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...

Biochemistry

Folic acid, and dietary forms of folate that are not in the reduced state, must undergo reduction of ring B for biological activity. Folic acid is first reduced to H2PteGlu by dihydrofolate reductase (DHFR EC 1.5.1.3) using NADPH as a cofactor and then to H4PteGlu by the same enzyme. These key steps are important in the understanding of the folate antagonists, such as methotrexate, that inhibit DHFR and, thereby, interfere with the utilization of all folates that are not in the reduced...

O

5-Nitro-2-furaldehyde semicarbazone (Furacin) occurs as a lemon-yellow crystalline solid that is sparingly soluble in water and practically insoluble in organic solvents. Nitrofurazone is chemically stable, but moderately light sensitive. It is used topically in the treatment of burns, especially when bacterial resistance to other agents may be a concern. It may also be used to prevent bacterial infection associated with skin grafts. Nitrofurazone has a broad spectrum of activity against...

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...

Info

Hydrocortisone Biosynthesis

A second use of finasteride is in the treatment of male pattern baldness. The conversion of testosterone to DHT in advancing years leads to thinning of hair in men. Inhibition of this conversion was envisioned as a possible baldness treatment. After finasteride was shown to be safe and effective in the treatment of BPH, a lower dose formulation was studied for treating male pattern baldness. The trials were a success, and Propecia (1 mg d) was the result. Although finasteride preferentially...

Products

Verapamil, 5- (3,4-dimethoxyphenethyl) (Calan, Isoptin), was introduced in 1962 as a coronary vasodilator and is the prototype of the Ca2+ antagonists used in cardiovascular diseases. It is used in the treatment of angina pectoris, arrhythmias from ischemic myocardial syndromes, and supraventricular arrhythmias. Verapamil's major effect is on the slow Ca2+ channel. The result is a slowing of AV conduction and the sinus rate. This inhibition of the action potential inhibits one limb...

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...

Chapter Overview

This chapter describes the role that the autonomic nervous system plays in regulating the mammalian system. This chapter supports the fact that acetylcholine (ACh) plays a critical role in the mechanisms of regulation of human physiology. This, in turn, not only serves in the development of agents that mimic the effect of ACh, but also those that block its effects as therapeutic agents. Through these developments, scientists are gaining a better understanding of how to treat diseases such as...

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...

References

NCBI, NLM, NIH Bethesda, MD 20894. e-mail info ncbi.nlm.nih.gov. 2. Benson, D. A. Nucl. Acids Res. 30(1) 17-20, 2002. 3. GenBank, NCBI https www.ncbi.nlm.nih.gov GenBank genbankstats.html. 4. Pharmaceutical Research and Manufacturers Association New Medicines in Biotechnology Survey. Washington, DC, Pharmaceutical Research and Manufacturers Association, 2002. 5. Pharmaceutical Research and Manufacturers Association New Medicines in Development for Pediatrics Survey. Washington, DC,...

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...

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...

Oh

Figure 25.15 Selective estrogen receptor modulators (SERMs) and antiestrogens. of the increased risk of endometrial cancer with tamoxifen therapy, tamoxifen should be used to prevent breast cancer only in women at high risk. Women without a family history of breast cancer or other risks should not use tamoxifen in this manner. Raloxifene is another SERM, but its profile of activity differs from that of tamoxifen. Raloxifene is an ER antagonist in both breast and endometrial tissue, but has...

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

Homology Based Cloning

Another cloning strategy involves the use of previously cloned genes to guide identification and cloning of evo-lutionarily related genes. This approach, referred to as homology-based cloning, takes advantage of the fact that nu-cleotide sequences encoding important functional domains of proteins tend to be conserved during the process of evolution. Thus, nucleotide sequences encoding regions involved with ligand binding or enzymatic activity can be used as probes that will hybridize to...

Allergic Reactions to Local Anesthetics

True allergic reactions to local anesthetics are very rare. Patients may be allergic to the anesthetic, a metabolite of the anesthetic or a preservative in the anesthetic. Allergies to the ester anesthetics are more common than allergies to the amide anesthetics. As discussed, the ester anesthetics may be metabolized to PABA, which is believed to be responsible for the allergic reactions (Fig. 22.15). Although the amide type local anesthetics are not metabolized to PABA they may contain a...

O Cholinergic Receptors

There are two distinct receptor types for ACh that differ in composition, location, and pharmacological function and have specific agonists and antagonists. Cholinergic receptors have been characterized as nicotinic and muscarinic on the basis of their ability to be bound by the naturally occurring alkaloids nicotine and muscarine, respectively. Receptor subtypes that differ in location and specificity to agonists and antagonists have been identified for both the nicotinic and muscarinic...

Aromatase Inhibitors

Aromatase is a cytochrome P450 enzyme complex that catalyzes the conversion of androstenedione to estrone and testosterone to estradiol (Figs. 25.5 and 25.16).67-69 The complex is made up of reduced nicotinamide adenine dinu-cleotide phosphate (NADPH)-cytochrome P450 reductase, and cytochrome P450 hemoprotein. In the first two steps, the C19 methyl is hydroxylated to CH2OH, and then to an alde hyde hydrate form that dehydrates to provide the C19 aldehyde. In the final aromatization step, the...

Why Is Monomethyl Compound Is Low In Sedativd Potential

Clomipramine (Anafranil) is up to 50 times as potent as imipramine in some bioassays. This does not imply clinical superiority, but it might be informative about tricyclic and, possibly, other reuptake inhibitors. The chloro replacing the H-substituent could increase potency by increasing distribution to the CNS, but it is unlikely that this would give the potency magnitude seen. It might be conjectured that an H-bond between the protonated amino group (as in vivo) and the unshared electrons of...

O Proteins And Proteinlike Compounds

The chemistry of proteins is complex, with many facets not completely understood. Protein structure is usually studied in basic organic chemistry and, to a greater extent, in biochemistry, but for the purposes of this chapter, some of the more important topics are summarized, with emphasis on relationships to medicinal chemistry. Much progress has been made in understanding the more sophisticated features of protein structure4 and its correlation with physicochemical and biological properties....

H2n

The 2 chloride substitution on the aromatic ring of chloropro-caine is an electron-withdrawing functional group. Thus, it pulls the electron density from the carbonyl carbon into the ring. The carbonyl carbon is now a stronger electrophile and more susceptible to ester hydrolysis. Therefore, chloropro-caine has a more rapid metabolism than procaine. The in vitro plasma half-life is approximately 25 seconds. The 2-chloro-4-aminobenzoic acid metabolite precludes this from being used in patients...

Thallium Radiopharmaceuticals

The most common clinical uses of this radiotracer are for the evaluation of myocardial perfusion and myocardial viability. It is also indicated for the localization of parathyroid hyperactivity. It is commercially available as a ready-to-use intravenous solution. Thallous (201Tl) chloride accumulates in viable myocardial tissue by Na+ K+ ATPase as well as Na+ K+ 2CU symporter27 much like potassium ions and is a dynamic exchange between the myocardial cell and the...

Alfentanil

The addition of a methoxy methyl on the 4-piperidine and the substitution of the phenethyl ring for an ethyl-substituted tetrazole-one yielded a compound with about one fourth to one third the potency of fentanyl (Fig. 24.9). Although less potent, it has a quicker onset of action, a shorter duration of action, and thus a better, safety profile for use as an anesthetic adjunct. The piperidine amine has a pKa of 6.5 compared with fentanyl's pKa of 8.4. This results in a higher proportion of...

Which Two Vitamin Absorbed Via Smvt And Can Competitively Inhibit Each Other

List the fat-soluble vitamins, the water-soluble vitamins, and the B-complex vitamins. 2. Explain the difference between enrichment and fortification. 3. How do most of the vitamins function How else might some vitamins function 4. Which vitamin is involved in proper function of the eye and how is it involved Would you recommend retinoic acid (Tretinoin) for treatment of a defiency of this vitamin Explain your reasoning. 5. Vitamin A is very toxic in high doses but the provitamin A carotenoids...

References Pharmaceutical Chemistry

Rev. 12 319, 2008. 2. Huang, J.-K., and Jan, C.-R. Life Sci. 68 611, 2000. 3. Tariq, S. H., et al. Clin. Geriatr. Med. 24 93, 2008. 4. Azabadi, E. Br. J. Clin. Pharmacol. 61(6) 761, 2006. 5. Weinberger, D. R. N. Engl. J. Med. 344 1247, 2001. 6. Nemeroff, C. B. Psychopharmacol. Bull. 37(4) 113, 2003 7. Xue, H., et al. J. Med. Chem. 44 1883, 2001. 8. Xue, H., et al. J. Mol. Biol. 296 739, 2000. 9. Renard, S., et al. J. Biol. Chem. 274 13370, 1999. 10. Buhr, A., et...

Vitamin B

Thiamine, the preferred name for vitamin B1, holds a prominent place in the history of vitamin discovery because beriberi, the disease resulting from insufficient thiamine intake, was one of the earliest recognized deficiency diseases. Its relationship to polyneuritis in birds was noted in the early work of Funk,3 and his work with pigeons led to the discovery that a water-soluble substance in rice polishings was curative. The early designation of water-soluble B was replaced with vitamin B by...

Vitamin B5

The first suggestion for the existance of vitamin B5 came from Carter et al.163 in 1930 although it was never characterized or isolated. In 1933, R. J. Williams164 and his collaborators found a growth determinant of universal occurrence and named it, according to the authors, pantothenic acid, the name being derived from the Greek, meaning from everywhere (probably from the Greek pantothen). Pantothenic acid, the preferred term, later became associated with the name vitamin B5. The synthesis...

Metabolism Of Estrogens

Ethinyl Estradiol Metabolism

The metabolism of natural estrogens has been reviewed in detail.37 The three primary estrogens in women are 17 -estradiol, estrone, and estriol (16a,17j6-estriol). Although 17 -estradiol is produced in the greatest amounts, it is quickly oxidized (see Fig. 25.12) to estrone, the estrogen found in highest concentration in the plasma. Estrone, in turn, is converted to estriol, the major estrogen found in human urine, by hydroxylation at C16 (to provide the 16a-hydroxyl) and reduction of the C17...

O Antipsychotic Drugs

Psychotic illness is a compilation of multiple disorders, including schizophrenia, the manic phase of bipolar syndrome, acute idiopathic psychosis, and other conditions marked by severe agitation,56 yet the term psychosis is most often associated with schizophrenia. Schizophrenia affects approximately 1 of the U.S. population,57 with both genetic58 and neurodevelopmental59 implications. Schizophrenia is characterized by delusions, abnormal behaviors, hallucinations, and thought disorders (i.e.,...

Vidarabine Phsphodiester Bond Inhibition

The antiviral action of vidarabine is completely confined to DNA viruses. Vidarabine inhibits viral DNA synthesis. Enzymes within the cell phosphorylate vidarabine to the triphosphate, which competes with deoxyadenosine triphosphate for viral DNA polymerase. Vidarabine triphosphate is also incorporated into cellular and viral DNA, where it acts as a chain terminator. The triphosphate form of vidarabine also inhibits a set of enzymes that are involved in methyla-tion of uridine to thymidine...

Methoxyflurane

Methoxyflurane is a volatile liquid (bp 105 C) with a high blood gas partition coefficient and thus a slow induction and prolonged recovery.20 Approximately 75 of the drug undergoes metabolism yielding dichloroacetate, difluoromethoxy-acetate, oxalate, and fluoride ions. The intrarenal inorganic fluoride concentration, as a result of renal defluorination, may be responsible for the nephrotoxicity seen with methoxyflu-rane. Both the concentration of generated and the duration for which it...

O Histamine As A Chemical Messenger

Knowledge of the biodisposition of histamine is important in understanding the involvement of this substance in various pathophysiologies as well as the actions of various li-gands that either enhance or block its actions. Each of the steps in the life cycle of histamine represents a potential point for pharmacological intervention. Histamine is synthesized in Golgi apparatus of its principal storage cells, mast cells, and basophils.6 Histamine is formed from the naturally occurring amino acid...

Jq

Methenamine is used internally as a urinary antiseptic for the treatment of chronic urinary tract infections. The free base has practically no bacteriostatic power formaldehyde release at the lower pH of the kidney is required. To optimize the antibacterial effect, an acidifying agent such as sodium biphosphate or ammonium chloride generally accompanies the administration of methenamine. Certain bacterial strains are resistant to the action of methenamine because they elaborate urease, an...

O Antithyroid Drugs

Hyperthyroidism (excessive production of thyroid hormones) usually requires surgery, but before surgery the patient must be prepared by preliminary abolition of the hyperthyroidism through the use of antithyroid drugs. Thiourea and related compounds show an antithyroid activity, but they are too toxic for clinical use. The more useful drugs are 2-thiouracil derivatives and a closely related 2-thioimidazole derivative. All of these appear to have a similar mechanism of action (i.e., prevention...

Calculated Log P Log D and pKa

The log P, log D at pH 7, and pKa values are from Chemical Abstracts Service, American Chemical Society, Columbus, OH, 2009, and were calculated using Advanced Chemistry Development (ACD Labs) Software V8.14 for Solaris ( 1994-2009 ACD Labs). The pKa values are for the most acidic HA acid and most weakly acidic BH+ groups. The latter represent the most basic nitrogen. Keep in mind that pKa values for HA acids that exceed 10 to 11 mean that there will be little, if any, anionic contribution in...

Ion Channels And Calcium

Calcium ions play an important role in the regulation of many cellular processes, such as synaptic transmission and muscle contraction. The role of calcium in these cellular functions is as a second messenger, for example, regulating enzymes and ion channels. The entry of extracellular Ca2+ in the cytosol of myocardial cells and the release of Ca2+ from intracellular storage sites is important for initiating contractions of the myocardium. Normally, the concentration of Ca2+ in the...

O Biotechnologyderived Pharmaceutical Products

More than 2 dozen FDA-approved biotechnology-derived pharmaceutical products are listed in Table 27.9. There are more than 200 other products in various stages of develop-ment.74 The FDA-approved products fall loosely into five major categories enzymes, hormones, lymphokines, hematopoietic factors, and biologicals. A detailed discussion of all of these products is beyond the scope of this chapter. Because most of these products are proteins or peptides, a cursory evaluation of them and their...

O Manipulation Of Dna Sequence Information

Perhaps the greatest impact of rDNA technology lies in its ability to alter a DNA sequence and create entirely new molecules that, if reintroduced into the genome, can be inherited and propagated in perpetuity. The ability to alter a DNA sequence, literally in a test tube, at the discretion of an individual, corporation, or nation, brings with it important questions about ownership, ethics, and social responsibility. There is no question, however, that potential benefits to the treatment of...

Gay

Figure 18.1 Renin-angiotensin system of blood pressure control. ACE and other carboxypeptidases.6 Although ACE causes activation of angiotensin and inactivation of bradykinin, actions that appear to be opposite, the balance of the system seems to favor vasoconstriction. ACE is a membrane-bound enzyme anchored to the cell membrane through a single transmembrane domain located near the carboxy-terminal extremity. The enzyme is a zinc-containing glycoprotein with an MW about 130,000. It is a...

Chlorinecontaining Compounds

Chlorine and chlorine-releasing compounds have been used in the disinfection of water supplies for more than a century. The discovery that hypochlorous acid (HClO) is the active germicidal species that is formed when chlorine is dissolved in water led to the development and use of the first inorganic hypochlorite salts such as NaOCl and Ca(OCl)2. Later, organic n-chloro compounds were developed as disinfectants. These compounds release hypochlor-ous acid when dissolved in water, especially in...

Celecoxib

Celecoxib (Celebrex) was the first selective COX-2 inhibitor drug introduced into the market in 1998 for use in the treatment of RA, OA, acute pain, and menstrual pain. The real benefit is that it has caused fewer GI complications when compared with other conventional NSAIDs. It has also been approved for reducing the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP). Celecoxib is well absorbed and undergoes rapid oxida-tive metabolism via CYP2C9 to give its...