An Increase In Blood Flow To Metabolically Active Tissue Principles of the Drug Administration II – Its Metabolism (Distribution)

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

In circulation, drugs are reversibly bound to plasma proteins. Rapid tissue penetration depends on blood flow and the ability of the drug to penetrate the tissues. Ease of entry into tissues depends on lipid solubility and concentration gradients across cell membranes. A large proportion of any drug is distributed into tissues where it has no pharmacological activity. In conditions such as “shock” when tissue permeability is impaired, the drug remains in the plasma in high concentrations without entering the tissues and causing toxicity. Certain tissues take up drugs selectively. Most of the tissues in the central nervous system block the entry of polar (ionized) compounds. Lipid soluble substances readily enter the concentration gradient, while sugars and amino acids are actively transported. This blood-brain barrier breaks down when meningeal inflammation occurs. At equilibrium, the drug is distributed among plasma water, plasma proteins, and tissues. Since lipid-soluble drugs enter cells more easily, their plasma concentrations are lower than those of water-soluble drugs. By hemodialysis, water-soluble compounds can be removed from the circulation, but this is not effective with lipid-soluble drugs. The magnitude of the response to any drug depends on the level of free drug at the receptor site. The level of free drug in plasma depends on two factors: plasma protein binding and ease of distribution to other tissues.

Plasma protein binding: Plasma proteins, especially albumin, form reversible complexes with circulating drugs. The degree of absorption depends on the plasma pH and the affinity of the drug for proteins. When multiple drugs compete for absorption, those with higher affinity displace those with lower affinity. When the body goes into acidosis, acidic drugs will be displaced from the protein complex. Since protein binding is reversible, it does not significantly affect the elimination of the drug.

Liver: As most absorbed drugs pass through the liver, they are either bound, metabolized and excreted in the bile. Hepatic metabolism of drugs occurs in two stages; Stage I reactions include oxidation, reduction, and hydrolysis; and stage II reactions involving the parent compound or its metabolites—acetylation, sulfation, O-methylation, and glycine-conjugation. These products are water soluble and are therefore excreted. Urinary excretion depends on the processes

1. Glomerular filtration,

2. Active tubular secretion and reabsorption,

3. Passive diffusion.

the lungs: Elemental compounds are selectively taken and isolated from the general circulation.

Transplacental transfer: Placenta acts as a selective barrier. Lipid-soluble drugs of molecular weight less than 1000 diffuse freely from the maternal to fetal circulation, whereas water-soluble drugs diffuse slowly. As the fetal drug elimination system is immature, severe toxicity will occur. The mechanism of elimination of the drug from the fetal circulation is diffusion back to the maternal side.

Elimination of drugs: Drugs are eliminated from the body

1. Metabolism in the liver and kidneys and

2. Excretion of the parent drug or its metabolites mainly by the kidneys, but also by the intestine, skin, lungs, sweat glands, mammary and salivary glands.

Administration of Medicines: The effective and safe dose of any drug should be determined by considering body mass or surface area. Although general dosing instructions are available, each dose should be tailored to the individual patient based on his weight, status of vital organs such as kidneys and liver, severity of infection, and immune status of the host. Although a long course of treatment is ideal for effective treatment, the possibility of toxicity limits the total dose.

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