Pharmacokinetic Phase

Pharmacokinetic Phase
Pharmacokinetics refers to activities within the body after a drug is administered. These activities include absorption, distribution, metabolism, and excretion (ADME). Another pharmacokinetic component is the half-life of the drug. Half-life is a measure of the rate at which drugs are removed from the body.

Following are phases of pharmacokinetics

1. Absorption
2. Distribution
3. Metabolism
4. Excretion
5. Half-Life

Half-Life

Half-life refers to the time required for the body to eliminate 50% of the drug. Knowledge of the half-life of a drug is important in planning the frequency of dosing. For example, drugs with a short half-life (2–4 hours) need to be administered frequently, whereas a drug with a long half-life (21–24 hours) requires less frequent dosing. It takes five to six half-lives to eliminate approximately 98% of a drug from the body. Although half-life is fairly stable, patients with liver or kidney disease may have problems excreting a drug. Difficulty in excreting a drug increases the half-life and increases the risk of toxicity. For example, digoxin (Lanoxin) has a long half-life (36 hours) and requires once-daily dosing. However, aspirin has a short half-life and requires frequent dosing. Older patients or patients with impaired kidney or liver function require frequent diagnostic tests measuring renal or hepatic function.

Excretion

The elimination of drugs from the body is called excretion. After the liver renders drugs inactive, the kidney excretes the inactive compounds from the body. Also, some drugs are excreted unchanged by the kidney without liver involvement. Patients with kidney disease may require a dosage reduction and careful monitoring of kidney function. Children have immature kidney function and may require dosage reduction and kidney function tests. Similarly, older adults have diminished kidney function and require careful monitoring and lower dosages. Other drugs are eliminated by sweat, breast milk, breath, or by the gastrointestinal tract in the feces.

Metabolism

Metabolism, also called biotransformation, is the process by which a drug is converted by the liver to inactive compounds through a series of chemical reactions. Patients with liver disease may require lower dosages of a drug detoxified by the liver, or the primary care provider may select a drug that does not undergo a biotransformation by the liver. Frequent liver function texts are necessary when liver disease is present. The kidneys, lungs, plasma, and intestinal mucosa also aid in the metabolism of drugs

Distribution

The systemic circulation distributes drugs to various body tissues or target sites. Drugs interact with specific receptors (see Fig.) during distribution. Some drugs travel by binding to protein (albumin) in the blood. Drugs bound to protein are pharmacologically inactive. Only when the protein molecules release the drug can the drug diffuse into the tissues, interact with receptors, and produce a therapeutic effect.

Drug-receptor interactions

As the drug circulates in the blood, a certain blood level must be maintained for the drugs to be effective. When the blood level decreases below the therapeutic level, the drug will not produce the desired effect. Should the blood level increase significantly over the therapeutic level, toxic symptoms develop. Specific therapeutic blood levels are discussed in the subsequent chapters when applicable.

Absorption

Absorption follows administration and is the process by which a drug is made available for use in the body. It occurs after dissolution of a solid form of the drug or after the administration of a liquid or parenteral drug. In this process the drug particles within the gastrointestinal tract are moved into the body fluids. This movement can be accomplished in several ways: active absorption, passive absorption, and pinocytosis. In active absorption a carrier molecule such as a protein or enzyme actively moves the drug across the membrane. Passive absorption occurs by diffusion (movement from a higher concentration to a lower concentration). In pinocytosis cells engulf the drug particle causing movement across the cell.

As the body transfers the drug from the body fluids to the tissue sites, absorption into the body tissues occurs. Several factors influence the rate of absorption, including the route of administration, the solubility of the drug, and the presence of certain body conditions. Drugs are most rapidly absorbed when given by the intravenous route, followed by the intramuscular route, the subcutaneous route, and lastly, the oral route. Some drugs are more soluble and
thus are absorbed more rapidly than others. For example, water-soluble drugs are readily absorbed into the systemic circulation. Bodily conditions, such as the development of lipodystrophy (atrophy of the subcutaneous tissue) from repeated subcutaneous injections, inhibit absorption of a drug given in the site of lipodystrophy.

AN OVERVIEW OF DRUG ACTION

AN OVERVIEW OF DRUG ACTION

Sites of Drug Action

Most medications given to patients have a direct effect on a particular and often specific molecule or class of molecules. These molecules are likely to be proteins serving as enzymes to catalyze chemical reactions, or as receptors, ion channels, or transport molecules. Other common sites of action include direct binding to nucleic acids. Some useful medications have less “interesting” sites of action, especially those drugs that do not enter the body. For example, sun-blocking creams stay on the surface of the skin to physically block UV rays in sunlight and have no specific molecular site of action. Antacid tablets (e.g., magnesium hydroxide or calcium carbonate) chemically buffer the HCl acid in the stomach, but could just as easily buffer other acids; this is hardly a specific molecular target of action.

FIGURE 3 More details about the process of care, as focused on the process of rational drug therapy.

Once a drug interacts with its target molecule, however, its pharmacologic effects then can become obvious at other levels. Interaction of a drug with its molecular target then has effects on the cell, subsequently on a tissue, eventually on an organ system, and ultimately, on the intact organism (or patient in clinical pharmacology). In fact, a further level of action might be on the patient's community. For example, the use of vancomycin in one hospitalized patient can have an effect on the broader hospital community by helping to increase the development of Staphylococci resistant to vancomycin within that hospital environment.

Thus the question “What does terazosin do?” might be answered by saying that the drug acts as an inhibitor of alpha-1 adrenoceptors (at the molecular level), thereby decreasing the influx of calcium into smooth muscle cells; thereby relaxing the smooth muscle tissue at the bladder neck and prostate; thereby facilitating bladder emptying and increasing rate of urine flow (at the system level); and thereby decreasing complaints of poor urine flow, frequency, dribbling, or nocturia (at the level of the 68-year-old man with bladder outlet obstruction due to benign prostatic hypertrophy with some component of reversibility). When treating patients with drugs, it is important to keep all of these levels of drug action in mind.

SUMMARY

Most drugs act at several important levels including the following.

• Molecular target
• Cell
• Tissue
• Organ/system
• Intact animal or patient
• Larger community of patients (for some drugs)