Caffeine is the most widely consumed behaviorally active substance in the world. Almost all caffeine comes from dietary sources (beverages and food), most of it from coffee and tea. Acute and, especially, chronic caffeine intake appear to have only minor negative consequences on health. For this

Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Observational studies have documented that women take a variety of medications during pregnancy. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs. The use of mechanistic-based approaches to drug interactions has significantly increased our ability to predict clinically significant drug interactions and improve clinical care. This same method can also be used to improve our understanding regarding the effect of pregnancy on pharmacokinetics of drugs. Limited studies suggest bioavailability of drugs is not altered during pregnancy. Increased plasma volume and protein binding changes can alter the apparent volume of distribution (Vd) of drugs. Through changes in Vd and clearance, pregnancy can cause increases or decreases in the terminal elimination half-life of drugs. Depending on whether a drug is excreted unchanged by the kidneys or which metabolic isoenzyme is involved in the metabolism of a drug can determine whether or not a change in dosage is needed during pregnancy. The renal excretion of unchanged drugs is increased during pregnancy. The metabolism of drugs catalysed by select cytochrome P450 (CYP) isoenzymes (i.e. CYP3A4, CYP2D6 and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes (i.e. UGT1A4 and UGT2B7) are increased during pregnancy. Dosages of drugs predominantly metabolised by these isoenzymes or excreted by the kidneys unchanged may need to be increased during pregnancy in order to avoid loss of efficacy. In contrast, CYP1A2 and CYP2C19 activity is decreased during pregnancy, suggesting that dosage reductions may be needed to minimise potential toxicity of their substrates. There are limitations to the available data. This analysis is based primarily on observational studies, many including small numbers of women. For some isoenzymes, the effect of pregnancy on only one drug has been evaluated. The full-time course of pharmacokinetic changes during pregnancy is often not studied. The effect of pregnancy on transport proteins is unknown. Drugs eliminated by non-CYP or non-UGT pathways or multiple pathways will need to be evaluated individually. In conclusion, by evaluating the pharmacokinetic data of a variety of drugs during pregnancy and using a mechanistic-based approach, we can start to predict the effect of pregnancy for a large number of clinically used drugs. However, because of the limitations, more clinical, evidence-based studies are needed to fully elucidate the effects of pregnancy on the pharmacokinetics of drugs.

Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach.

Are we dependent upon coffee and caffeine? A review on human and animal data.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies was asked to deliver a scientific opinion on the safety of caffeine, providing advice on caffeine intakes, from all dietary sources that do not give rise to concerns about adverse health effects for the general healthy population and subgroups thereof. Possible interactions between caffeine and other constituents of so-called “energy drinks”, alcohol, p-synephrine and physical exercise should also be addressed. Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) do not give rise to safety concerns. The same amount does not give rise to safety concerns when consumed < 2 hours prior to intense physical exercise under normal environmental conditions. Other constituents of “energy drinks” at typical concentrations in such beverages (about 300–320, 4 000 and 2 400 mg/L of caffeine, taurine and D-glucurono-γ-lactone, respectively), as well as alcohol at doses up to about 0.65 g/kg bw, would not affect the safety of single doses of caffeine up to 200 mg. Habitual caffeine consumption up to 400 mg per day does not give rise to safety concerns for non-pregnant adults. Habitual caffeine consumption up to 200 mg per day by pregnant women does not give rise to safety concerns for the fetus. Single doses of caffeine and habitual caffeine intakes up to 200 mg consumed by lactating women do not give rise to safety concerns for breastfed infants. For children and adolescents, the information available is insufficient to derive a safe caffeine intake. The Panel considers that caffeine intakes of no concern derived for acute caffeine consumption by adults (3 mg/kg bw per day) may serve as a basis to derive single doses of caffeine and daily caffeine intakes of no concern for these population subgroups. © European Food Safety Authority, 2015

https://orbit.dtu.dk/files/118543075/4102.pdf

Scientific Opinion on the safety of caffeine

Objective: We review the published data relating to intake of coffee and caffeine on blood pressure in man. We also refer to studies on the possible mechanisms of actions of these effects of caffeine. Design: The MEDLINE and Current Contents databases were searched from 1966 to April 1999 using the text words ‘coffee or caffeine’ and ‘blood pressure or hypertension’. Controlled clinical and epidemiologic studies on the blood pressure effects of coffee or caffeine are reviewed. We also refer to studies on the possible mechanisms of action of these effects of caffeine. Results: Acute intake of coffee and caffeine increases blood pressure. Caffeine is probably the main active component in coffee. The pressor response is strongest in hypertensive subjects. Some studies with repeated administration of caffeine showed a persistent pressor effect, whereas in others chronic caffeine ingestion did not increase blood pressure. Epidemiologic studies have produced contradictory findings regarding the association between blood pressure and coffee consumption. During regular use tolerance to the cardiovascular responses develops in some people, and therefore no systematic elevation of blood pressure in long-term and in population studies can be shown. Conclusions: We conclude that regular coffee may be harmful to some hypertension-prone subjects. The hemodynamic effects of chronic coffee and caffeine consumption have not been sufficiently studied. The possible mechanisms of the cardiovascular effects of caffeine include the blocking of adenosine receptors and the inhibition of phosphodiesterases.

Coffee, caffeine and blood pressure: a critical review

Caffeine is eliminated mainly by metabolism to demethylated and oxidised derivatives. High individual variability is therefore expected from variations and changes in the capability of the organism to metabolize xenobiotics. An increase of the half-life of elimination of caffeine has been reported during the final weeks of pregnancy. In this study, the half-lifes of caffeine were determined by HPLC-analysis of samples of saliva in male and non-pregnant females and in women during pregnancy and after parturition.

Effect of pregnancy on the pharmacokinetics of caffeine

In der vorliegenden Studie wurde festgestellt, das die Narkosegasexpositionen in der Kinderanasthesie in der Regel erheblich hoher sind als bei Narkosen an Erwachsenen. Die wahrend 55 Kindernarkosen durchgefuhrten Messungen zeigten, das sowohl durch effiziente Absauganlagen als auch durch Verwendung kleiner Frischgasflows Expositionsreduktionen von 85% erzielt werden konnen. In Operationssalen, die einen hohen Raumluftwechsel aufwiesen, wurden um uber 50% geringere Expositionskonzentrationen vorgefunden. Bei Narkosen, die intravenos oder mit Doppelmaskensystem eingeleitet wurden, war die Narkosegasbelastung um 80% geringer als bei Narkosen mit Maskeneinleitung. Laryngealmasken- und Intubationsnarkosen fuhrten zu einer erheblich geringeren Belastung als Maskennarkosen. Ein ganz zentraler Stellenwert in der Expositionsproblematik kommt der Arbeitstechnik zu. Schlechte Arbeitstechniken bei Maskennarkosen fuhrten auch unter ansonsten gunstigen Bedingungen zu einer um ein Vielfaches hoheren Narkosegasbelastung des Anasthesisten und des ubrigen OP-Personals. Die Mesergebnisse zeigten ferner, das sich die Grenzwerte des Stickoxyduls und der volatilen Anasthetika durch entsprechende Schutzmasnahmen auch in der Kinderanasthesie einhalten lassen.

Narkosegasbelastung des Personals in der Kinderanästhesie

Methods To assess the occupational exposure of the anaesthetist to anaesthetic gases, a total of 1 German and 25 Swiss hospitals were investigated. A Bruel & Kjaer Type 1302 multi-gas monitor was used to measure concentrations of nitrous oxide and halogenated anaesthetic agents in the anaesthetist's breathing zone. Measurements were performed during 114 general anaesthetic, 55 of which were in patients under 11 years of age. In these 55 patients, the influence of various factors on the exposure (time-weighted average concentrations) was estimated by comparing different data groups. The efficiency of the applied scavenging equipment was examined by surveying the exhalation valve with a leak detector (type TIF 5600, TIF Instruments, Miami). Results Sessions with patients under 11 years of age revealed much higher anaesthetic gas exposures compared to older patients. The concentrations of nitrous oxide were on average threefold (Fig. 1), those of the halogenated anaesthetics fivefold higher (Fig. 2) for the younger patients. In 11- to 16-year-old patients the exposure level was the same as in adult patients. The measurements showed a reduction of 85% in exposure if an efficient scavenging system (i.e., no waste gas discharge to room air through the exhalation valve) or lower fresh gas flow were used (Fig. 4); 42% of the inspected scavengers were inefficient, and reduced the exposure on average by only 30%. In operating theatres with a ventilation rate of at least ten air changes per h, the measured concentrations of anaesthetic gases in the inhalation zone of the anaesthetists were reduced more than 50% compared to poorly ventilated rooms (Figs. 4 and 5). The use of tracheal intubation or laryngeal mask airway (LMA) anaesthesia resulted in a reduction of 80% in exposure compared to standard face masks if efficient scavenging was used. The exposures during sessions with inefficiently scavenged Bain coaxial systems or unscavenged semi-open delivery systems of the Jackson-Rees type were tenfold higher than with scavenged rebreathing circuit systems (Fig. 6). During anaesthesia with IV or double-mask induction, the average levels of inhalation anaesthetics were reduced by about 80% compared to inhalational induction with standard masks (Fig. 7). The anaesthetist's working technique is a very important factor that strongly influences the concentrations. Poor work practices, like lifting off the face mask with anaesthetic gas flow turned on, increased the exposure of the anaesthetist and other operating room personnel drastically, even if the other conditions (scavenger and room ventilation) were good. Discussion The exposure levels of anaesthetic gases are generally higher during anaesthesia in children up to 10 years of age than in older patients. Nevertheless, the measurements showed that exposure during paediatric anaesthesia can be kept below the recommended limit (8-h TWA in Switzerland) of 100 ppm nitrous oxide and 5 ppm halothane or 10 ppm enflurane or isoflurane. Causes of high exposures were particularly high fresh gas flows often applied without scavenging or together with inefficient scavenging devices and the high part of mask anaesthesia and inhalation induction with a loosely held mask. To achieve an effective reduction of occupational exposure, well-adjusted and maintained scavenging systems and low-leakage work practices are of primary importance. As leakage can never be completely avoided, a ventilation rate of at least ten air changes per h should be maintained in operating rooms and rooms where anaesthesia is induced to keep down concentrations of waste anaesthetic gases. High exposure during mask anaesthesia and inhalation induction can be prevented by further measures. Using a LMA instead of a standard mask reduces the exposure to the same level as endotracheal intubation.

R. Knutti

Papers

Effect of pregnancy on the pharmacokinetics of caffeine

Narkosegasbelastung des Personals in der Kinderanästhesie

Narcotic gas burden of personnel in pediatric anesthesia

Aluminium transfer during hemodialysis

Effect of Pregnancy on the Pharmacokinetics of Caffeine