Principles of the Drug Administration II – Its Metabolism (Distribution)

In the circulation, the drugs are reversibly bound to plasma proteins. Early into the tissues it depends upon the blood flow and the ability of the drug to enter the tissues. Easy entry into the tissues depends upon lipid solubility, and the concentration gradient across the cell membranes. Major proportion of any drug is distributed to the tissues where it has no pharmacological action. In conditions like “shock” when tissue perforation is poor, the drug remains in the plasma in high concentrations without entering the tissues and this leads to toxicity. Specialized tissues take up drugs selectively. Most tissues of the central nervous system restrict the entry of polar (ionized) compounds. Lipid soluble substances enter easily down a concentration gradient, while sugars and amino acids are actively transported. This blood-brain barrier breaks down when there is meningeal inflammation. At conditions of equilibrium, the drug is distributed among the plasma water, plasma proteins and tissues. Since lipid soluble drugs enter cells more readily, their concentration in the plasma is lower compared to water soluble drugs. By hemodialysis, water-soluble compounds can be removed from circulation, but this is not effective with lipid-soluble drugs. Magnitude of responses of any drug depends on the level of free drug at the receptor site. The level of free drug in the plasma depends upon two factors: Plasma protein binding and ease of distribution to other tissues.

Plasma protein binding: Plasma proteins, especially albumin forms reversible complexes with drugs in circulation. The degree of absorption depends upon the plasma pH and affinity of the drug to the protein. When many drugs compete for absorption, the high affinity ones displace the ones with weak affinity. Acidic drugs will be displaced from protein complex when the body goes into acidosis. Since the protein binding is reversible, this has little effect on the elimination of the drug.

Liver: Since most of the absorbed drugs pass through the liver, they are either bound, metabolized excreted in the bile. Hepatic metabolism of drugs occurs in two stages; stage I reactions include oxidations, reductions and hydrolysis; and stage II reactions involved conjugation of the original compound or its metabolites-acetylation, sulphation, O-methylation and glyceine-conjugation. These products are water-soluble and hence are excreted. Urinary excretion depends upon the processes of
1. Glomerular filtration,
2. Active tubular secretion and reabsorption,
3. Passive diffusion.

Lungs: Basic compounds are selectively taken up and sequestered from the general circulation.

Transplacental transfer: The placenta behaves like a selective barrier. Lipid soluble drugs of molecular weight lower than 1000 diffuse Drogenmarktplatz freely from the maternal to fetal cericulation, while water soluble drugs diffuse only slowly. Since the drug elimination systems of the fetus are immature, serious toxicity will ensue. The mechanism to remove the drug from the fetal circulation is diffusion back to the maternal side.

Elimination of drugs: Drugs are eliminated from the body by
1. Metabolism in the liver and Kidney and
2. Excretion of the parent drug as such or its metabolites by the Kidneys predominantly, but also by the gut, skin, lungs, sweat glands, breasts and salivary glands.

Administration of drugs: The effective and safe dose of any drug should be determined by considering the body mass or surface area. Though general instructions regarding dose are available, each dose should be tailored to the individual patient, based on his weight, status of vital organs like kidneys and liver, the severity of the infection and the immune status of the host. Though a long course of therapy is ideal for effecting cure, yet chances for toxicity limits the total dose.