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...

O

Figure 14.8 Metabolism of carbamazepine and oxcarbazepine. O-glucuronide or can be further oxidized to the 10,11-CBZ-diol as an inactive metabolite (Fig. 14.8). Thus, OXC is said to have much fewer hepatic and idiosyncratic side effects associated with CBZ.23 Although OXC does not induce its own metabolism, it is a weak inducer of CYP3A4 and UDP-glucuronyl transferase and also inhibits CYP2C19. Thus, severe drug-drug interactions with medications metabolized by these enzymes are to be...

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...

Products

Captopril, (Capoten), blocks the conversion of angiotensin I to angiotensin II by inhibiting the converting enzyme. The rational development of captopril as an inhibitor of ACE was based on the hypothesis that ACE and car-boxypeptidase A functioned by similar mechanisms. It was noted that d-2-benzylsuccinic acid7 was a potent inhibitor of carboxypeptidase A, but not ACE. By use of this small Figure 18.4 Model showing cleavage of the histidine-phenylalanine residue of angiotensin I by...

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,...

Info

N1 group has the largest effect on protein binding. N4-acetate metabolites of the sulfonamides are more lipid soluble and, therefore, more protein bound than the starting drugs themselves (which have a free 4-amino group that decreases lipid solubility). Surprisingly, the N4-acetylated metabolites, although more strongly protein bound, are excreted more rapidly than the parent compounds. Currently, the relationship between plasma protein binding and biological half-life is unclear. Many...

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...

Ch3

Meprobamate R H Carisoprodol R CH (CH3)2 Carisoprodol, USP. Carisoprodol, dicarbamate, 2-methyl-2-propyl-1,3-propanediol carbamate isopropylcarbamate (Soma), is the mono-N-isopropyl-substituted relative of meprobamate. The structure is given in the discussion of meprobamate. It is indicated in acute skeletomuscular conditions characterized by pain, stiffness, and spasm. As can be expected, a major side effect of the drug is drowsiness. Chlorphenesin Carbamate. Chlorphenesin carbamate,...

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...

Biochemistry

Vitamin A is involved in numerous biochemical functions. The best-known action of vitamin A is in its function in the chemistry of vision. The requirement for vitamin A for proper visual response to light in the retina has been well characterized. However, its role in cellular growth and differentiation continues to expand. The molecular mechanism of action of vitamin A, in the form of 11-cis retinal, in the visual process has been under investigation for many years.34,35 Figure 28.4 represents...

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...

Selected Reading

Abraham, D. (ed.) Burger's Medicinal Chemistry and Drug Discovery, 6th ed. New York, Wiley-Interscience, 2003. Albert, A. Selective Toxicity, 7th ed. New York, Chapman & Hall, 1985. Cramer, C. J. Essentials of Computational Chemistry Theories and Models. New York, Wiley, 2002. Dean, P. M. (ed.) Molecular Similarity in Drug Design. New York, Chapman & Hall, 1995. Devillers, J., and Balaban, A. T., (eds.) Topological Indices and Related Descriptors in QSAR and QSPR. Amsterdam, Gordon and...

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...

References

SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD, 2007 2. Weinberg, R. A. The Biology of Cancer, Garland Science, 2007, Chapters 8 and 9, pp. 209-356. 3. Ziegler, A. M., et al. Nature 372 773, 2002. 4. Topal, M. D., and Fresco, J. R. Nature 263 285, 1976. 5. Gilman, A., and Phillips, F. S. Science 103 409, 1946. 6. Kohn, S., et al. J. Mol. Biol. 19 266, 1966. 7. Everett, R. L., et al. J. Chem. Soc. 2386, 1953. 8. Bergel, F., and Stock, J....

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...

Chemistry

There is no doubt that echinacea has immunomodulating properties. The chemistry of the constituents of the plant has been studied extensively, but it is difficult to correlate a major activity with any plant fraction. Indeed, no single component appears to be responsible for the activity of echi-nacea. Standardization of echinacea preparations has also proved to be a problem. The consumer is presented with three potential preparations sold under the name echi-nacea E. purpurea, E. angustifolia,...

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...

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

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...

Dna

Cloning of, 123, 123 expression of, 127 strategies for, 126, 126t manipulation of, 127-128, 128 protein production, 121-122, 122 DNA ligases, 124, 909 DNA microarrays, 151-152 DNA polymerase inhibitors, 339-343 DNA viruses, 331, 331f-332f, 335 DNM. See Daunorubicin hydrochloride DNR. See Daunorubicin hydrochloride Dobutamine, 110-111, 540, 647 methylation, 102-103 Dobutrex. See Dobutamine Docetaxel, 398-399, 398 Docking programs, 35 Dofetilide, 636 Dolobid. See Diflunisal Dolophine. See...

O Ganglionic Blocking Agents

Autonomic ganglia have been the subject of interest for many years in the study of interactions between drugs and nervous tissues. The first important account84 was given by Langley and described the stimulating and blocking actions of nicotine on sympathetic ganglia. It was found that small amounts of nicotine stimulated ganglia and then produced a blockade of ganglionic transmission because of persistent depolarization. From these experiments, Langley was able to outline the general pattern...

Ci

The structures of these two compounds derive from those of the fluorobutyrophenone antipsychotics. They have ff- arylamine-like structures that permit binding to the SERT and inhibit 5-HT reuptake. In these compounds, the additional hydrophobic substituent can be viewed as being attached to the nitrogen of the ff-arylamine-like group. Additionally, they are 5-HT2A antagonists. That antagonism may or may not afford antipsychotic effectiveness is discussed under antipsychotics. 5-HT2A antagonists...

An

To obtain the number of decaying atoms for a measurable period of time, the differential equation must be integrated. Therefore, the basic equation for radioactive decay is expressed as follows in terms of atoms where Nt (number of atoms at time t) and N0 (number of atoms at time 0). Activity (A) of a radionuclide is also expressed as the number of atoms disintegrating per unit of time (A AN). With the substitution of A A into the equation above for N and simplifying the result, where At is the...

Structure Activity Relationships of the Volatile General Anesthetics

The inhalation anesthetics in use today are nitrous oxide, halothane, isoflurane, desflurane, and sevoflurane. The chemical structures for these compounds and some of historical interest can be seen in Figure 22.1. While it is true that there is no single pharmacophore for the inhaled anesthetics, the chemical structure is related to the activity of the drug molecule. The first SAR studies conducted independently by Meyer and Overton in the 1880s showed a distinct positive correlation between...

Nitrogen Mustards

Chlorambucil Conjugate Solubility

The nitrogen mustards are compounds that are chemically similar to sulfur mustard or mustard gas developed and used in World War I. The term mustard comes from the similarity in the blisters produced by the compound and those seen upon exposure to the oil of black mustard seeds. Investigation of sulfur mustard revealed that it possessed an-tineoplastic properties but because the compound existed as a gas at room temperature, handling and administration of the material were difficult. Conversion...

T

Figure 17.19 Neurotransmission at the sympathetic cervical ganglion. pathway for ganglionic transmission.86 The slowly generating or late EPSP is blocked by atropine but not by the traditional ganglionic blocking agents. This receptor has muscarinic properties because methacholine causes generation of the late EPSP without causing the initial spike characteristic of ACh. Atropine also blocks the late EPSP produced by methacholine. There may be more than one type of muscarinic receptor in...

O Antifungal Agents

General Introduction to Fungi Medical Mycology The discovery that some infectious diseases could be attributed to fungi actually preceded the pioneering work of Pasteur and Koch with pathogenic bacteria by several years. Two microbiologists, Schonlein and Gruby, studied the fungus Trichophyton schoenleinii in 1839. In that same year, Langenbeck reported the yeastlike microorganism responsible for thrush (C. albicans). Gruby isolated the fungus responsible for favus on potato slices, rubbed it...

Phagocytes

The phagocytic process is initiated by contact and adhesion of an invading cell with a phagocyte cell membrane. Adhesion triggers a process whereby the phagocytic cell extrudes pseudopodia that surround the adhering microbe. As this process progresses, the microbe is actually surrounded by the phagocyte cell membrane. Then, invagination of the membrane fully engulfs the particle, and the membrane is Scheme 5.1 Lineages of blood cells. All blood cells derive from a pluripotent stem cell. Various...

Drugs That Inhibit Gaba Degradation

Vigabatrin (y-vinyl-GABA) is an irreversible inhibitor of GABA-T, rationally designed based on the biochemical mechanism of transamination reaction.19,33 Briefly, vigabatrin, because of its structural similarity, competes with GABA for binding to GABA-T and forms a Schiff base intermediate with the cofactor, pyridoxal phosphate similar to GABA. However, unlike its substrate GABA, during the process of transferring the amino group to the pyridoxal phosphate, a reactive intermediate is formed...

Class I Antiarrhythmics

Quinidine sulfate is the sulfate of an alkaloid obtained from various species of Cinchona and their hybrids. It is a dextrorotatory di-astereoisomer of quinine. The salt crystallizes from water as the dihydrate, in the form of fine, needlelike, white crystals. Quinidine sulfate contains a hydroxy methyl group that serves as a link between a quinoline ring and a quinu-clidine moiety. The structure contains two basic nitrogens, of which the quinuclidine nitrogen is the...

Shengquan

Adrenergic drugs exert their principal pharmacological and therapeutic effects by either enhancing or reducing the activity of the various components of the sympathetic division of the autonomic nervous system. In general, substances that produce effects similar to stimulation of sympathetic nervous activity are known as sympathomimetics or adrenergic stimulants. Those that decrease sympathetic activity are referred to as sympatholytics, antiadrenergics, or adrenergic-blocking agents....

Opioid Ligand Binding Site

There are no x-ray crystal structures reported for any opioid receptor, and most modeling work has been based on the crystal structure of rhodopsin. Many groups have attempted to find the specific binding site through homology modeling, molecular dynamics, site-directed mutagenesis, chimeric receptors, truncated receptors, and SAR studies. As of yet, no definitive model of the ligand-binding site is available. The opioid-binding site for all four opioid receptors is believed to be an inner...

Alkanol Series

A similar increase in potency with increase in carbon length was seen in the n-alkanol series. In addition, the n-alkanol with a given number of carbons is more potent than the n-alkane with the same chain length.9 EFFECT OF HALOGENATION ETHER HALOGENATION The first inhaled anesthetics used in the late 1800s, diethyl ether and cyclopropane caused laryngospasms. These compounds were also explosive and flammable requiring careful handling. Early studies found that halogenating the ethers...

Xenon Radiopharmaceuticals

Radioactive xenon (133Xe) gas is supplied at standard pressure and room temperature in a septum-sealed glass vial in doses of 10 to 20 mCi (370-740 MBq) in either stable xenon carrier mixed with atmospheric air or 5 xenon carrier mixed with 95 carbon dioxide suitable for inhalation by the patient for diagnostic evaluation of pulmonary function and imaging of the lungs. The shelf life of the vials is 14 days because of the more rapid decay of xenon (133Xe) gas when compared with...

The Sreceptor

Opioid peptides for the S-receptor include the endogenous peptides described previously, Met and Leu enkephalin, as well as some synthetic peptides such as DADLE, DSLET, and DPDPE (see Fig. 24.2 for amino acid sequences). These pep-tides have high affinity for the receptor but low bioavailability and thus limited clinical usefulness. They are used in animal in vitro studies as probes for S-receptor location and function. In an attempt to distinguish the amino acids responsible for S-receptor...

The Neurogenic Inflammation Theory Of Migraines

This theory suggests that migraine headaches occur as a result of an abnormal firing of meningeal nociceptors at the TGVS. Activation of trigeminal neurons releases vasoac-tive peptides including calcitonin gene-related peptide (CGRP, a vasodilator peptide), substance P, and neurokinin A (both play an important role in pain transmission as well as activation of immune responses and neurogenic inflammation) onto dural tissue where these peptides produce a local response known as neurogenic...

Risperidone

A dibenzoxazepine derivative in use is loxapine succinate, f 1,4 oxazepine succinate (Daxolin). The structural relationship to the phenothiazine antipsychotics is apparent. Examples in this group are clothiapine, metiapine, zotepine, and others. They have electron-withdrawing groups at position 2, relatively close to the side-chain nitrogen atoms. Loxapine, an effective antipsychotic, blocks D2-type receptors and has side effects similar to those reported for the phenothiazines. Its...

O Future Directions

DA has long been linked with PD and schizophrenia in a unique and multifaceted relationship. Although this close association ensures that DA and the dopaminergic systems will remain a primary focus for the treatment of both PD and schizophrenia, other avenues of therapy are on the horizon. A focus on neuroprotective agents for the treatment of PD may provide a more efficacious approach than DA symptomology-based therapies. Such treatments would target the mechanisms involved in the pathogenesis...

Tolazoline Phentolamine

Figure 16.14 Mechanism of inactivation of -adrenergic receptors by S-haloalkylamines. Figure 16.14 Mechanism of inactivation of -adrenergic receptors by S-haloalkylamines. responses of smooth muscle and of the heart muscle. Although phenoxybenzamine is capable of blocking acetylcholine, histamine, and serotonin receptors, its primary pharmacological effects, especially that of vaso-dilation, may be attributed to its -adrenergic blocking capability. As would be expected of a drug that produces...

Viral Vaccines12

Smallpox vaccine is live vaccinia (cowpox) virus grown on the skin of a bovine calf. Smallpox is a highly lethal and disfiguring disease that was common throughout history. Smallpox vaccine was used routinely in the United States but today is no longer recommended. (There have been no reported cases of smallpox since the 1940s.) In 1982, smallpox was declared eradicated worldwide. With smallpox, the risks of the vaccine outweigh the benefits the vaccine penetrates the central nervous system and...