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Dehydration and drug distribution

Dehydration can affect the way in which drugs act in the body. An important pharmacokinetic parameter is the "volume of distribution". The volume of distribution is used to describe the relationship between the amount of drug in the body and the concentration of drug in the blood or plasma. In some cases this is simply related to the amount of body water, but the volume of distribution can vary widely depending of the type of drug and the extent to which it is circulating freely or bound to plasma proteins and other tissues.(1,2)

The precise effect that dehydration has on a drug will depend on its volume of distribution, which in turn is dependent on other factors such as the type of drug and the route of administration (eg oral, injection, inhalation and topical application). Some studies have been undertaken to investigate the effects of dehydration in relation to specific drugs, examples of which are outlined below.

In a study of hydration status and responses to the drug piretanide (a diuretic), the effects of hydration status were complex.(3) The key findings showed that plasma concentrations of piretanide, including the maximally achieved concentrations of the drug, were generally higher in the nonhydrated subjects when compared with the hydrated subjects. There were consistent decreases in mean residence time (MRT) and the fraction of the drug excreted unchanged (fe) after i.v. piretanide in the nonhydrated state compared with the hydrated state. For oral administration, renal clearance (CLR) and fe showed significant decreases in the nonhydrated state compared to the hydrated state. The mean bioavailability of piretanide was found to be 112 + 11% in the nonhydrated and 133% in the fully hydrated state. Urinary excretion of piretanide was consistently lower in the nonhydrated state when compared with the hydrated state and this was associated with a lower natriuretic response when compared with the corresponding response in the hydrated state. The authors speculate as to why maximal hydration influenced the systemic disposition of the drug. "Factors such as initial water load and subsequent maintenance of the state of maximal hydration may have led to an increase in the extracellular volume and hence the potential volume of drug distribution."

In another study, it was found that free fat mass and total body water were better indicators of fluorouracil clearance and the volume of distribution of the drug, than other parameters such as body surface area or weight. This highlights the close relationship between hydration status of the individual and the distribution and clearance of the drug. In order to calculate the most appropriate dose of fluorouracil, doctors should take into consideration a combination of total body water, free fat mass and sex.(4)

Medication and water loss

Some medications produce water loss from the body. For example, diuretics are drugs which cause the body to lose water by increasing the amount of urine produced. They are used for treating conditions such as hypertension. However, unintentional dehydration may occur when the individual reduces their fluid intake, whilst continuing to take the diuretic. Another drug, lithium, is used to stabilise moods, but it can interfere with hormones which affect the kidney function, causing to much urine to be produced.(5)

Medication and water intake

There are no medications that directly stimulate water intake. Some drugs, such as anticholinergic drugs that cause a dry mouth, may indirectly encourage drinking. Other drugs that improve metabolic and cognitive function in patients who are dehydrated may also indirectly improve patients hydration status by helping them to increase their fluid intake and enabling the body to re-establish water balance. Such drugs might include antibiotics for infection, insulin for unstable diabetes, analgesics to control severe pain, and antidepressants to improve mood.(5)

Water is often consumed to aid the administration of oral medication. In one study, the effect of water intake on the absorption of Diazepam tablets was examined.(6) Most tablets and capsules contain a swelling agent to facilitate rapid disintegration (eg starch). When a tablet is swallowed with minimal quantities of water the hygroscopic properties of the swelling agent may cause it to get stuck in the throat or oesophagus. As a result, the tablet takes longer to dissolve and absorption of the drug may be delayed. Ideally, tablets should pass directly into the stomach where they would rapidly absorb water and disintegrate, giving rise to a high peak plasma concentration of the drug. However, tablets which stick in the oesophagus would start to disintegrate slowly at the site of the hold-up, producing lower peak plasma concentrations. The study found that attainment of the peak plasma concentration was delayed in a substantial number of patients, even though these patients had not experienced difficulty swallowing the tablets. Patients should be encouraged to swallow tablets with larger volumes of water in order to prevent the tablet getting stuck and to help it dissolve in the stomach.

Another study looked at the benefit of drinking water when taking capsules. Hard gelatin capsules absorb water and become stuck to the moist mucosa of the oesophagus if their passage is delayed for more than two minutes. Disintegration then occurs and the contents are released onto the non-absorptive mucosa of the oesophagus. In this study, the capsule got stuck in 22% of patients, although other studies have reported higher sticking rates of 52% and 58%. Only three patients (11.5%) were aware that a capsule had lodged in their oesophagus. Once again, this highlights the importance of taking tablets with a drink of water while standing to avoid any local irritant effect of drug contact and ensure proper absorption.(7)

Some tablets are designed to be taken without water. Lansoprazole is a fast disintegrating tablet and is easy to take without water. One study considered whether there were any disadvantages to taking Lansoprazole with water. The pharmacokinetics of the drug were found to be unaffected when the drug was taken with water, and there were no significant differences between taking it with, or without water.(8)

Last updated: December 2006

(1) The Pharmacological basis of therapeutics. 9th ed. Eds JG Hardman, AG Gillman, L E Limbird. McGraw-Hill, 1996
(2) Human pharmacology: molecular to clinical. 3rd ed. Eds T M Brody, J Larner, KP Minneman. Missouri: Mosby-Year Book, 1994
(3) Noormohamed FH, McNabb WR, Dixey JJ, Lant AF. Renal responses and pharmacokinetics of Piretanide in humans: effect of route of administration, state of hydration and probenecid pretreatment. Journal of Pharmacology and Experimental Therapeutics 1990;254;992-9
(4) Gusella M, Toso S, Ferrazzi E, Ferrari M and Padrini R. Relationships between body composition parameters and fluorouracil pharmacokinetics 2002;54:131-9
(5) Dietary Reference Intakes for Water, Potassium, Sodium, Chloride and Sulfate (2004) Institute of Medicine of the National Academies. Washington DC: The National Academies Press (http://books.nap.edu/catalog/10925.html)
(6) Richards DG, McPherson JJ, Evans KT and Rosen M. Effect of volume of water taken with Diazepam tablets on absorption. Br J Anaesth 1986;58:41-44
(7) Channer KS, Virjee J. Effect of posture and drink volume on the swallowing of capsules. BMJ 1982;285:1702
(8) Iwasaki K, Ito Y, Shibata N, Takada K, Sakurai Y, Takagi N, Irie S, Nakamura K. Effect of water intake on parmacokinetics of lansoprazole from fast disintegrating tablet in human subjects. Drug Metab Pharmacokineet 2004;19:390-5