Figure 1–1 Relationship between pharmacokinetics and pharmacodynamics.
Toxicology
Toxicology is the study of poisons and organ toxicity. It focuses on the harmful effects of drugs and other chemicals, and on the mechanisms by which these agents produce pathologic changes, disease, and death. As with pharmacology, toxicology is concerned with the relationship between the dose of an agent and the resulting tissue concentration and biologic effects that the agent produces. Most drugs have toxic effects at high enough doses and may have adverse effects related to toxicity at therapeutic doses.
Pharmacotherapeutics
Pharmacotherapeutics is the medical science concerned with the use of drugs in the treatment of disease. Pharmacology provides a rational basis for pharmacotherapeutics by explaining the mechanisms and effects of drugs on the body and the relationship between dose and drug response. Human studies known as clinical trials are then used to determine the efficacy and safety of drug therapy in human subjects. The purpose, design, and evaluation of human drug studies are discussed in Chapter 4.
Pharmacy and Related Sciences
Pharmacy is the science and profession concerned with the preparation, storage, dispensing, and proper use of drug products. Related sciences include pharmacognosy, medicinal chemistry, and pharmaceutical chemistry. Pharmacognosy is the study of drugs isolated from natural sources, including plants, microbes, animal tissues, and minerals. Medicinal chemistry is a branch of organic chemistry that specializes in the design and chemical synthesis of drugs. Pharmaceutical chemistry, or pharmaceutics, is concerned with the formulation and chemical properties of pharmaceutical products, such as tablets, liquid solutions and suspensions, and aerosols.
DRUG SOURCES AND PREPARATIONS
A drug can be defined as a natural product, chemical substance, or pharmaceutical preparation intended for administration to a human or animal to diagnose or treat a disease. The word drug is derived from the French drogue, which originally meant dried herbs and was applied to herbs in the marketplace used for cooking rather than for any medicinal reason. Ironically, the medical use of the drug marijuana, a dried herb, is hotly debated in many societies today. Medication, and less frequently, medicament are terms that are synonymous with the word drug.
Natural Sources of Drugs
Drugs have been obtained from plants, microbes, animal tissues, and minerals. Among the various types of drugs derived from plants are alkaloids, which are substances containing nitrogen groups and give an alkaline reaction in aqueous solution. Examples of alkaloids include morphine, cocaine, atropine, and quinine. Antibiotics have been isolated from numerous microorganisms, including Penicillium and Streptomyces species. Hormones are the most common type of drug obtained from animals, whereas minerals have yielded a few useful therapeutic agents, including the lithium compounds used to treat bipolar mental illness.
Synthetic Drugs
Modern chemistry in the 19th century enabled scientists to synthesize new compounds and to modify naturally occurring drugs. Aspirin, barbiturates, and local anesthetics (e.g., procaine) were among the first drugs to be synthesized in the laboratory. Semisynthetic derivatives of naturally occurring compounds have led to new drugs with different properties, such as the morphine derivative oxycodone.
In some cases, new drug uses were discovered by accident when drugs were used for another purpose, or by actively screening a huge number of related molecules for a specific pharmacologic activity. Medicinal chemists now use molecular modeling software to discern the structure-activity relationship, which is the relationship between the drug molecule, its target receptor, and the resulting pharmacologic activity. In this way, a virtual model for the receptor of a particular drug is created, and drug molecules that best fit the three-dimensional conformation of the receptor are synthesized. This approach has been used, for example, to design agents that inhibit angiotensin synthesis, treat hypertension, and inhibit the maturation of the human immunodeficiency virus in AIDS patients.
Drug Preparations
Drug preparations include crude drug preparations obtained from natural sources, pure drug compounds isolated from natural sources or synthesized in the laboratory, and pharmaceutical preparations of drugs intended for administration to patients. The relationship between these types of drug preparations is illustrated in Figure 1–2.
Figure 1–2 Types of drug preparations. A crude drug preparation retains most or all of the active and inactive compounds contained in the natural source from which it was derived. After a pure drug compound (e.g., morphine) is extracted from a crude drug preparation (in this case, opium), it is possible to manufacture pharmaceutic preparations that are suitable for administration of a particular dose to the patient.
Crude Drug Preparations
Some crude drug preparations are made by drying or pulverizing a plant or animal tissue. Others are made by extracting substances from a natural product with the aid of hot water or a solvent such as alcohol. Familiar examples of crude drug preparations are coffee and tea, made from distillates of the beans and leaves of Coffea arabica and Camellia sinensis plants, and opium, which is the dried juice of the unripe poppy capsule of the plant, Papaver somniferum.
Pure Drug Compounds
It is difficult to identify and quantify the pharmacologic effects of crude drug preparations because these products contain multiple ingredients, the amounts of which may vary from batch to batch. Hence, the development of methods to isolate pure drug compounds from natural sources was an important step in the growth of pharmacology and rational therapeutics. Frederick Sertürner, a German apothecary, isolated the first pure drug from a natural source when he extracted a potent analgesic agent from opium in 1804 and named it morphine, from Morpheus, the Greek god of dreams. The subsequent isolation of many other drugs from natural sources provided pharmacologists with a number of pure compounds for study and characterization. One of the greatest medical achievements of the early 20th century was the isolation of insulin from the pancreas. This achievement by Frederick Banting and Charles Best led to the development of insulin preparations for treating diabetes mellitus.
Pharmaceutical Preparations
Pharmaceutical preparations or dosage forms are drug products suitable for administration of a specific dose of a drug to a patient by a particular route of administration. Most of these preparations are made from pure drug compounds, but a few are made from crude drug preparations and sold as herbal remedies.
TABLETS AND CAPSULES
Tablets and capsules are the most common preparations for oral administration because they are suitable for mass production, are stable and convenient to use, and can be formulated to release the drug immediately after ingestion or to release it over a period of hours.
In the manufacture of tablets, a machine with a punch and die mechanism compresses a mixture of powdered drug and inert ingredients into a hard pill. The inert ingredients include specific components that provide bulk, prevent sticking to the punch and die during manufacture, maintain tablet stability in the bottle, and facilitate solubilization of the tablet when it reaches gastrointestinal fluids. These ingredients are called fillers, lubricants, adhesives, and disintegrants, respectively.
A tablet must disintegrate after it is ingested, and then the drug must dissolve in gastrointestinal fluids before it can be absorbed into the circulation. Variations in the rate and extent of tablet disintegration and drug dissolution can give rise to differences in the oral bioavailability of drugs from different tablet formulations (see Chapter 4).
Tablets may have various types of coatings. Enteric coatings consist of polymers that will not disintegrate in gastric acid but will break down in the more basic pH of the intestines. Enteric coatings are used to protect drugs that would otherwise be destroyed by gastric acid and are also to slow the release and absorption of a drug when a large dose is given at one time, for example, in the formulation of the antidepressant, fluoxetine, called Prozac Weekly.
Sustained-release products, or extended-release products, release the drug from the preparation over many hours. The two methods used to extend the release of the drug are controlled diffusion and controlled dissolution. With controlled diffusion, release of the drug from the pharmaceutical product is regulated by a rate-controlling membrane. Controlled dissolution is done by inert polymers that gradually break down in body fluids. These polymers may be part of the tablet matrix, or they may be used as coatings over small pellets of drug enclosed in a capsule. In either case, the drug is gradually released into the gastrointestinal tract as the polymers dissolve.
Some products use osmotic pressure to provide a sustained release of a drug. These products contain an osmotic agent that attracts gastrointestinal fluid at a constant rate. The attracted fluid then forces the drug out of the tablet through a small laser-drilled hole (Fig. 1–3A).
Figure 1–3 Mechanisms of sustained-release drug products. In the sustained-release tablet (A), water is attracted by an osmotic agent in the tablet, and this forces the drug out through a small orifice. In the transdermal skin patch (B), the drug diffuses through a rate-controlling membrane and is absorbed through the skin into the circulation.
Capsules are hard or soft gelatin shells enclosing a powdered or liquid medication. Hard capsules are used to enclose powdered drugs, whereas soft capsules enclose a drug in solution. The gelatin shell quickly dissolves in gastrointestinal fluids to release the drug for absorption into the circulation.
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