Immunobiologicals

The immune system constitutes the body's defense against infectious agents. It protects the host by identifying and eliminating or neutralizing agents that are recognized as nonself. The entire range of immunological responses affects essentially every organ, tissue, and cell of the body. Immune responses include, in part, antibody (Ab) production, allergy, inflammation, phagocytosis, cytotoxicity, transplant and tumor rejection, and the many signals that regulate these responses.1 At its most...

G

Figure 16.6 Mechanism of a-i-receptor-mediated signal transduction. Figure 16.6 Mechanism of a-i-receptor-mediated signal transduction. receptors that are linked to stimulation of biochemical processes in the postsynaptic cell. The function of presynaptic jS-receptors is, however, unclear. The jS-adrenoceptor subtypes also differ in terms of the rank order of potency of the adrenergic receptor agonists NE, E, and ISO (Table 16.4). The use of jS2-agonists as bronchodilators and jS 1- or Si...

O Impact Of Biotechnology On The Development And Commercial Production Of Proteins And Peptides As Pharmaceutical

Over the past decade and a half, far-reaching and revolutionary breakthroughs in molecular biology, especially research involving gene manipulations (i.e., genetic engineering), have led the way in the development of new biotechnology-derived products for the treatment of diseases. The term biotherapy has been coined to describe the clinical and diagnostic use of biotechnology-derived products. Generally, these products are proteins, peptides, or nucleic acids that are structurally and or...

Si

< alendronate < pamidronate < zoledronate (highest). As noted in later discussion, this order does not completely parallel antiresorptive potency. A key difference between the non-N-containing and N-containing bisphosphonates is the ability of the latter to form positive charges on their nitrogens at physiological pH. In general, the more positively charged bisphosphonates (zoledronate, ibandronate, and alendronate) produce a positive surface on the bone, attracting additional...

Info

Figure 16.5 Metabolism of norepinephrine and epinephrine by MAO and COMT. Figure 16.5 Metabolism of norepinephrine and epinephrine by MAO and COMT. exclusively on the meta-OH group of the catechol, regardless of whether the catechol is NE, E, or one of the metabolic products. For example, the action of COMT on NE and E gives normetanephrine and metanephrine, respectively. A converging pattern of the metabolism of NE and E in which 3'-methoxy-4'-hydroxymandelic acid (VMA) and...

O

Figure 24.22 Mechanism of action of acetaminophen on PGH2 synthesis. of glutathione (GSH), which is a known cofactor for PGE synthase. Thus, with this illustration, it is now possible to see why acetaminophen's action depends on the level of peroxide generated in solution (i.e., PGG2 and other lipid peroxides, generated by the lipoxygenase pathway), and its effectiveness varies with COX activity.207 At low peroxide concentrations, acetaminophen can compete effectively with the electron transfer...

Selective Estrogen Receptor Modulators And Antiestrogens

Whereas estrogens have been very important in chemical contraception and HRT, compounds that can antagonize the ER have been of great interest for the treatment of estrogen-dependent breast cancers. Tumor biopsies have shown ER to be present in about 60 of primary breast cancers, and most are responsive to estrogen blockade. Unfortunately, most of these ER-related breast cancers also develop resistance to antiestrogen therapy within 5 years. In contrast, only about 6 of nonmalignant breast...

Isoflurane

Isoflurane is a volatile liquid (bp 48.5 C) with an MAC of 1.15, a blood gas partition coefficient of 1.43 and high solubility in fat. Isoflurane is a structural isomer of enflurane. It is a known respiratory irritant, but less so than desflurane. Approximately 0.2 of the administered drug undergoes metabolism, the rest is exhaled unchanged. The metabolism of isoflurane yields low levels of the nephrotoxic fluoride ion as well as a potentially hepatotoxic trifluoroacetylating compound (Fig....

Enflurane

Enflurane is a volatile liquid (bp 56.5 C) with a blood gas partition coefficient of 1.8 and an MAC of 1.68 . Approximately 2 to 8 of the drug is metabolized primarily at the chlorofluoromethyl carbon. Little chlorofluo-roacetic acid is produced suggesting minor metabolism at the difluoromethyl carbon. Difluoromethoxydifluoroacetate and fluoride ion have been reported as metabolites. Enflurane may increase heart rate, cause cardiac arrhythmias, increase cerebral blood flow, and increase...

Meyeroverton Theory

As discussed, work of Meyer and Overton in the 1880s showed that there was strong correlation between the potency of the anesthetic and its solubility in olive oil. This correlation holds true for a surprising number of inhaled anesthetics but it does not explain the drugs mechanism of action. When biological membranes were found to be composed mainly of lipids, the work of Meyer and Overton was extended to offer a proposed mechanism of action of the inhaled anesthetics. Namely, that the...

Chemical Contraceptive Agents

The most notable achievement in chemical contraception came in the late 1950s and early 1960s with the development of oral contraceptive agents the pill. Since then, various contraceptive products have been introduced, including hormone-releasing intrauterine devices, polymer implants, injectable formulations, and a transdermal patch. In addition, postcoital contraceptives and abortifacients have been developed. Despite the advances in chemical contraceptive agents for women, no hormonal male...

Nicotinic Receptor Subtypes

Nicotinic receptors located in the neuromuscular junction differ from those on neurons, such as those in the CNS and autonomic ganglia, in that they have different ligand specificities. Nicotinic receptors at the neuromuscular junction (N1) are blocked by succinylcholine, d-tubocurarine, and decamethonium and stimulated by phenyltrimethylammo-nium. N2-nicotinic receptors are found in autonomic ganglia. They are blocked by hexamethonium and trimethaphan but stimulated by tetramethylammonium and...

Oml

Figure 22.4 Sevoflurane metabolism and chemical instability. Approximately 5 to 8 of the administered dose of sevoflurane is metabolized in man by CYP2E1 to hexafluo-roisopropanol, CO2 and the potentially nephrotoxic fluoride ion. (Fig. 22.4).27,30,31 Patients should be monitored for increases in blood urea nitrogen (BUN) and creatine levels as high fluoride ion levels, and concerns about Compound A exposure, may induce renal toxicity. Sevoflurane has been studied in a small number of patients...

O Acknowledgment

Portions of this text were taken from Dr. Eugene Isaacson's chapter in the 11th edition of this book. 1. What is the mechanism of action of the benzodiazepines 2. What is the mechanism by which antipsychotics work 3. What pharmacokinetic properties are shared by most of the antipsychotic drugs 4. Which benzodiazepines shown below is are short acting 5. Which of the following drugs is are metabolized to a compound that will continue to have significant sedative and hypnotic effect

Comvax

Comvax is a combination of Haemophilus influenzae type b conjugate and hepatitis B (recombinant). It was recently approved by the Advisory Committee on Immunization Practices (ACIP). Each 0.5-mL dose contains 7.5 g of H. influenzae type b polyribosylribitol phosphate (PRP), 125 fMg of Neisseria meningitidis outer membrane protein complex (OMPC), and 5 g of hepatitis B surface antigen (HBsAg) on an aluminum hydroxide adjuvant. The Committee on Infectious Diseases, the American Academy of...

Orole Of Cytochrome P450 Monooxygenases In Oxidative Biotransformations

Of the various phase I reactions that are considered in this chapter, oxidative biotransformation processes are, by far, the most common and important in drug metabolism. The TABLE 3.2 Cytochrome P450 Enzymes Nomenclature CYP-Arabic Number-Capital Letter-Arabic Number 1. CYP Cytochrome P450 enzymes 2. Arabic number Family (CYP1, CYP2, CYP3, etc.) Must have more than 40 identical amino acid sequence 3. Capital letter Subfamily (CYP1A, CYP2C, CYP3A, etc.) Must have more than 55 identical amino...

Preganglionic Cholinergic Fibers

Atropine - + - blocked by -adrenergic DOPAMINE antagonists Chapter 17 Cholinergic Drugs and Related Agents 597 Muscarinic Cholinergic-- atropine - + - blocked by -adrenergic DOPAMINE antagonists Chapter 17 Cholinergic Drugs and Related Agents 597 Muscarinic Cholinergic--

Class I Membranedepressant Drugs

Class I antiarrhythmic agents are drugs that have membrane-stabilizing properties (i.e., they shift membranes to more negative potentials). Drugs in this class act on the fast Na+ channels and interfere with the process by which the depolarizing charge is transferred across the membrane. It is assumed that these drugs bind to the Na+ channel and block its function, preventing Na+ conductance as long as the drug is bound. The prototypical drugs in this class are quinidine and procainamide....

N

Figure 17.17 Aging of phosphorylated enzyme. Figure 17.17 Aging of phosphorylated enzyme. these poisons. Several compounds can provide a nucleophilic attack on the phosphorylated enzyme and cause regeneration of the free enzyme. Substances such as choline, hydroxyl-amine, and hydroxamic acid have led to the development of more effective cholinesterase reactivators, such as nicotinic hydroxamic acid and pyridine-2-aldoxime methiodide (2-PAM). A proposed mode of action for the reactivation of...

Class Iii Repolarization Prolongators

Drugs in this class (e.g., amiodarone, bretylium, sotalol, ibu-tilide, dofetilide) cause several different electrophysiologi-cal changes on myocardial tissue but share one common effect, prolonging the action potential, which increases the effective refractory period of the membrane action potential without altering the phase of depolarization or the resting membrane potential. Drugs in this class produce their effects by more than one mechanism. Sotalol is a K+ channel blocker and has some...

References

Detoxication Mechanisms, 2nd ed. New York, John Wiley & Sons, 1959. 2. Drayer, D. E. Clin. Pharmacokinet. 1 426, 1976. 3. Drayer, D. E. Drugs 24 519, 1982. 4. Jollow, D. J., et al. Biological Reactive Intermediates. New York, Plenum Press, 1977. 5. Gillette, J. R., et al. Annu. Rev. Pharmacol. 14 271, 1974. 6. Nelson, S. D., et al. In Jerina, D. M. (ed.). Drug Metabolism Concepts. Washington, DC, American Chemical Society, 1977, p. 155. 7. Testa, B., and Jenner, P. Drug...

Therapeutic Uses

Folic acid is used in the treatment of known or suspected folate deficiency or increased need as occurs during Tetrahyd rof olate Tetra hyd rofolates Figure 28.43 Bioactivation of folic acid to tetrahydrofolate polyglutamates. Figure 28.44 Interconversion of active folates. Figure 28.44 Interconversion of active folates. TABLE 28.11 Folic Acid-Dependent Enzymes TABLE 28.11 Folic Acid-Dependent Enzymes

Chapter Overview

Since Alexander Fleming accidentally discovered penicillin in 1929, the numbers of antibiotics that have been added to our therapeutic armamentarium has grown tremendously. Along with immunizing biologicals, antibiotics have turned the tide in terms of the treatment of infectious disease. They are truly medical miracles. Yet, because of the overuse of many of these agents and the biochemical fickleness of many bacteria, resistance to antibiotics has become a serious problem in the 21st century....

Nalbuphine

Nalbuphine (Nubain) is structurally a member of the phenanthrene class of compounds and resembles oxymor-phone with a cyclobutyl methyl group on the nitrogen, equivalent to naloxone's substitution. It was introduced in 1979 as an agonist antagonist with the hope of becoming an effective pain reliever with little abuse potential. Although the abuse potential of nalbuphine is low, it is not zero, and increasing reports of diversion and abuse can be found in the literature and the Internet.105 At...

E

East African sleeping sickness, 221, 223-224 Ecstasy. See 2,5-Dimethyl-dicyanoquinonediimine Eculizumab, 658 EDCF. See Endothelium-derived contracting factor EDRF. See Endothelium-derived relaxing factor Edrophonium chloride, 572t, 575-576, 601 EES. See Erythromycin ethylsuccinate approved for human use, 876-877 biological activities observed with, 868, 869t biosynthesis of, 869-871, 870 -871 degradation of, 872, 873 drug action mediated by, 872 drug design for, 872, 873 , 874t-875t history of,...

Active Elimination t12 94 h

Figure 12.10 Major metabolic pathway for aripiprazole. Ziprasidone. Ziprasidone (Geodon, a benzisothia-zolpiprazinylindolone derivative) also has the structural features of a hybrid molecule between a butyrophenone antipsychotic and a trazodone-like antidepressant. It is highly metabolized to four major metabolites, only one of which, S-methyldihydroziprasidone, likely contributes to its clinical activity (see Fig. 12.9). In humans, less than 5 of the dose is excreted unchanged. Reduction by...

Indomethacin Double Bond Binding Region

Figure 24.15 Hypothetical binding models of indomethacin to COX-1 and Celecoxib to COX-2. A. Binding of the conventional NSAID, indomethacin, to the active site of COX-1 B. Binding of celecoxib, a selective COX-2 inhibitor to the active site of COX-2 with crystallographic maps suggested by Luong et al. (Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat. Struct. Biol. 1996 3 927-933)

Q

Thiamine diphosphate Figure 28.20 Thiamine and thiamine diphosphate. a common form available for vitamin supplementation, is stable in acid but unstable in aqueous solutions with a pH above 5. Under these conditions, it undergoes decomposition of the thiazolium ring forming an inactive product (Fig. 28.22). Exposure of thiamine to air or to oxidizing agents such as hydrogen peroxide, permanganate, or alkaline potassium ferricyanide oxidizes it readily to thiochrome (Fig. 28.23). Thiochrome...

Sevoflurane

Sevoflurane is a volatile, nonpungent, nonflammable, and nonexplosive liquid with a boiling point of 58.6 C. The blood gas partition coefficient is 0.65, the oil gas partition coefficient is 50, and the MAC is 2.1 . Sevoflurane reacts with desiccated carbon dioxide adsorbents, to produce compounds (A and B) with known toxicity (Fig. 22.4). The type of CO2 absorbent used, the temperature of the absorbent, and the duration of exposure can influence the degree to which sevoflurane breaks down.25...

Oh

EC 1.4.3.5 pyridoxal 5'-phosphate synthase EC 2.7.1.35 pyridoxal kinase EC 3.1.3.74 pyridoxal phosphatase EC 1.2.3.1 aldehyde oxidase a cotransaminase in the transamination of alanine to form pyruvic acid and as a codecarboxylase in the decarboxylation of dihydroxyphenylalanine (DOPA) to form dopamine. Other biological transformations of amino acids in which pyridoxal can function are racemization, elimination of the -hydrogen together with a -sub-stituent (i.e., OH or SH) or a y-substituent,...

Other Enzymes

RECOMBINANT HUMAN DEOXYRIBONUCLEASE I (DNASE)143 DNAse is a human endonuclease, normally present in saliva, urine, pancreatic secretions, and blood. The enzyme catalyzes the hydrolysis of extracellular DNA into oligonu-cleotides. Aerosolized recombinant human deoxyribonu-clease I (rhDNAse), dornase alfa, Pulmozyme, has been formulated into an inhalation agent for the treatment of pulmonary disease in patients with CF. Among the clinical manifestations of CF are obstruction of the airways by...

Biochemistry

Niacin synthesis into the active cofactors, NAD+ and NADP+, is shown in Figure 28.29. Both niacin and niacinamide react with 5-phosphoribosyl-1-pyrophosphate (PRPP) to form the respective mononucleotide derivative, which then reacts with ATP to produce the corresponding dinucleotide product. For niacinamide, this is NAD + however, for niacin this product is converted to NAD+ by transformation of the carboxyl of the nico-tinic acid moiety to the amide using free ammonia. An alternative pathway...

Products

Protamine sulfate has an anticoagulant effect, but if used in the proper amount, it counteracts the action of heparin and is used as an antidote for the latter in cases of overdosage. It is administered intravenously in a dose that depends on the circumstances. Dicumarol, USP. Dicumarol, 3,3'-methylenebis 4-hy-droxycoumarin , is a white or creamy white crystalline powder with a faint, pleasant odor and a slightly bitter taste. It is practically insoluble in water or...

O Additional Resources

Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Edition, includes additional resources for both instructors and students that are available on the book's companion Web site at Approved adopting instructors will be given access to the following additional resources Image bank of all the figures and tables in the book Students who have purchased Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Edition, have access to the...

Chemical Complexation

The sulfate esters and sulfonate derivatives of polysaccha-rides and lignin form chemical complexes with the enzyme pepsin. These complexes have no proteolytic activity. Because polysulfates and polysulfonates are poorly absorbed from the GI tract, specific chemical complexation appears to be a desirable mechanism of pepsin inhibition.77 Unfortunately, these polymers are also potent anticoagulants. The properties of chemical complexation and anticoagulant action are separable by structural...

Benzamides

The benzamides evolved from observations that the gastro-prokinetic and antiemetic agent, metoclopramide, has an-tipsychotic activity related to D2 receptor block. It was hoped that the group might yield compounds with diminished EPS liability. This expectation appears to have been met. An H-bond between the amido H and the unshared electrons of the methoxyl group to generate a pseudo ring is considered important for antipsychotic activity in these compounds. Presumably, when the protonated...

Rr

R Alky I, Aryl, Benzylic, Allylic X - Br, CI, I, 0S03 0S02R, OPO(OR)2 Figure 3.15 Formation of GSH conjugates of electrophilic xenobiotics or metabolites (E) and their conversion to mercapturic acids. Figure 3.15 Formation of GSH conjugates of electrophilic xenobiotics or metabolites (E) and their conversion to mercapturic acids. The carbon center is rendered electrophilic as a result of the electron-withdrawing group (e.g., halide, sulfate, phosphate) attached to it. Nucleophilic displacement...

Gaba

Degradation inhibition, 494 enhancement of, 493-494, 493 reuptake inhibition, 494 GABAa receptors, 444 51 alcohols and carbamate derivatives, 455-456 aldehydes and derivatives, 456-457 amides and imides, 454-455 anticonvulsants and, 493-494 barbiturates, 452-454, 453 , 454f benzodiazepines, 447 51 binding to, 444-445 general anesthetic interaction with, 713, 717 melatonin receptor agonist, 451 52 modulation of, 494 pentylenetetrazole, 504 picrotoxin, 504 subunits of, 444 Gabapentin, 493, 498,...

Ch3

Bupivacaine was synthesized simultaneously with mepiva-caine in 1957 but was at first overlooked because of the increased toxicity compared with mepivacaine. When the methyl on the cyclic amine of mepivacaine is exchanged for a butyl group the lipophilicity, potency and the duration of action all increase. Literature reports of cardiovascular toxi-city, including severe hypotension and bradycardia, are abundant in the literature.91 Bupivacaine is highly bound to plasma proteins (95 ), and thus...

O Aldosterone Antagonists

Aldosterone antagonists are, as the name implies, receptor antagonists at the mineralcorticoid receptor. Antagonism of these receptors inhibits sodium resorption in the distal tubule of the nephron, which in turn, interferes with sodium potas sium exchange, reducing urinary potassium excretion. Overall, this results in a weak diuretic effect and decreases cardiac workload. Agents that block aldosterone may be used in the management of hypertension or heart failure. The two agents approved for...

Tuberculosis Vaccine

Tuberculosis (TB) is a serious disease caused by Mycobacterium tuberculosis. The organism becomes established in the lungs and forms walled-off abscesses that shield the bacterium from the immune system. The disease is diagnosed by a chest radiograph. Until the 1940s, persons with TB were sent to sanatoria, special hospitals to isolate TB patients. The vaccine is referred to as the bacillus Calmette-Guerin (BCG) vaccine and is a live attenuated strain of Mycobacterium bovis. The antigenic form...

Mlck

Vascular smooth muscle cells to form nitric oxide (NO). NO mediates smooth muscle relaxation by activating guanylate cyclase to increase intracellular concentrations of cGMP. cGMP activates protein kinases that can regulate free Ca2+ levels in the muscle cell and cause relaxation of smooth muscle by phosphorylating MLCK. A short-lived free radical gas, NO is widely distributed in the body and plays an important role by its effect through cGMP on the smooth muscle vasculature. It is synthesized...

Indium Radiopharmaceuticals

Indium (111In) Capromab (ProstaScint). Capromab pendetide is a murine monoclonal immunoglobulin G (IgG) antibody conjugated to the linker-chelator, glycyl-tyrosyl-(N,-diethylenetriamine pentaacetic acid)-lysine hydrochloride (Gly-Tyr-Lys-DTPA-HCl). This conjugated antibody is directed against the glycoprotein expressed on prostate epithelium, prostate-specific membrane antigen. It is indicated in the evaluation of newly diagnosed patients with biopsy-proven prostate cancer who are at high risk...

S Ch3

5'-Hydroxymethylmeloxicam, R CH2OH, 5'-Carboxymeloxicam, R COOH Figure 24.16 Metabolism of Piroxicam and meloxicam. 5'-hydroxy-methylmeloxicam and 5'-carboxymeloxicam metabolites are shown in Figure 24.16.154-156 Thus, with the proposed binding interaction of indomethacin described earlier (Fig. 24.15), it is reasonable to assume that the pyridyl group of the piroxicam or the 5'-hydroxy-pyridyl group of its active metabolite will be directed to bind to the A11-double-bond binding region...

O Genomics

Genomics177 is a term that means a study of genes and their functions. Currently, genomics is probably the central driving force for new drug discovery and for novel treatments for disease. Gene therapy is a concept that is often discussed. The human genome project, which was largely completed in the year 2000, provided over 4 billion bp of data that have been deposited in public databases. Sequencing the genome itself was an enormous task, but the correlation of genomic data with disease...

O Chemical And Physical Properties Of Steroids

With few exceptions, the steroids are white crystalline solids. They may be in the form of needles, leaflets, platelets, or amorphous particles, depending on the particular compound, the solvent used in crystallization, and the skill and luck of the chemist. Because the steroids have 17 or more carbon atoms, it is not surprising that they tend to be water insoluble. Addition of hydroxyls or other polar groups (or decreasing carbons) increases water solubility slightly, as expected. Salts are...

Sars Of Enkephalins

Opioid Receptor Discovery and Endogenous Ligands There was no direct evidence for the existence of specific opioid receptors until the 1970s when Goldstein et al.20 found that radiolabeled levorphanol bound stereospecifi-cally to certain mouse brain fractions. They hypothesized that this compound bound to an opiate receptor. This prediction gained credence in 1973 when additional studies showed that opioid agonists and opioid antagonists compete for the same binding site. Building on these...

On O

Cefuroxime is distributed throughout the body. It penetrates inflamed meninges in high enough concentrations to be effective in meningitis caused by susceptible organisms. Three-times-daily dosing is required to maintain effective plasma levels for most sensitive organisms, such as Neisseria meningitidis, Streptococcus pneumoniae, and H. influenzae. It has a plasma half-life of 1.4 hours. Cefuroxime axetil (Ceftin) is the 1-acetyoxyethyl ester of cefuroxime. During absorption, this acid-stable,...

Steroid Biosynthesis

Steroid hormones in mammals are biosynthesized from cholesterol, which in turn is made in vivo from acetyl-coenzyme A (acetyl-CoA) via the mevalonate pathway. Although humans do obtain approximately 300 mg of cholesterol per day in their diets, a greater amount (about 1 g) is biosynthesized per day. A schematic outline of these biosynthetic pathways is shown in Figure 25.5. Conversion of cholesterol to pregnenolone is the rate-limiting step in steroid hormone biosynthesis. It is not the...

Hydrocodone

Hydrocodone is the 3 methoxy version of hydromorphone. The loss of the 3-OH group yields a compound that is approximately 4 to 5 times less potent than hydromorphone, thus about equal to morphine. Unlike codeine, the agonist activity of hydrocodone does not require 3-O-demethylation, although it does occur via CYP2D6 representing 4.6 of total clearance.64 The protected 3-position has better brain penetration, and the 7,8-dihydro-6-keto C ring contributes to the increased binding of the compound...

Carbazochrome Synthesis

Synthesis Carbazochrome

*Indicates adrenergic prescription drugs in the top 200 for 2005. *Indicates adrenergic prescription drugs in the top 200 for 2005. Norepinephrine (NE) Epinephrine (E) Isoproterenol (ISO) Figure 16.1 Adrenergic neurotransmitters and related compounds. A quinone analog Figure 16.2 Oxidation of Epinephrine (E). Diffusion and metabolism Figure 16.3 Model of life cycle of NE. Figure 16.4 Biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Figure 16.4 Biosynthesis of the...

Selected Reading

Castilla-Guerra, L., Fern ndez-Moreno, M. del C., L pez-Chozas, J. M., et al. Electrolytes Disturbances and Seizures. Epilepsia 47 1990-1998, 2006. Gidal, B. E., and Garnett, W. R. Epilepsy. In DiPiro, J. T., Talbert, R. L., Yee, G. C., et al. (eds.). Pharmacotherapy A Pathophysiologic Approach, 6th ed. New York, NY, McGraw-Hill, 2005, pp. 1023-1048. Johannessen, C. U., and Johannessen, S. I. Valroate past, present, and future. CNS Drug Rev. 9 199-216, 2003. Kaneko, S., Okada, M., Iwasa, H., et...

Chemistry

Three classes of compounds have been linked to the sedative properties of valerian. The rhizome contains monoter-penes and sesquiterpenes (valerenic acid and its acetoxy derivative), iridoids (valepotrioates), and pyridine alkaloids (Fig. 29.16).69,70 At present, it is not possible to state which class of compound is responsible for the sedative activity. Most researchers believe that the valepotrioate is the active component, but some studies have shown that valerenic acid is more potent....

Crotamiton

or N-ethyl-o-crotonotoluidide (Eurax), is a colorless, odorless oily liquid. It is virtually insoluble in water but soluble in most organic solvents. Its antipruritic effect is probably because of a local anesthetic action. Permethrin is acid (3-phenoxyphenyl)methyl ester or 3-(phenoxyphenyl)methyl ( )-cis, (Nix). This synthetic pyrethrinoid compound is more stable chemically than most natural pyrethrins and is at least as active as an insecticide. Of the four isomers present, the 1(R),trans...

Inhaled Corticosteroids For Asthma And Allergic Rhinitis

The National Asthma Education and Prevention Program has provided recent recommendations on the treatment of asthma, including a strong recommendation for the first-line use of inhaled corticosteroids for severe and moderate persistent asthma in all age groups. The corticosteroids currently used in inhaled formulations are all relatively potent topical corticos-teroids that have the advantage of rapid deactivation inactiva-tion for the portion of the dose that is swallowed. The development of...

Ibritumomab Tiuxetan

Ibritumomab (Zevalin kits to prepare In-111 Zevalin and Y-90 Zevalin, murine) is an MAb derived from an initial sen-sitization with CD20 antigen, expressed on the surface of normal and malignant B cells. The antibody is a murine IgG1 k subtype, directed against CD20 antigen. It is produced in a CHO cell line. Ibritumomab is indicated for use as a multistage regimen to treat patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma, including patients...

Serm And Antiestrogen Products

Tamoxifen, A-dimethylethanamine (Nolvadex), is a triphenylethylene SERM used to treat early and advanced breast carcinoma in postmenopausal women. Tamoxifen is used as adjuvant treatment for breast cancer in women following mastectomy and breast irradiation. It reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy. It is also effective in the treatment of metastatic breast cancer in both women and men. In premenopausal...

O Preface

For 6 decades, Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry has been a standard in the literature of medicinal chemistry. Generations of students and faculty have depended on this textbook not only for undergraduate courses in medicinal chemistry but also as a supplement for graduate studies. Moreover, students in other health sciences have found certain chapters useful. The current editors and authors worked on the 12th edition with the objective of...

Oo

Technetium (99mTc) Mertiatide (TechneScan MAG3). Technetium (99mTc) mertiatide complex is the radiopharma-ceutical agent of choice to provide information about relative function of the kidneys and urine outflow because of its high renal extraction efficiency. Indications include renal artery stenosis in nonperfused kidneys, renal transplant assessment, and outflow obstruction. The kit includes a reaction vial containing betiatide (a mertiatide prodrug), stannous chloride dihydrate, sodium...

The Vascular Theory Of Migraines

According to the vascular theory, the vasodilatation of cranial carotid arteriovenous anastomoses (sites of many 5-HT1B 1D receptors) and meningeal, dural, cerebral, or pial vessels (primary sites of 5-HT1B receptors) plays an important role in the pathogenesis of migraines and is responsible for the pain associated with migraine headaches.259,261 The fact that sumatriptan-induced cranial vasoconstriction is selectively blocked by a selective 5-HT1B antagonist, and not by a 5-Ht1D antagonist,...

Hypervitaminosis

Niacin, in doses that range above the DRI but below that required for dyslipidemias, is unlikely to produce adverse effects. However, adverse effects of niacin are seen when this vitamin is used at pharmacological doses above 1 g day in the treatment of dyslipidemia. Notable adverse effects include flushing because of vasodilation dermatological effects including dry skin, pruritus and hyperkeratosis gastrointestinal effects including peptic ulcer, stomach pain, nausea, and diarrhea elevations...

Smooth Muscle Relaxation

The contractile activity of all types of muscle (smooth, skeletal) is regulated primarily by the reversible phosphorylation of myosin. Myosin of smooth muscle consists of two heavy chains (molecular weight MW 200,000 each) that are coiled to produce a filamentous tail. Each heavy chain is associated with two pairs of light chains (MW 20,000 and 16,000) that serve as substrates for calcium- and calmodulin-dependent protein kinases in the contraction process. Together with actin (MW 43,000), they...

O Antianginal Agents And Vasodilators

Most coronary artery disease conditions are caused by deposits of atheromas in the intima of large and medium-sized arteries serving the heart. The process is characterized by an insidious onset of episodes of cardiac discomfort caused by ischemia from inadequate blood supply to the tissues. Angina pectoris (angina), the principal symptom of ischemic heart disease, is characterized by a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the...

Chemical Instability of Proteins67

Hydrolytic reactions of the peptide bonds can break the polymer chain. Aspartate residues hydrolyze 100 times faster in dilute acids than do other amino acids under the same conditions. As a general rule of peptide hydrolysis, Asp-Pro > Asp-X or X-Asp bonds. This property of Asp is probably a result of an autocatalytic function of the Asp side chain carboxyl group. Asn, Asp, Gln, and Glu hydrolyze exceptionally easily if they occur next to Gly, Ser, Ala, and Pro. Within these...

Mechanism Of Action

Pharmaceutical Chemistry Mechanism

The effects of the azoles on fungal biochemistry have been studied extensively, but there is still much to be learned.45 At high in vitro concentrations (micromolar), the azoles are fungicidal at low in vitro concentrations (nanomolar), they are fungistatic. The fungicidal effect is clearly associated with damage to the cell membrane, with the loss of essential cellular components such as potassium ions and amino acids. The fungistatic effect of the azoles at low concentration has been...

Halothane

Halothane is a nonflammable, nonpungent, volatile, liquid, halogenated (F, Cl, and Br) ethane (bp 50 C), introduced in 1956. Halothane may increase heart rate, cause cardiac arrhythmias, increase cerebral blood flow, and increase in-tracranial pressure.17 It can undergo spontaneous oxidation when exposed to ultraviolet light to yield HCl, HBr, Cl, Br, and phosgene (COCl2). To prevent oxidation it is packaged in amber bottles with a low concentration of thymol (0.01 ) as a stabilizer. The drug...

O Biotechnology And New Drug Development

Yearly Development Biotechnology

The tools of biotechnology are also being brought to bear in the search for new biological targets for presently available drugs as well as for the discovery of new biological molecules with therapeutic utility. Molecular cloning of novel receptors can provide access to tremendous tools for the testing of drugs (e.g., the adrenergic receptors), whereas cloning of a novel growth factor might potentially provide a new therapeutic agent. Biotechnology is also being used to screen compounds for...

Iodophors

Elemental iodine (I2) is probably the oldest germicide still in use today. It was listed in 1830 in USP-II as a tincture and a liniment. Iodine tincture (2 iodine in 50 alcohol with sodium iodide), strong iodine solution (Lugol's solution, 5 iodine in water with potassium iodide), and iodine solution (2 iodine in water with sodium iodide) are currently official preparations in the USP. The iodide salt is admixed to increase the solubility of the iodine and to reduce its volatility. Iodine is...

Propofol

Propofol is an injectable sedative-hypnotic used for the induction and maintenance of anesthesia or sedation. Propofol is only slightly soluble in water with an octanol water partition coefficient of 6,761 1 thus, it is formulated as an oil-in-water emulsion. The fat component of the emulsion consists of soybean oil, glycerol, and egg lecithin. The pKa of the propanol hydroxyl is 11 and the injectable emulsion has a pH of 7 to 8.5. Formulations contain either disodium...

Ergot Derivatives

Pergolide binds with high affinity as an agonist at D2-type and 5-HT2B receptors.37 The compound also binds at D1 receptors but with approximately 300-fold less affinity than at D2 receptors. Pergolide is believed to induce valvular heart disease by acting on 5-HT2B receptors.38 Because of the potential for cardiac valve damage, pergolide has been recently withdrawn from the market.23 Cabergoline exhibits high affinity at D2-like receptors with over 50-fold selectivity compared with D1-like...

O Recent Antihistamine

DEVELOPMENTS THE DUAL-ACTING ANTIHISTAMINES Over the several past decades, there has been considerable interest in the development of novel antihistaminic compounds with dual mechanisms of action including H1-receptor antihistaminic action and mast cell stabilization. Currently available drugs that exhibit such dual antihistaminic actions include azelastine and ketotifen. These compounds contain the basic pharmacophore to produce relatively selective anti-histaminic action (diarylalkylamines)...

O Newer Antibiotics

Tigecycline (Tygacil) is a first-in-class (a glycylcycline) intravenous antibiotic that was designed to circumvent many important bacterial resistance mechanisms. It is not affected by resistance mechanisms such as ribosomal protection, efflux pumps, target site modifications, S-lactamases, or DNA gyrase mutations. Tigecycline binds to the 30S ribosomal subunit and blocks peptide synthesis. The glycylcyclines bind to the ribosome with five times the affinity of common tetracyclines. Tigecycline...

Physical Instability of Proteins96

Chemical alterations are not the only source of protein instability. A protein is a large, globular polymer that exists in some specific forms of secondary, tertiary, and quaternary structure. A protein is not a fixed, rigid structure. The molecule is in dynamic motion, and the structure samples an array of three-dimensional space. During this motion, non-covalent intramolecular bonds can break, reform, and break again, but the overall shape remains centered around an energy minimum that...

Itraconazole

The oral bioavailability of fluconazole, following administration of either tablet or oral suspension dosage forms, is excellent. Apparently, the presence of two weakly basic tri-azole rings in the molecule confers sufficient aqueous solubility to balance the lipophilicity of the 2,4-difluorophenyl group. The oral absorption of fluconazole, in contrast to the oral absorption of ketoconazole or itraconazole, is not affected by alteration in gastrointestinal acidity or the presence of food....

S

Molecule as a prototype, captopril was designed with a car-boxyl group on a proline and a thiol group was introduced to enhance the binding to the zinc ion of ACE. The important binding points at the active site of ACE are thought to be an arginine residue, which provides a cationic site that attracts a carboxylate ion, and a zinc ion, which can polarize a carbonyl group of an amide function to make it more susceptible to hydrolysis. Hydrophobic pockets lie between these groups in the active...

Changes To Modify Pharmacokinetic Properties Of Steroids

As with many other compounds described in previous chapters, the steroids can be made more lipid soluble or more water soluble by making suitable ester derivatives of hy-droxyl (OH) groups. Derivatives with increased lipid solubility are often made to decrease the release rate of the drug from intramuscular (IM) injection sites (i.e., in depot preparations). More lipid-soluble derivatives also have improved skin absorption properties and thus, are preferred for derma-tological preparations....

Remifentanil

Remifentanil (Ultiva) was designed as a soft drug. Soft drugs are designed to undergo metabolism quickly and thus have ultrashort durations of action. In place of the ethyl aromatic ring seen on the other piperidine opioids, remifen-tanil has an ester group (Fig. 24.9). This ester group is metabolized by esterases in the blood and tissue to a weakly active metabolite (1 300-1 1,000 the potency of remifentanil).89 The n-octanol water partition coefficient of remifentanil is 17.9. The pKa of...

Class Iv Calcium Channel Blockers

Although not all Ca2+ channel blockers possess antiarrhyth-mic activity, some members of this class of antiarrhythmic drugs (verapamil, diltiazem) block the slow inward current of Ca2+ ions during phase 2 of the membrane action potential in cardiac cells. For example, the prototypical drug in this group, verapamil, selectively blocks entry of Ca2+ into the myocardial cell. It acts on the slow-response fibers found in the sinus node and the AV node, slowing conduction velocity and increasing...

Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) is a glycoprotein synthesized by the placenta. Estrogens stimulate the anterior pituitary to produce placentotropin, which in turn stimulates hCG synthesis and secretion. hCG is produced primarily during the first trimester of pregnancy. It exerts effects that are similar to those of pituitary LH. hCG is used therapeutically in the management of cryp-torchidism in prepubertal boys. It also is used in women in conjunction with menotropins to induce ovulation...

Antiviral Agents

Viral diseases constitute a set of difficult-to-treat conditions. Over the years, many different antiviral agents have been discovered and synthesized, and these have provided various means of treatment of viral conditions. This chapter will begin with some concepts of viral taxonomy and the steps in the infectious cycle of viruses, as well as biochemical steps that can be used as targets in antiviral therapy. We will then move into the arena of prevention of viral infection through the use of...

Radiological Contrast Agents

From the earliest days of radiology, considerable effort has been devoted to developing compounds that if swallowed or injected would increase the radiographic contrast between various tissues and organs. Injection of air or other gases into a GI tube in the esophagus, stomach, or duodenum or into a rectal tube in the colon provides increased radiographic contrast for evaluating the gut however, the information obtained by this technique is limited, and more opaque substances have been...

Risk Of Systemic Absorption

The topical corticosteroids do not typically cause significant absorption effects when used on small areas of intact skin. When these compounds are used on large areas of the body, however, systemic absorption may occur, especially if the skin is damaged or if occlusive dressings are used. Up to 20 to 40 of hydrocortisone given rectally may also be absorbed. Therapeutic Uses of Adrenal Cortex Hormones The adrenocortical steroids are used primarily for their GC effects, including...

Glucagon

The hyperglycemic-glycogenolytic hormone elaborated by the a-cells of the pancreas is known as glucagon. It contains 29 amino acid residues in the sequence shown. Glucagon has been isolated from the amorphous fraction of a commercial insulin sample (4 glucagon). TABLE 27.8 Dosage and Source of Insulin Preparations Insulin injection (regular insulin, crystalline zinc insulin, Cispro) Isophane insulin suspension (NPH insulin) and insulin injection (30 ) Insulin zinc suspension...

Osteoporosis Prevention And Treatment104106

Osteoporosis is an enormous public health problem, responsible for approximately 1.5 million fractures in the United States each year. Because of the prevalence of osteoporosis, especially in older women, the prevention and treatment of this condition have received much attention. Prior to menopause, a good diet and exercise are essential for young women, to decrease the risk of osteoporosis later in life. After menopause, supplemental estrogens can have a positive effect relative to...

Methods Of Vaccine Production

Vaccine production methods have varied greatly over the years and are best discussed according to a parallel chronological and sophistication approach. In this method, the normal pathogen is treated with a strong, denaturing disinfectant like formaldehyde or phenol. The process denatures the proteins and carbohydrates that are essential for the organism to live and infect a host, but if treated properly, the surface antigens are left intact. The process must be done carefully to control the...

Contraceptive Implants

The first implantable contraceptive was Norplant, a set of six flexible Silastic (dimethylsiloxane methylvinylsiloxane copolymer) capsules that contain levo-norgestrel. The capsules implanted in the midportion of the upper arm provided contraception for up to 5 years. Contraceptive efficacy was very high, but the insertion and removal procedures required extra training of physicians, a feature that reduced the desirability of this product. Although Norplant was extremely effective as...

Prostaglandins

The prostaglandins are endogenous 20-carbon unsaturated fatty acids biosynthetically derived from arachidonic acid. These bioactive substances and their synthetic derivatives have been of considerable research and development interest as potential therapeutic agents because of their widespread physiological and pharmacological actions on the cardiovascular system, GI smooth muscle, the reproductive system, the nervous system, platelets, kidney, the eye, etc. Prostaglandins of the E, F, and I...

Iodine Pharmaceuticals

The major indications for thyroid imaging with sodium iodide (123I) are for evaluation of thyroid function (uptake) and or morphology (imaging). The patient fasts before receiving the oral dose of 0.1 to 0.4 mCi (3.7 14.8 MBq) of sodium iodide (123I) typically in an encapsulated dosage form. Images are obtained of the thyroid and surrounding area 4 to 6 hours after ingestion. Sodium Iodide (131I). Diagnostic use of sodium iodide (131I) with microcurie doses for evaluating...

O Miscellaneous Compounds

Temsirolimus (Fig. 10.27) is an esterified derivative of rap-amycin and in a similar manner binds initially to the protein FKBP-12(FK506-binding protein).159 This complex then acts to inhibit the mammalian target of rapamycin (mTOR), a serine-threonine kinase that plays a crucial role in cell division. It is somewhat unique in its method of ki-nase inhibition, because it actually binds to an allosteric modulator of the kinase rather than just binding to the ATP-binding site like most other...

N-dealkylation Of Barbiturates

Aromatic Amines and Heterocyclic Nitrogen Compounds. The biotransformation of aromatic amines parallels the carbon and nitrogen oxidation reactions seen for aliphatic amines.221-223 For tertiary aromatic amines, such as N,N-dimethylaniline, oxidative N-dealkylation as well as N-oxide formation take place.224 Secondary aromatic amines may undergo N-dealkylation or N-hydroxylation to give the corresponding N-hydroxylamines. Further oxidation of the N-hydroxylamine leads to nitrone products, which...

Benzilylcarbocholine

Bacampicillin hydrochloride, 272 Bacitracins, 260t, 315, 317-318 chemical classification of, 260 Bacterial resistance, to penicillins, 265-267 Bacterial vaccines, 172-173 Bactericidal factor, 159-160, 159t Bacteriolysis, immunological, 164 Bacteriophage, for vector cloning, 125, 125 Bactroban. See Mupirocin BAL. See Dimercaprol Baltimore Classification Scheme, for viruses, 330-331, 331t Banthine bromide. See Methantheline bromide Barbiturates, 452 54, 453 , 454t intermediate duration, 454, 454t...

H3n

Figure 22.12 Mechanism of inactivation of sodium channels. The hinged-lid mechanism. The intracellular loop connecting domains III and IV of the sodium channel is depicted as forming a hinged lid with the critical phenylalanine (F1489) within the IFM motif shown occluding the mouth of the pore during the inactivation process. The circles represent the transmembrane helices. (Reprinted from Catterall, W. A. Ionic currents to molecular mechanisms the structure and function of voltage-gated sodium...

Chohch3

Refractory urinary tract infections caused by Gram-negative organisms such as Aerobacter, Bordetella, Escherichia, Klebsiella, Pseudomonas, Salmonella, and Shigella spp. Chemically, colistin is a polypeptide, reported by Suzuki et al.255 whose major component is colistin A. They proposed the structure shown below for colistin A, which differs from polymyxin B only by the substitution of d-leucine for d-phenylalanine as one of the amino acid fragments in the cyclic portion of the structure....

O Diseases Of Bone Tissue Utilizing Approved Drug Therapies

Paget Disease of Bone (Osteo Deformans) Paget disease can be thought of as improper resorption of bone. Essentially, bones grow larger leading to deformation of the affected bones and become weaker than normal with increasing risk of fracture. It can occur on several bones or be isolated to one bone. It most likely occurs in the pelvis, skull, spine, or leg bones. The bones may become misshapen and break more easily. There may or may not be pain. Manifestations of Paget disease tend to appear...

Hlx

Figure 29.11 Beta-phenethylamines in ma huang. the heart hence, the herb may be dangerous to people with cardiac disease. The amounts of ephedra-type compounds and the relative composition differ so widely that it is difficult to be certain what one is getting in any given preparation. Ma huang's main active ingredient is the j-phenethyl-amine compound (-)-ephedrine. Plants grown in China may contain 0.5 to 2.5 of this compound. Many ephedrine congeners are represented in the plant,11 and many...

Tramadol

Tramadol (Ultram) is an analgesic agent with multiple mechanisms of action. It is a weak -agonist with approximately 30 of the analgesic effect antagonized by the opioid antagonist naloxone. Used at recommended doses, it has minimal effects on respiratory rate, heart rate, blood pressure, or GI transit times. Structurally, tramadol resembles codeine with the B, D, and E ring removed. The manufacturer states that patients allergic to codeine should not receive tramadol, because they may be at...

O Steroid Hormone Receptors

Steroid hormones regulate tissue-specific gene expression. The individual hormones exhibit remarkable tissue selectivity, even though their structural differences are relatively minor. Estrogens such as estradiol increase uterine cell proliferation, for example, but not prostate cell proliferation. Androgens such as testosterone do the reverse, but neither androgens nor estrogens affect stomach epithelium. The Figure 25.6 Common steroid modifications to alter therapeutic utility. (*, prodrug.)...

Ch2 c

Xenobiotics, such as the hallucinogenic agents mescaline208'209 and (DOM or STP),210,211 are oxidatively deaminated. Primary amine metabolites arising from N-dealkylation or decarboxylation reactions also undergo deamination. The example of the bisdesmethyl primary amine metabolite derived from bromopheniramine is discussed previously in this chapter (see section on tertiary aliphatic and alicyclic amines).181 In addition, many tertiary aliphatic amines (e.g., antihistamines) and secondary...

Mineralocorticoids

Fludrocortisone acetate, 21-acetyloxy-9-fluoro-11 jS ,17-dihydroxypregn-4-ene-3,20-dione, 9a-fluorohydrocortisone (Florinef Acetate), is used only for the treatment of Addison disease and for inhibition of endogenous adrenocortical secretions. As shown in Table 25.7, it has up to about 800 times the MC activity of hydrocortisone and about 11 times the GC activity. Its potent activity stimulated the synthesis and study of the many fluorinated steroids shown in...

Diphenoxylate

Diphenoxylate (Fig. 24.9) is a weak opioid agonist and is available combined with atropine (Lomotil) for use as an an-tidiarrheal agent. At low doses, the opioid effect is minimal, and the atropine is added to dissuade abuse. One study found both codeine and loperamide to be superior to diphenoxylate for treating chronic diarrhea.83 The manufacturer has strict dosing guidelines for pediatric use because opioid intoxication and deaths from diphenoxylate have been reported.84