Drug Management Principles II - Its Metabolism (Distribution)

In the blood circulation, drugs are reversibly bound to plasma proteins. Previously, it depends on the blood flow and the ability of the drug to penetrate the tissue. Easy entry into tissues depends on lipid solubility and concentration gradient over cell membranes. The main part of any drug is distributed to the tissues, where it has no pharmacological action. In such conditions as “shock” with poor tissue perforation, the drug remains in plasma in high concentrations, not falling into the tissue, and this leads to toxicity. Specialized tissues take drugs selectively. Most tissues of the central nervous system limit the penetration of polar (ionized) compounds. Lipid soluble substances easily penetrate the concentration gradient, while sugars and amino acids are actively transported. This blood-brain barrier is destroyed in the presence of meningeal inflammation. In equilibrium conditions, the drug is distributed between plasma water, plasma proteins and tissues. Since lipid-soluble drugs penetrate cells more easily, their plasma concentration is lower compared to water-soluble drugs. In hemodialysis, water-soluble compounds can be removed from the circulation, but this is not effective with lipid-soluble drugs. The magnitude of the responses of any drug depends on the level of the free drug on the receptor site. The level of free drug in plasma depends on two factors: the binding of plasma protein and ease of distribution in other tissues.

Plasma Protein Binding : Plasma proteins, especially aluminum, form reversible complexes with drugs in circulation. The degree of absorption depends on the pH of the plasma and the affinity of the drug to the protein. When many drugs compete for absorption, high affinities replace them with weak closeness. Acid preparations will be shifted from the protein complex when the body goes into acidosis. Since 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 or metabolized from the body into bile. Hepatic drug metabolism occurs in two stages; Stage I reactions include oxidation, reduction and hydrolysis; and the reaction stage II involved the conjugation of the parent compound or its metabolites — acetylation, sulfation, O-methylation, and conjugation of glycein. These products are water soluble and therefore excreted from the body. Urine excretion depends on the processes
1. Glomerular filtration,
2. Active tubular secretion and reabsorption,
3. Passive diffusion.

Lungs : The main compounds are selectively collected and sequestered from the general circulation.

Transplacental transfer The placenta behaves as a selective barrier. Lipid-soluble drugs with a molecular weight of less than 1000 freely diffuse from mother cirrhosis to fetuses, whereas water-soluble drugs only spread slowly. Since the systems for eliminating fetal drugs are immature, serious toxicity occurs. The mechanism for removing the drug from the fetal circulation extends to the maternal side.

Drug elimination : Drugs are removed from the body
1. Metabolism in the liver and kidneys and
2. Excretion of the parent drug itself or its metabolites by the kidneys predominantly, but also of the intestine, skin, lungs, sweat glands, breasts and salivary glands.

The introduction of drugs : An effective and safe dose of any drug should be determined based on body weight or surface area. Although general dose instructions are available, each dose must be individualized for the individual patient based on their weight, the condition of vital organs such as the kidneys and liver, the severity of the infection, and the host immune status. Although a long course of therapy is ideal for treatment, the chances of toxicity limit the total dose.