General Principles Of Pharmacology:Drug dilution in body water
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Body water constitutes as much as 75% of the total body weight of very lean animals and as little as 45% in very fat ones. The
average is about 60%. This is distributed between intracellular fluid (~35% of body weight), interstitial fluid (~18%), blood
plasma (~5%), and transcellular fluid (~2%).
Transcellular fluids are separated from the interstitial fluid by an epithelium. They include:
Table 4. List of Body fluids present in human beings
|
Cerebrospinal fluid Aqueous humor of the eye Contents of renal tubules Urine in the bladder Gland contents Synovial fluid in joints |
Pleural fluids Peritoneal fluids Bile Saliva Gastrointestinal secretions |
The distribution of drugs between these body water compartments will depend on their volume and the barriers (for example, lipid
membranes, plasma binding proteins, pH gradients) they encounter. Accumulation of drugs at other sites also depends upon the
Contents |
Cells
Many drugs accumulate in muscle and other cells. Since the pH difference between the cytoplasm (~7.0) and the extracellular space (~7.4) is small, there is little pH trapping. Accumulation is either due to active transport or, more commonly, to binding.
Fat
Highly lipid soluble drugs accumulate in fat (for example, chlorinated hydrocarbons). Larger doses of lipid-soluble drugs may be necessary in obese animals.
Bone
Some drugs (for example, lead, fluoride, tetracyclines) are deposited in bone and teeth.
Drug Reservoirs
Sites other than the site of action can act as reservoirs for a drug. For example, plasma proteins can sequester digitoxin and phenytoin, fat can sequester thiopental and organochlorine pesticides, and bone can sequester tetracyclines and lead. The rate at which a drug is released from a reservoir is governed by the same factors as those described for its distribution. Such reservoirs can be useful in achieving a prolonged effect with an otherwise short-acting drug.
Drug Residues in Food Animals
The existence of drug reservoirs and its prolonged sequestration is a major concern in food animals. Residues can be found in muscle, milk, eggs, liver, etc. For this reason, many drugs are not approved for use in food animals. For example, a drug will not be approved for use in milking dairy cattle if drug residues can be detected for longer than 96 hours (8 milkings) in milk.
Sites of Drug Binding and Binding to Plasma Proteins
Many drugs are bound to plasma proteins. Most bind to albumin, although certain drugs bind to other plasma proteins. In general, binding is reversible and obeys the law of mass action:
(free drug) + (albumin) 
(drug-albumin complex)
where k1 and k2 are the association and dissociation rate constants, respectively. At equilibrium:
Where KD is the equilibrium dissociation constant. It is a measure of the affinity of the drug for albumin: The lower the KD, the higher the affinity.The higher the KD, the lower the affinity. At low concentrations of drug (less than the KD), the fraction bound is largely a function of the concentration of binding sites and the KD. At high concentrations (greater than the KD), the fraction bound is largely a function of the number of binding sites and the drug concentration.
As the concentration of drug increases in plasma, the percent that is bound will decrease. Other factors affecting binding:
- Number of drug binding sites on the protein
- Protein concentration
- Lipid solubility
- Weak acids are bound more extensively than weak bases
- Competing molecules
- Species variations
- Disease
Next Page: Sites of Drug Binding and its
Effect on Drug Distribution
Previous Page: Passage of drug into the Placenta
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