Medical brain Notes 3

  Pharmacokinetics   Whatever the actual mechanism of action of a drug may be, we will want to know: Does the drug actually reach its site of action, and for how long does it stay there? This is governed by three factors:   1.    Absorption: Uptake of the drug from the compartment of application into the blood   2.    Distribution: Transport / equilibration between the blood and the rest of the organism   3.    Elimination: Filtration and secretion in the kidneys; chemical modification in the liver   Broadly speaking, absorption and distribution determine the whether a drug will be available at its target site at all, while elimination determines for how long the drug effect will last. The issues of drug absorption, distribution and elimination are collectively referred to as `pharmacoki-netics'.

  Drug application and uptake   You are certainly aware that drugs are applied by various routes; the choice depends largely on the pharmacokinetic properties of the drug in question. Table 2.1 lists some characteristics of the major routes.   We will look at the various routes of application in turn. Oral uptake is the most common one, so let's start with this one.   Oral drug application   Inside the digestive tract, drug molecules encounter a quite aggressive chemical milieu. E.g., the acidic pH in the stom-ach (pH ~2) and the presence of proteases and nucleases in the gut preclude the application of proteins, nucleic acids, and other labile molecules. The gut mucous membrane presents a barrier to uptake; many drugs are not able to ef-ficiently cross it by way of diffusion.   For those drugs that make it from the gut lumen into the blood, the liver presents another formidable barrier. All blood drained from the intestines (as well as the spleen and the p...

  Drug distribution   Once the drug has entered the systemic circulation, it needs to reach its target site. Target sites may be located in vari-ous compartments:   1.    Within the blood vessels. Example: blood coagulation / clot dissolution. No problems of distribution here, drug molecules of any size and shape can be used (when intravenously applied).   2.    In the organ tissue, outside the blood vessels, but extra-cellular or superficially exposed on the cell surface. Ex-ample: Most receptors for hormones and transmitters.   3.    In the organ tissue, intracellularly located. Example: Many enzyme inhibitors.   1. Vascular permeability; the blood brain barrier   An important factor in the distribution of drugs is the per-meability of the capillaries. Capillaries are the microscop-ically small blood vessels across the very thin walls of which metabolites and gases are exchanged between blood and tissues. Capillaries hav...

  Drug elimination: Kidneys   Ultimately, most drugs are eliminated from the body via the kidney. As a rule of thumb, drugs can be directly elim-inated there if they are hydrophilic; hydrophobic drug molecules are typically metabolized to more hydrophilic derivatives in the liver before elimination (Figure 2.14).   To understand drug elimination in the kidney, we first have to consider some aspects of its structure and function. 1. Kidney anatomy and function   The kidneys are located close to the aorta (Figure 2.15a) and, in terms of blood flow / tissue mass, are the most strongly perfused organ. Urine is `distilled' from the blood in several stages:   1.    Filtration: The kidneys are perfused at a rate of ~1.2 l/min. Approximately 10% of the blood plasma vol-ume is squeezed across a filtering membrane that re-tains most macromolecules but lets through small molecules.   2.    Re-absorption: Most small solutes – glucose, salts, and ami...