[...]... potential risks, benefits, and discomforts PHASES OF CLINICAL INVESTIGATION The clinical development of new drugs usually takes place in steps or phases conventionally described as clinical pharmacology (phase I), clinical investigation (phase II), clinical trials (phase III), and postmarketing studies (phase IV) Table 1.1 summarizes the four phases of clinical evaluation Phase I When a drug is administered... receptors for norepinephrine and epinephrine ( - and ␤-adrenoceptors), 5-hydroxytryptamine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors Figure 2.1 presents the structure of one of these, the ␣2-adrenoceptor from the human kidney All members of this family of G protein–coupled receptors are characterized by having seven membrane-enclosed domains plus extracellular and intracellular... relatively close-packed cellular arrangement and decreased amount of lipid in these cells Thus, even highly lipid-soluble compounds will be absorbed much more slowly through the skin than from other sites The dermis, on the other hand, is well supplied with blood and lymph capillaries and therefore is permeable to both lipid-soluble and water-soluble compounds If penetration of the skin by lipid-insoluble... (eds.) Handbook of Phase I/II Clinical Drug Trials Boca Raton, FL: CRC, 1997 Parascandola J John J Abel and the emergence of U.S pharmacology Pharmaceut News 1995;2:911 Spilker, B Guide to Clinical Trials New York: Raven, 1991 2 Mechanisms of Drug Action William W Fleming RECEPTORS A fundamental concept of pharmacology is that to initiate an effect in a cell, most drugs combine with some molecular structure... observing the subject in a hospital or clinical pharmacology unit with emergency facilities If no adverse reactions occur, the dose is increased progressively until a predetermined dose or serum level is reached or toxicity supervenes Phase I studies are usually confined to a group of 20 to 80 subjects If no untoward effects result from single doses, short-term multiple-dose studies are initiated Phase II... to the right (curve c), still with no decrease in the maximum effect of the agonist However, the amount of agonist required to achieve maximum response is greater with each increase in the amount of antagonist Examples of equilibrium-competitive antagonists are atropine, d-tubocurarine phentolamine, and naloxone Of course, this continual shift of the curve to the right with no change in maximum as the... signal transduction process EXCEPT (A) Combination of an agonist with its receptor (B) Combination of an antagonist with its receptor (C) Combination of a neurotransmitter with its receptor (D) Combination of a hormone with its receptor 3 Which of the following chemical bonds would create an irreversible combination of an antagonist with its receptor? (A) Ionic bond (B) Hydrogen bond (C) Van der Waals... cell Type of transport Membrane Diffusion Non-electrolytes and unionized form of weak acids and weak bases Filtration and bulk flow Absorbed molecule Molecules of varying sizes Vesicle Endocytosis Ϫ Ion-pair ϩ Ϫ ϩ Drug Ϫ ϩ Carrier Facilitated or active Drug-carrier complex FIGURE 3.4 Mechanisms involved in the passage of drugs across membranes (Adapted with permission from Smyth DH Absorption and Distribution... The purpose of these studies is to broaden the experience with the drug and to compare the new drug with other agents that are being used clinically 3 C John Jacob Abel occupied the first chair of a department of pharmacology in the United States This was at the University of Michigan Abel subsequently left Michigan to chair the first department of pharmacology at Johns Hopkins University Claude Bernard... many drugs may interact with the same binding site A drug with a higher affinity may displace a drug with weaker affinity Increases in the non–protein-bound drug fraction (i.e., free drug) can theoretically result in an increase in the drug’s intensity of pharmacological response, side effects, and potential toxicity However, in practice, changes in protein binding result in clinically significant effects . sixth edition of Modern Pharmacology With Clinical Applications continues our commitment to enlisting experts in pharmacology to provide a textbook that is up-to-date and comprehensive. De- signed. receptor types are coupled to G pro- teins, including receptors for norepinephrine and epi- nephrine ( - and ␤-adrenoceptors), 5-hydroxytrypta- mine (serotonin or 5-HT receptors), and muscarinic acetylcholine. orthostatic hypoten- sion with some antihypertensive agents, arrhythmias with certain cardioactive drugs, and electrolyte imbal- ance with diuretics. Other adverse effects are not pre- dictable and