Basic Pharmacology

Understanding Drug Actions and Reactions

Maria A. Hernandez, Ph.D.,Appu Rathinavelu, Ph.D.

• Publisher: Routledge
• Year: 2017
• ISBN:
  9781351988650
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Intended for use in an introductory pharmacology course, Basic Pharmacology: Understanding Drug Actions and Reaction s provides an in-depth discussion of how to apply the chemical and molecular pharmacology concepts, a discussion students need for more advanced study. The textbook introduces the principles of chemistry and biology necessary to understand drug interactions at the cellular level. The authors highlight chemical and physical properties of drugs, drug absorption and distribution, drug interactions with cellular receptors, and drug metabolism and elimination.

The book begins with a review of chemical principles as they apply to drug molecules, focusing mainly on those for commonly prescribed drugs. The authors use drug structures to illustrate the chemical concepts learned in general and organic chemistry courses. They cover the dynamics of receptors in mediating the pharmacological effects of drugs. They clarify theories, drawn from the scientific literature, which explain drug-receptor interactions and the quantitative relationship between drug binding and its effects at the cellular level.

The authors' extensive use of drug structures for teaching chemical and molecular pharmacology principles, and their emphasis on the relevance of these principles in future professional life makes this book unique. It provides the framework for better understanding of advanced pharmacology and therapeutics topics. Blending medicinal chemistry and pharmacodynamics aspects, this textbook clearly elucidates the essential concepts that form the cornerstone for further work in pharmacology.

III

PRINCIPLES OF DRUG-RECEPTOR AND DRUG-ENZYME INTERACTIONS

8

DRUG RECEPTORS AND PHARMACODYNAMICS

MECHANISMS OF DRUG ACTION

A drug can be taken through different routes — oral (PO), intravenous (IV), intraperitoneal (IP), intramuscular (IM), etc. Once the drug enters the body, before it is metabolized into an inactive form through one of many different pathways and excreted from the body, it produces a desired pharmacological effect. The pharmacological as well as toxicological effects of most drugs result from their interaction with cellular components such as DNA, RNA, or proteins of a target organism (Figure 8.1). The interactions between drug molecules and the macromolecules of the body eventually initiate biochemical and physiological changes that are very characteristic of the drugs.

Drug interactions occur through different forms of macromolecules that may have specific functions. For example, the protein molecules interacting with drugs may be receptors, enzymes, transporters, or just a membrane component of a cell (Figure 8.2). As a result of a drug interaction their function may be either enhanced or decreased. The imposed changes on the macromolecules may act independently or initiate chain reactions that are responsible for the pharmacological effect of the drug.

CHEMICAL SIGNALING AND RECEPTOR FUNCTION

Chemical Signaling

Communication between cells is required to coordinate the activities of different organs within the body. Cells of various organs and tissues interact with each other by transmitting chemical signals. Signals activating a cell may come from distant sites or from very close proximity in the form of hormones, growth factors, neurotransmitters, or other substances. These signaling molecules are called first messengers. The cells present in any organism are thought to communicate in five different ways, as illustrated in Figure 8.3:

Figure 8.1 The three important macromolecule targets that interact with drug molecules.

Figure 8.2 The different kinds of intracellular and extracellular macromolecules and receptors that can bind a ligand.

1. Autocrine: Signaling chemicals coming from a cell act on their own receptors (e.g., norepinephrine acting on the presynaptic receptors and cytokines acting on lymphocytes).

2. Paracrine: Signaling chemicals influence the function of neighboring cells and cells present in the close vicinity (e.g., histamine, serotonin).

3. Endocrine: Signaling chemicals are carried to the distant sites and act on discrete organs (insulin, estrogen, testosterone, etc.).

Figure 8.3 Some examples of signaling molecules.

4. Neurotransmission: Signaling chemicals are present in gap junctions and activate postsynaptic neurons or interacting cells (acetylcholine, norepinephrine, etc.).

5. Cell-cell communication: Direct communication occurs through interaction of signaling molecules anchored on the cell membranes (T cell-B cell interaction, HIV [gp120]–T cell [CD4] interaction).

Autocrine, Paracrine, and Endocrine Function

The signaling molecules involved in autocrine and paracrine function are the local chemical mediators that are normally referred as autocoids (Greek: “self-remedy”). The autocoids could be short-lived biochemicals whose actions are often limited to receptors found on the cells or tissues within a close viscinity from the origin of the autocoids. Some examples of autocoids are lymphokines, histamine, and prostaglandin E₂. On the other hand, hormones that are secreted from glands or glandular tissues generally carry out endocrine functions. Hormones are biochemicals that are stable and are able to reach target receptors located on distant organs and remote tissues. Some good examples of hormones are insulin, adrenocorticotropic hormone, thyroid stimulating hormone, somatropin, and epidermal growth factor. Examples of various types of signaling molecules are given in Table 8.1.

Nature of the Signaling Molecules (Ligands)

Signaling molecules can be either water soluble or lipid soluble. All known neurotransmitters as well as most hormones and local chemical mediators are water-soluble molecules. The main exceptions are the steroid and thyroid hormones, which are relatively water insoluble. These water-insoluble hormones are made soluble for transport in the bloodstream by binding to specific carrier proteins. This difference in solubility gives rise to a fundamental difference in the mechanism by which the two classes of molecules influence target cells. Due to their hydrophilic nature the water-soluble ligands cannot pass through the lipid bilayer, due to the hydrophylic nature; hence, they bind to receptor proteins on the cell surface. On the other hand, the steroid and thyroid hormones are hydrophobic (lipophilic); hence, they can easily pass through the plasma membrane of the target cells. These hormones bind to specific receptor proteins that are located inside the cell (Figure 8.4).

In the body all three kinds of signaling molecules may coordinate to produce a desired effect. For example, when the body is suddenly exposed to severe cold temperature, subsequent events leading to the release and hormonal action of thyroxine (T₄), which controls metabolic activity in target cells, involve the action of all three types of signaling molecules — local chemical mediators, neurotansmitters, and hormones. The signaling cascade starts when nerve cells in the hypothalamic regions of the brain are stimulated to secrete local chemical mediators into the blood vessels of the pituitary to activate the pi...