine generated synergistic excitatory effects on the cardiovascular system of the dogs. CFR showed significant decrease.

To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers. This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg /per/ day, range: 400-1000 mg /per/ day ). Serum concentrations of clozapine and its metabolites desmethyl-clozapine and clozapine-N-oxide were measured during a 48 hr period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored. A 19% increase in mean clozapine AUC(0,infinity) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0, 12hr) for desmethyl-clozapine and AUC(0,12hr) for clozapine (-18%), and between AUC(0,12hr) for clozapine-N-oxide and AUC(0,12hr) for clozapine (-23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0, 12hr) for desmethyl-clozapine/AUC(0,12hr) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively). These results suggest that caffeine in daily doses of 400-1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.

The effects of the widely consumed drugs caffeine and phenylpropanolamine are mediated through activation of the central and sympathetic nervous systems. Severe, life-threatening, and occasionally fatal hypertensive reactions have been reported after their combined use. This study examined the possible pharmacokinetic interaction of phenylpropanolamine and caffeine. Sixteen normal subjects received combinations of caffeine, phenylpropanolamine, and placebo. In subjects receiving 400 mg caffeine plus 75 mg phenylpropanolamine, the mean (+/- SEM) peak plasma caffeine concentration of 8.0 +/- 2.2 micrograms/mL was significantly greater than after 400 mg caffeine alone (2.1 +/- 0.3 micrograms/mL; t[24] = 2.4; p less than 0.01). Physical side effects were more frequent after the phenylpropanolamine-caffeine combination than after either drug alone or after placebo. Greater increases in both systolic and diastolic blood pressures occurred after the combination than after either drug alone. Because caffeine levels can be increased greatly when certain other drugs are coconsumed, these data indicate that phenylpropanolamine may enhance absorption or inhibit elimination of caffeine and may explain increased side effects reported after their combined use.

For more Interactions (Complete) data for CAFFEINE (21 total), please visit the HSDB record page.

Caffeine may increase rates of miscarriage and low birth weight. Caffeine withdrawal symptoms include fatigue, headache, nausea and irritability. Using large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion.

Some degree of caffeine intake is almost universal in modern society and an estimated 90% of adults in the United States consume caffeine daily, the average amount being 200 mg daily. Yet despite its widescale use, there is no evidence that regular consumption of caffeine or coffee has adverse effects on the liver. Indeed, epidemiological studies suggest that regular coffee intake may have modest protective effects against the progression of chronic liver disease and development of liver cancer. In high, toxic doses, caffeine can have severe effects on brain, heart and muscle function but has not been linked to clinically apparent liver injury. In contrast, there have been several reports of liver injury linked to use of caffeine rich energy drinks. These reports have not been very convincing and most were not well documented. In many instances, the hepatic injury resembled acute hepatic necrosis or ischemic hepatitis (Case 1). In other cases, other diagnoses were more likely than liver injury from the energy drinks (Case 2). Furthermore, it remains unclear whether the hepatic effects were caused by caffeine per se or to other components in typical energy drinks, such as vitamins, herbs or other botanical products. In reports of caffeine overdose including cases with autopsies, hepatic injury has been absent or not mentioned. Thus, caffeine is unlikely to cause liver injury, but the various high caffeine energy drinks which are widely used may possibly cause liver injury when used to excess.

LC50; Species: Ceriodaphnia dubia (Water flea); Conditions: freshwater, static; Concentration: 60 mg/L for 48 hr

LC50; Species: Ceriodaphnia dubia (Water flea); Conditions: freshwater, daily renewed static; Concentration: 46 mg/L for 7 days

LC50; Species: Chironomus dilutus (Midge); Conditions: freshwater, static; Concentration: 1230 mg/L for 48 hr

LC50; Species: Pimephales promelas (Fathead minnow); Conditions: freshwater, static; Concentration: 100 mg/L for 48 hr

For more Ecotoxicity Values (Complete) data for CAFFEINE (14 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 741 and 7762 determined in a silt loam soil and sandy loam soil respectively(2), indicates that caffeine is expected to have low to no mobility in soil(SRC). Sorption tests in sand estimate a Koc value of 71(2) suggesting high mobility; however, sand contains no clay content and very low organic carbon content which may be responsible for caffeine's adsorption in soil(SRC). Caffeine is both a weak acid and a weak base with pKa values of 14.0(3) and 0.7(4). Although partial ionization to cation and anion forms may occur, electrochemical studies have found that the neutral form of caffeine was predominant in the pH range of 5.5 to 9.0(4). Cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(5) suggesting that the cation form of caffeine may have higher Koc values than the neutral form(SRC). Volatilization of caffeine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.1X10-11 atm-cu m/mole(SRC), derived from its vapor pressure, 9.0X10-7 mm Hg(6), and water solubility, 2.16X10+4 mg/L(7). Caffeine is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure. In biodegradation studies using 3 soils from Ontario Canada and a 34-day incubation period, 14C-caffeine was rapidly mineralized to 14-CO2 in a sandy loam and loam soil, and less rapidly in a silt loam soil(8); mineralization in the sandy loam and loam soils reached about 60% in 20 days (50% in 3-10 days) with mineralization in the silt loam soil reaching about 25% in 34 days(8). Various biodegradation studies have found caffeine and similar analogs to be readily biodegradable(9,10).

AQUATIC FATE: Based on a classification scheme(1), Koc values of 741 and 7762 determined in a silt loam soil and sandy loam soil respectively(2), indicates that caffeine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.1X10-11 atm-cu m/mole(SRC), derived from its vapor pressure, 9X10-7 mm Hg(4), and water solubility, 2.16X10+4 mg/L(5). Caffeine is both a weak acid and a weak base with pKa values of 14.0(6) and 0.7(7). Although partial ionization to cation and anion forms may occur, electrochemical studies have found that the neutral form of caffeine was predominant in the pH range of 5.5 to 9.0(7). According to a classification scheme(8), an estimated BCF of 3(SRC), from its log Kow of -0.07(9) and a regression-derived equation(10), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Caffeine absorbs UV light >290 nm (11) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). The rate constant for the reaction of photochemically-produced hydroxyl radicals in aqueous solutions is 6.9X10+9 L/mol-sec(12) which corresponds to an aquatic half-life of 116 days. Caffeine contains an imidazole function and imidazoles can react with photochemically-produced singlet oxygen radicals in natural water with half-lives on the order of hours to days(13). Caffeine had a mean half-life of 1.5 days in an aquatic microcosm study using sunlight exposure with photodegradation suggested as the primary fate process(14). The hydrolysis half-life of caffeine in water is reported to be greater than 1 year(15). The estimated half-life for caffeine in the Rhine River, Netherlands, was 0.8 days which was thought to occur as a result of biological removal processes(16). Various biodegradation studies have found caffeine and similar analogs to be readily biodegradable(15,17).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), caffeine, which has a vapor pressure of 9.0X10-7 mm Hg at 25 °C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase caffeine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 20 hours(SRC), calculated from its rate constant of 1.9X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase caffeine may be removed from the air by wet and dry deposition(SRC) and caffeine has been detected in rainwater sampling studies(4). Caffeine absorbs UV light > 290 nm(5) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Chocolate bars (in a typical 28-g serving) contain from 11 to 115 mg of caffeine. In general, one serving of coffee ranges from 64 mg for a single cup (30 mL) of espresso to about 145 mg for an 8-oz. ounce cup (237 mL) of automatic drip coffee. Tea (Camellia sinensis) fresh leaves contain about 4% caffeine Tea beverages typically contain about 20 to 80 mg of caffeine per cup, or about half the caffeine per serving of coffee. Caffeine is commonly added to soft drinks, typically, from 30 to 40 mg of caffeine per 12 oz (355 mL) serving. Energy drinks may contain as much as 200 mg of caffeine per 12 fl oz (355 mL) serving(1).

Typical caffeine concentrations for 150 mL (5 oz) cup of coffee range from 29-176 mg(1). Soft drinks typically contain anywhere from 6.2-62 mg of caffeine per 12 oz can(1).

Neurotoxin - Other CNS neurotoxin

As with many drugs or medications, a wide array of adverse effects is associated with caffeine use. These effects vary from mild to severe and, in some cases, can be fatal, depending on the dose consumed and an individual's sensitivity to the drug. The most frequently reported adverse effects are outlined below. Mortality is usually associated with cardiac arrhythmia, hypotension, myocardial infarction, electrolyte disturbances, and aspiration.

The substance can be absorbed into the body by inhalation and by ingestion.

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.

Caffeine was detected in 6 of 28 human breast milk samples from France and Canada at concentrations ranging from <0.5 ng/L to 4.5 ng/L(1).

EXPERIMENTAL: A study was carried out to determine the caffeine concentration in milk of lactating women ingesting known amounts of caffeine and to determine serum concentration of caffeine of their infants. 9 lactating women and their infants were studied for 9 days. For the first 5 days, the women ingested 750 mg of caffeine daily, and for the next 4 days they ingested no caffeine and avoided coffee and other caffeine-containing products. The concentration of caffeine in samples of milk obtained by pooling aliquots from each feeding on day 5 averaged 4.3 micrograms/mL for 7 mothers who were 11-22 days after delivery on the 1st day of study. Values ranged from nondetectable (less than 0.25 micrograms/mL) to 15.7 micrograms/mL. No caffeine was detected in milk samples obtained on day 9. The mean concentration of caffeine in sera of the infants on day 5 was 1.4 micrograms/mL (range: nondetectable to 2.8 micrograms/mL). Caffeine was still detectable in 2 infants' sera obtained on day 9. Concentrations had decreased only slightly since day 5. 2 older infants and their mothers were studied as described except that on days 5 and 9 samples of milk were obtained from each feeding and analyzed individually. The average caffeine concentrations in milk consumed on day 5 were 13.4 and 28.6 micrograms/mL, respectively. The concentrations of caffeine in infants' sera on day 5 were less than 0.25 and 3.2 micrograms/mL. On day 9 milk and serum caffeine levels were below the limits of detectability.

Safe in the present practices of use and concentration. Ingredient, concentration, and use information are available in documents discoverable at https://cir-reports.cir-safety.org

Signs and Symptoms of Overdose

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&prime;,5&prime;-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.

(a) Product: Caffeine. (b) Tolerance: 0.02 percent. (c) Limitations, restrictions, or explanation: This substance is generally recognized as safe when used in cola-type beverages in accordance with good manufacturing practice.

Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: caffeine and caffeine citrate are is included in weight control products.

Stimulant drug products for over-the-counter human use. Stimulant active ingredient. The active ingredient of the product consists of caffeine when used within the dosage limits established in section 340.50(d).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, incl caffeine citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Caffeine citrate/

N06BC01

N - Nervous system

D - Dermatologicals

QD - Dermatologicals

QN - Nervous system

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.

The mechanism of action of caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: **General and cellular actions** Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. **Respiratory** The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. **Central nervous system** Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. **Renal system** Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. **Cardiovascular system** Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain.

Caffeine competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3',5'-adenosine monophosphate (AMP). Increased levels of intracellular cyclic AMP mediate most of caffeine's pharmacologic actions.

Caffeine stimulates all levels of the CNS... Caffeine's cortical effects are milder and of shorter duration than those of amphetamines. In slightly larger doses, caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate.

Caffeine constricts cerebral vasculature. In contrast, the drug directly dilates peripheral blood vessels...

In an average-sized adult or child above the age of 9, the half-life of caffeine is approximately 5 hours. Various characteristics and conditions can alter caffeine half-life. It can be reduced by up to 50% in smokers. Pregnant women show an increased half-life of 15 hours or higher, especially in the third trimester. The half-life in newborns is prolonged to about 8 hours at full-term and 100 hours in premature infants, likely due to reduced ability to metabolize it. Liver disease or drugs that inhibit CYP1A2 can increase caffeine half-life.

Elimination 1/2 life in adults = 2.5-4.5 hours; [Reference #1]

Caffeine has a plasma half-life (t1/2) of 3 to 5 hours in adults. In one study, when administered to pregnant women prior to delivery, caffeine had a prolonged mean half-life of 80 hours in neonates after delivery.

Mean half-life /T 1/2/ and fraction excreted unchanged in urine of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. In neonates, the /T 1/2/ is approximately 3-4 days...

The half-time for caffeine is 0.7-1.0 hr in rats and mice, 1-1.6 hr in rabbits, 3-5 hr in monkeys, 4-4.3 hr in dogs and 11-12 hr in baboons.

/The authors/ studied 17 preterm infants receiving caffeine, and measured their plasma levels of caffeine and the theophylline metabolite by high-pressure liquid chromatography. The half-life was calculated by computer analysis using the least-square method. The mean gestational age of our patients was 29.7 +/- 1.9 weeks (mean +/- SD) and they were studied at 20.7 +/- 6.6 days (mean +/- SD) postnatal age. The caffeine half-life was 52.03 +/- 23.87 hr (means +/- SD) and the theophylline half-life was 77.04 +/- 65.01 hr (mean +/- SD).

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) also participate in the metabolism of caffeine.

Caffeine is metabolized by the cytochrome P-450 (CYP) enzyme system, principally by isoenzyme 1A2. Therefore, caffeine has the potential to interact with drugs that are metabolized by CYP1A2 or with drugs that induce or inhibit this isoenzyme.

In adults, the drug is rapidly metabolized in the liver to 1-methyluric acid, 1-methylxanthine, and 7-methylxanthine.

Interconversion between caffeine and theophylline has been reported in preterm neonates...

In-vivo and in-vitro experiments showed a progressive increase in the activity of the hepatic microsomal enzymes that metabolize caffeine during neonatal development. In beagle puppies, change in caffeine clearance was determined by the rate of maturation of caffeine-7-demethylase. Caffeine is eliminated in animals by biotransformation in the liver to dimethylxanthines, dimethyl- and monomethyluric acids and uracil derivatives; important quantitative differences have been demonstrated in the formation and elimination of metabolites in rats, mice and Chinese hamsters. These differences are even more important in monkeys, where caffeine is almost completely metabolized to theophylline. ... Some species-dependent metabolites have been identified. Trimethylallantoin was first reported in rats. A ... derivative of paraxanthine was found in mice and identified as the 3-beta-D-glucuronide of paraxanthine. Methylated ureas and sulfur-containing derivatives found in urine in trace amounts are produced by the intestinal flora. In contrast, the acetylated uracil derivative, 5-acetylamino-6-formylamino-3-methyluracil, one of the most important caffeine metabolites in humans, has not been identified in rodents or other animal species. Other uracil derivatives produced from caffeine, theobromine and paraxanthine in rats were found in human urine. In rats, the hepatic demethylation of caffeine shows an age-related decline, resulting in a greatly increased elimination half-time in older adult rats.

Caffeine metabolism is qualitatively relatively similar in animals and humans ... . The main metabolic pathways are: demethylation and hydroxylation of the 8-position leading to the formation of the respective uracil and uric acid derivatives. There are, however, some quantitative differences in the metabolic profile. Humans are characterized by the importance of 3-methyl demethylation leading to the formation of paraxanthine and especially metabolites thereof through subsequent metabolic steps. The main urinary metabolites in humans are 1-methyluric acid, 1-methylxanthine, 5-acetylamino-6-formylamino-3- methyluracil (not found in rats and mice), 1,7-dimethyluric acid and paraxanthin. In rats and mice, the metabolism of caffeine is predominantly via theobromine and theophylline. The main urinary metabolites are 1,3-dimethyluracil, paraxanthine, trimethyluric acid, theophylline, and theobromine. Caffeine metabolism decreases during pregnancy, resulting in higher serum concentrations.

3G6A5W338E

CAFFEINE

Established Pharmacologic Class [EPC] - Central Nervous System Stimulant

Physiologic Effects [PE] - Central Nervous System Stimulation

Established Pharmacologic Class [EPC] - Methylxanthine

Chemical Structure [CS] - Xanthines

A loosely defined group of drugs that tend to increase behavioral alertness, agitation, or excitation. They work by a variety of mechanisms, but usually not by direct excitation of neurons. The many drugs that have such actions as side effects to their main therapeutic use are not included here.

Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases.

Compounds that bind to and block the stimulation of PURINERGIC P1 RECEPTORS.

Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, onset of action takes place within 45 to 1 hour. Food may delay caffeine absorption. The peak plasma level for caffeine ranges from 6-10mg/L. The absolute bioavailability is unavailable in neonates, but reaches about 100% in adults.

The major metabolites of caffeine can be found excreted in the urine. About 0.5% to 2% of a caffeine dose is found excreted in urine, as it because it is heavily absorbed in the renal tubules.

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.

The clearance of caffeine varies, but on average, is about 0.078 L/kg/h (1.3 mL/min/kg).

World-wide, many fetuses and infants are exposed to methylxanthines via maternal consumption of coffee and other beverages containing these substances. Methylxanthines (caffeine, theophylline and aminophylline) are also commonly used as a medication for apnea of prematurity. ... Methylxanthines readily passes the placenta barrier and enters all tissues and thus may affect the fetus/newborn at any time during pregnancy or postnatal life, given that the effector systems are mature. ...

Caffeine and citrated caffeine are well absorbed following oral administration. Absorption of caffeine following oral administration may be more rapid than that following IM injection of caffeine and sodium benzoate. Absorption following rectal administration of caffeine in suppositories may be slow and erratic. ... Following oral administration of 100 mg of caffeine (as coffee), peak plasma concentrations of about 1.5-1.8 ug/mL are reached after 50-75 minutes.

CIR ingredient: Caffeine

Occurs naturally in tea leaves, coffee beans, cocoa beans, mate leaves, guarana paste, and kola nuts; [Merck Index] Used in beverages, cardiac and respiratory stimulants, and diuretics; [HSDB] Also used in cosmetics; [eChemPortal: SIDSUNEP]

For caffeine (USEPA/OPP Pesticide Code: 000660) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Beverages, medicine

Caffeine is a substance in wide use. It is predominantly used in the food sector and pharma sector (80% and 16% rspectively). A smaller part is used in cosmetics (3%) or in technical applications (1%). Furthermore caffeine is a naturally occurring substance in various plant species (e.g. 0.9 to 2.6% in green coffee beans). It is a component in coffee, tea and cocoa.

Stimulant for central nervous and respiratory systems; cardiac and respiratory stimulant; diuretic

(1972) 9.37X10+5 grams

(1975) 7.1X10+9 grams

(1984) 1.74x10+9 g

1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl- is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438).

Production volumes for non-confidential chemicals reported under the Inventory Update Rule.[Table#17]

Production volume for non-confidential chemicals reported under the 2006 Inventory Update Rule. Chemical: 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-. Aggregated National Production Volume: < 500,000 pounds.

Non-confidential 2012 Chemical Data Reporting (CDR) information on the production and use of chemicals manufactured or imported into the United States. Chemical: 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-. National Production Volume: 422,806 lb/yr.

Usually obtained from tea dust in which it is present up to 5% or as a by-product from the manufacture of caffeine-free coffee; synthetically prepared starting with dimethylurea and malonic acid.

Caffeine occurs naturally in tea and coffee, but is prepared synthetically for commercial drug use.

Caffeine is isolated by solvent extraction from green coffee beans and tea leaves. The Zosel high-pressure extraction process is a more sophisticated procedure involving supercritical carbon dioxide, resulting in mild, selective, and toxicologically safe decaffeination.

Caffeine may be isolated from tea or coffee by boiling with water in the presence of lime or magnesium oxide, which serves to precipitate the tannins and some of the coloring matter. After filtration, the crude caffeine that separates in recrystallized from hot water after treatment with decolorizing charcoal. A source of the commercial supply is tea dust or sweepings. Increasing quantities of caffeine are now obtained as a byproduct in the manufacture of "decaffeinized coffee."

Grades: Technical; USP; FCC

Nodoz Keep Alert Tablets contain 100% caffeine in each tablet

Vivarin contains 200 mg caffeine alkaloid and 150 mg dextrose in each tablet

Table: Caffeine Preparations [Table#11]

For more Formulations/Preparations (Complete) data for CAFFEINE (6 total), please visit the HSDB record page.

Cosmetics product ingredient: Caffeine

Information on 22 consumer products that contain Caffeine in the following categories is provided:

Natural products -> Stimulants -> Nervous System -> Psychoanaleptics -> Psycostimulants, agents used for ADHD and nootropics -> Xanthine derivatives

Cosmetics -> Skin conditioning

1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-: ACTIVE

Caffeine is thermally stable, and only a small part of the quantity present in the raw bean is lost by sublimation during roasting. About 85% passes into the domestic brew and almost 100% into industrial extracts. The caffeine content of industrial extracts varies between 3.0 and 5.1% (dry basis) for spray-dried powders, which usually contain mainly Robustas, and between 2.5 and 3.7% for milder freeze-dried products, which contain more Arabicas.

Caffeine is present in amounts of about 100-150 mg/180 mL of brewed coffee; 60-80 mg/180 mL of instant coffee; 40-100 mg/180 mL of tea; and 17-55 mg/180 mL of cola beverage.