Aspirin overdose commonly causes a mixed respiratory alkalosis and metabolic acidosis. Because aspirin is a weak acid, serum acidosis favors entry of the drug into tissues (increasing toxicity), and urinary acidosis favors reabsorp-tion of excreted drug back into the blood (prolonging the effects of the overdose). Sodium bicarbonate, a weak base, is an important component of the management of aspirin overdose. It causes alkalosis, reducing entry into tissues, and increases the pH of the urine, enhancing renal clearance of the drug. See the discussion of the ionization of weak acids and weak bases in the text.
Mark von Zastrow, MD, PhD*
A 51-year-old man presents to the emergency department due to acute difficulty breathing. The patient is afebrile and normotensive but anxious, tachycardic, and markedly tachy-pneic. Auscultation of the chest reveals diffuse wheezes. The physician provisionally makes the diagnosis of bronchial asthma and administers epinephrine by intramuscular injec-tion, improving the patient’s breathing over several minutes. A normal chest X-ray is subsequently obtained, and the medical history is remarkable only for mild hypertension that is being treated with propranolol. The physician instructs the patient to discontinue use of propranolol, and changes the patient’s antihypertensive medication to verapamil. Why is the physician correct to discontinue propranolol? Why is verapamil a better choice for managing hypertension in this patient? What alternative treatment change might the physi-cian consider?
Therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules’ biochemical or biophysical activities. This idea, more than a century old, is embodied in the term receptor: the component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects.
Receptors have become the central focus of investigation of drug effects and their mechanisms of action (pharmacodynamics). The receptor concept, extended to endocrinology, immunology, and molecular biology, has proved essential for explaining many aspects of biologic regulation. Many drug receptors have been isolated and characterized in detail, thus opening the way to precise understanding of the molecular basis of drug action.
The receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice. These consequences form the basis for understanding the actions and clinical uses of drugs described in almost every chapter of this book. They may be briefly summarized as follows: * The author thanks Henry R. Bourne, MD, for major contributions to this chapter.
1.
Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The receptor’s affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce.
2.
Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether—and with what affinity—it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, tissue, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug’s affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.
3.
Receptors mediate the actions of pharmacologic agonists and antagonists. Some drugs and many natural ligands, such as hormones and neurotransmitters, regulate the function of receptor macromolecules as agonists; this means that they activate the receptor to signal as a direct result of binding to it. Some agonists activate a single kind of receptor to produce all their biologic functions, whereas others selectively promote one receptor function more than another.