Branches of Pharmacology

This chapter introduces some fundamentals of “physiological pharmacology” or “pharmacological physiology”—referring to the same anatomy, physiology, and biochemistry discussed in Chapter 2 (Chemistry of Life) and Chapter 3 (Cell Structure and Function). Although all drugs are potential poisons (substances that cause severe distress or death), when given in subtoxic doses they are medicinal tools. The goal of rational drug therapy is to aid and maintain the body and its biological systems in healthy working order. In therapy, drugs give living tissues added chemical support to prevent and to meet physical and pathological challenges to which biological systems are exposed. Pharmacology is organized into separate disciplines that describe actions of drugs:

Drug Nomenclature

Because all drugs are potential poisons, understanding their nomenclature is essential. It is also practical because it specifically identifies the correct drug for the correct use. This starts with their manufacture in the pharmaceutical industry; continues to distribution at pharmacies where drugs are dispensed; and ends with medical personnel who administer them to patients. Moreover, drug nomenclature is needed for a precise chemical description that can help to avoid medical disasters.

In general, therapeutic chemicals are broadly divided into two groups, nonprescription and prescription drugs:

Individual drugs have three names: chemical, generic, and proprietary or trade (brand) name (Table 21.1):

Sources of Drug Information

Sources for drug information can be people or published information. People who generally have particular drug information include the following:

Published information can be found in the following:

Administration

Drugs are administered enterally via the digestive system or parenterally via a system other than the digestive system. They are given to affect only the site of administration, or systemically, for distribution to various sites of action via the circulatory system.

For direct local action, drugs may be given (Figure 21.1) in the following ways:

For systemic effects, drugs may be given (Figure 21.2) in the following ways:

Absorption

After administration, drugs must proceed to a site where they can act. Absorption describes the rate at which a drug leaves its site of administration and the extent to which it appears at the site of action. Regardless of the route of administration, the drug must be dissolved in body fluids and pass through biological barriers before it can arrive at the cellular site of action (Box 21.1). The term used to indicate the extent to which a drug reaches its site of action is bioavailability. Drugs are biotransported across these biological barriers via mechanisms discussed previously (see Chapter 2 [Chemistry of Life] and Chapter 3 [Cell Structure and Function]). For example, drugs administered orally, dermally, topically, or by inhalation must traverse the epithelium, whereas those given subcutaneously or intramuscularly must traverse the capillary wall. There are three general sites of action:

BOX 21.1   Transport of Drugs Through Biological Membranes

Transport of the various forms of drugs can be described by formulas that show:

• The percentage that will be available for successful transport through phospholipid (biological) membranes

• The percentage that will be available for excretion through the kidney

• The amounts of materials that potentially will be available for movement

• Specific information and/or general information about the substances and their mobilities

For example:

• Water-soluble forms of substances:

• Are ionized (see Chapter 2, Chemistry of Life)

• Have difficulty passing through biological (phospholipid) membranes such as blood vessels

• Are readily excreted via an organ system such as the kidney

• Are transformed in the body from lipid- to water-soluble forms by biotransformation.

• Lipid-soluble forms of substances:

• Are nonionized

• Readily pass through biological (phospholipid) membranes such as are found in blood vessels

• Can be reabsorbed in the kidney, that is, are not readily excreted like water-soluble drugs

• Can be biotransformed to water-soluble (kidney-excretable) forms in the body

The abbreviated relationships that give this information as a percentage are as follows:

< ?xml:namespace prefix = "mml" />I(ionized percentage) of drug×100I(ionized)+Nonion (nonionized percentage of drug)

and

Nonion (percentage)×100I(percentage)+Nonion (percentage)=Percent available for biological transport,respectively

The rate of drug absorption is influenced by the anatomical and physiological properties of the site of administration and the physical and chemical properties of the drug itself. These factors include the following:

Distribution

Distribution is the transfer of drugs across biological membranes into body compartments such as the combined intracellular and extracellular fluid compartments (see Chapter 3, Cell Structure and Function). These two compartments combined make one compartment with approximately 40 liters of fluid. Drug distribution is dependent on the drug’s chemical properties and solubility, on the amount of blood flow to the target, and on the drug’s molecular size and rate of excretion, to name a few. Water-soluble drugs are readily excreted and lost unless bound. Blood flow to the site and molecular size of the drug are additional factors as well. Blood flow to the brain reveals the blood–brain barrier as another obstacle, and blood flow to the fetus must traverse the placental circulation. The placenta presents a pathway for transfer of substances from the mother to the fetus, such as nicotine and marijuana as well as alcohol.

Biotransformation

Biotransformation involves the metabolism of drugs, a mechanism by which the body inactivates drugs and engages phase I and phase II reactions. Phase I reactions convert drugs into more ionized molecules by the introduction of (or by the exposure of) already existing ionized components of the compounds (Table 21.3). Phase II reactions are synthetic reactions in which new compounds are introduced to chemically altered drugs. Some examples include conjugations of moieties with amino (–NH₂), hydroxyl (OH), or sulfhydryl (SH) groups if added to the molecules (Table 21.4).

Although the liver plays the major role in drug metabolism, lungs, kidneys, and adrenal glands contribute as well. The majority of active drugs need high lipid solubility to be transported through bilipid cellular membranes. Drug metabolites also require high water solubility in order to be transported to the kidneys and eliminated in urine formed in nephrons of the kidneys (Figure 21.3). Lipid-soluble drugs can be made more water soluble by metabolic processes such as conjugation, or other metabolic processes that render the metabolite water soluble. Although metabolic processes can inactivate a drug, this is not always the case (see Medical Highlights: Prodrugs).

Clearance (Elimination)

Drugs are excreted from the body primarily via the kidneys, and this excretion into the urine requires three processes (see Chapter 15, Infections of the Urinary System; and also Figure 21.3):

Some drugs metabolized in the liver are also excreted via bile and the biliary tract as well as via feces. The lungs, in addition to being a route of administration, are also a potential path of elimination for drug metabolites in the expired air. Other paths of clearance include sweat, saliva, tears, and production of breastmilk, which can be a hazard for the newborn if the mother breastfeeds.

Dose Effects

Recalling that all drugs are potential poisons depending on the dose given, the effect of a drug depends on the dose, and it is essential to determine what a given dose will do to a patient. The dose of a drug is the amount given at a single time. Dosage refers to the total amount given over a period of time. For example, say the dose of a drug given to a patient is a 5-mg tablet; if administered for 5 days this equals a dosage of 25 mg. Dose and dosage are not terms to be used interchangeably.

Therapeutic Index

Paul Ehrlich recognized that drugs needed to be judged not only by their useful properties, but also by their toxic effects. The therapeutic index, also referred to as the “margin of safety,” is the ratio between a drug dose causing undesirable effects and the dose that causes the desired therapeutic response. The therapeutic index is the ratio of a drug’s LD₅₀ to its ED₅₀ and is determined in laboratory animals. The LD₅₀ is the lethal dose in 50% of the tested animals and the ED₅₀ is the effective dose of the drug in 50% of the treated animals.

Therapeutic index (TI)=LD50ED50

A high therapeutic index indicates that a drug is relatively safe, whereas a low therapeutic index indicates that the drug is relatively unsafe (Figure 21.4). Figure 21.4, B shows an overlap between the curves representing the therapeutic effect and the curve representing the lethal effect. This means that the drug dose needed to produce a therapeutic effect is very high, and may be large enough to cause death in some patients. For a drug to be safe, the highest dose necessary to produce a therapeutic effect must be substantially lower than the lowest dose required to produce death.

Individuals may vary considerably in their responsiveness to a drug. These biological variations among patients lead to pharmacological variations in the dose response of patients. Overcoming pharmacological variation requires quantitation in order to minimize errors of prediction. This begins with sampling of the collected data having a common characteristic such as age, gender, species, strain, weight, and environmental conditions. Because of biological variations patients will not necessarily respond to the same minimal effective dose (ED). However, by use of appropriate statistical methods, generalizations can be drawn with some degree of statistical probability. Normal distribution will predict that a few respond at the low dose range and a few respond at the highest doses, with most responding to a dose range in between (Figure 21.5).

It is essential to know what the response to a given dose of a drug will be. Responses are either:

• Graded: For example, the incremental amount of increase or decrease in blood pressure as the dose increases

or

• Quantal (all-or-none): The number of patients or animals responding per dose, such as with a drug either inducing sleep or not

Time Effects

Dose response includes magnitude of response after a single dose, excluding other factors that affect concentration at the site of action (SOA), such as time. A selected time is chosen and measurements are taken to determine minimal, maximal, or any other chosen level of response for that time (Figure 21.6).

The time response measures the following:

Latency (time 0–1) is regulated primarily by the time a drug takes to get to its SOA (i.e., the rates of absorption, distribution, and focusing after it arrives at the SOA in the target organ). This may also include conversion time from the inactive to active form of the drug.

The peak effect occurs when the receptors are maximally activated. This effect is largely determined by the rates of movement of the drug to the SOA and removal of drug from the SOA. It should be noted that with high concentrations of drug the rates of elimination are also high.

The effective concentration can be achieved by a single administration or after multiple administrations. The rate of elimination of a drug is a deciding factor in its cessation of action, and biotransformation is a decisive factor within this process. The rate of biotransformation determines the duration of action and effective concentrations are measured by the biological half-life of the drug. The biological half-life is the amount of time needed for the drug concentration in the plasma to be reduced to half the value from the previous measurement.

Antimicrobial drugs (see Chapter 22, Antimicrobial Drugs) are generally given by multiple administrations in order to achieve effective concentrations. Ongoing antimicrobial therapy should be reassessed regularly, and therapy should be appropriately adapted after initial culture results return. Dangerous negative effects can occur after toxic doses of antimicrobial drugs are accumulated or given; therefore, monitoring the patients’ vital signs as well as serum levels of drug concentration is essential. Drugs are typically withdrawn after the first sign of toxic or negative effect.

Variability

There are other variables such as age, gender, and species that influence the preparation for excretion or elimination. These include the following:

Toxicity

Toxic, adverse, and/or undesired drug effects are somewhat interchangeable terms. A toxic effect is an effect that is harmful to a biological system, whereas an adverse effect may be harmful in some but not all systems. Mild reactions include drowsiness, nausea, itching, and rash, whereas more severe adverse effects include respiratory depression, neutropenia, hepatocellular injury, anaphylaxis, and hemorrhage—all of which may lead to death.

Toxic effects are classified as:

Toxicology, the study of poisons, includes evaluation of the following characteristics:

Determination of drug safety (drug toxicity) is based on comparisons with other drugs or poisons to measure relative safety levels. For example, penicillin is considered safe compared with the poisonous organophosphate malathion as well as compared with the antimicrobial drug neomycin. Human drug safety evaluated by pharmacological animal testing procedures is shown in Table 21.5.

Nonspecific treatment of suspected poisoning always includes support of respiration and circulation in addition to:

Specific treatment for poisons (Table 21.6) is as follows:

Development

Development begins with extraction of the active constituent from the natural product. This active constituent is then tested on a biological system to develop a pharmacological profile. This screening process is time-consuming. For example, even though thousands of soil samples can be screened in the search for therapeutically active antimicrobials, only a few have actually been found. When a pharmacologically active natural compound is found, synthetic chemistry is used to identify a process to make it and/or modify the structure to reduce side effects that are undesirable or to add structural changes that make the new synthetic compound more therapeutically desirable. Some notable drugs are still feasible to obtain as natural products, such as morphine for pain control or the digitalis glycosides for cardiovascular therapies. Cell cultures from plant sources are also being investigated as potential sources to improve yields from screening procedures.

In addition, these investigations with plants have led to technological advances that:

The development of synthetic chemicals led to the study of structure–activity relationships (SAR) and the evolution of pharmacological prototypes (agents with similar structures that have similar therapeutic properties). With synthetic chemicals and the use of synthetic chemistry, structures of classes of drugs could be manipulated to:

Many natural products are broken down in the stomach; hence the advent of oral synthetic drugs, such as oral antidiabetics and oral contraceptives, has made a major impact on therapeutic practice. For example, not only have oral contraceptives impacted gynecological medicine but the availability of oral synthetic estrogenic and progestatonal hormones have revolutionized the practice of these medical disciplines as well.

Public Safety

Protection of the public has received the attention of the federal government beginning with federal regulations to guide the manufacture, distribution, and sales of new drugs—and in many instances existing drugs—and through a program of rational tests before permitting use in humans.

The Pure Food and Drug Act of 1906 dealt only with drugs already on the market. Basically, it used the Pharmacopeia of the United States and the National Formulary as the official standards of the U.S. government. In addition, the federal government was entrusted with enforcing claims that the purity and strength of drugs were accurate and true.

The Federal Food, Drug and Cosmetic Act of 1938 empowered the Food and Drug Administration (FDA) to require, for their review and approval, a New Drug Application (NDA) that showed the safety of new therapeutic agents. This was prompted by the use of diethylene glycol as a liquid diluent with no toxicity tests. More than 100 fatalities had been reported from severe liver and kidney damage and pulmonary edema linked to diethylene glycol. At present, if the formulation of an existing drug is changed, it becomes a “new drug” for review by the FDA.

The Federal Food, Drug and Cosmetic Act of 1938 was modified by the Kefauver-Harris Amendment of 1962 to require proof that a new drug was not only safe but also effective. These substantial requirements to demonstrate evidence of efficacy as well as safety were retroactive to drugs and products marketed between 1938 and 1962. The governmental authority was extended to enforce requirements that preclinical studies be done before clinical testing and distribution of new drugs.

In 1971, the Controlled Substances Act became law. This legislation focused on drugs that had the potential for abuse. Those who manufacture, dispense, prescribe, or administer any of these controlled substances must register annually with the Attorney General of the United States. Enforcement is the responsibility of the Drug Enforcement Administration (DEA). The five schedules of controlled substances are as follows:

Orphan drugs are those drugs needed to treat diseases affecting fewer than 200,000 U.S. patients, and that fail to receive attention for development primarily because of cost and demand. The Federal Food, Drug and Cosmetic Act of 1938 was amended with the Orphan Drug Act of 1983, which gave incentives to develop drugs for rare diseases.

An Investigational New Drug Application (IND) is required for approval by the Center for Drug Evaluation and Research of the FDA, and must include specified information required by the Federal Food, Drug and Cosmetic Act. A new drug is:

Furthermore, the IND must contain all preclinical data (see Life Application: Drug Development).