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...

Info

Figure 2.8 Plot of log BR versus log PC. The most lethal compound in this assay was chlorpromazine, with a BR (LDi00) of only 0.00000631 mmol and the least active was ethanol, with a BR of 0.087096 mmol. In other words, it takes about 13,800 times as many millimoles of ethanol than of chlorpromazine to kill 100 of the test subjects in this particular assay. Plotting BR versus PC (partition coefficient) produces the nonlinear scatter shown in Figure 2.7. Note that compounds 1 and 11 lie at a...

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...

Mechanism of Action

Triptans are specifically designed to bind to the 5-HT1B 1D receptors based on the findings that 5-HT1B receptors are present in the cranial blood vessels279,280 and 5-HT1B 1D receptors are found in the trigeminal pain pathway.280,281 Three distinct mechanisms have been suggested to explain the actions of triptans (a) Triptans abort migraine headache by its agonist action at the 5-HT1B receptors, thereby inducing vasoconstriction of the meningeal, dural, or pial blood vessels.279 (b) Triptans...

Chemistry

Chemically, the various forms of vitamin D are broken-open steroids referred to as secosteroids. The term vitamin D is currently applied to all steroids possessing biological activity like that of cholecalciferol.61 Irradiation of yeast ergos-terol yields a 1 1 mixture of ergocalciferol and lumisterol known as vitamin D1. Because all the activities reside in the ergocalciferol, the term vitamin D1 is no longer used. The photoconversion of ergocalciferol (ercalciol, previously calciferol,...

Ci

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...

References

A., and Davalos, A. Stroke 38 2196-2203, 2007. 2. Blaha, M. J., Bansal, S., Rouf, R., et al. Mayo Clin. Proc. 83(8) 932-943, 2008. 3. Remedi, M. S., and Nichols, C. G. PLoS Med. 5(10) e206, 2008. 4. Winkler, M., Stephan, D., Bieger, S., et al. J. Pharmacol. Exp. Ther. 322(2) 701-708, 2007. 5. Babenko, A. P., Aguilar-Bryan, L., and Bryan, J Annu. Rev. Physiol. 60 667-687, 1998. 6. Tusnady, G. E., Bakos E., Varadi A., et al. FEBS Lett. 402(1) 1-3, 1997. 7. Roane, D. S.,...

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.,...

Ho Oh

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...

Biochemistry

The accepted mechanism for vitamin K is to function as a cofactor in the posttranslational synthesis of y-carboxyglu-tamic acid (Gla) from glutamic acid (Glu) residues.112 The discovery of Gla in 1974113,114 clarified the mechanism of vitamin K and led to the identification of additional vitamin K-dependent proteins. All vitamin K-dependent proteins contain propeptide possessing Glu residues. Vitamin K participates in the carboxylation of several specific Glu residues to form Gla residues,...

O

Carbidopa, acid, is a white crystalline powder, slightly soluble in water (pKa 7.8). Carbidopa is absorbed slower than levodopa and is 36 plasma protein bound.23 Carbidopa is metabolized to two main metabolites acid and a-methyl-3,4-dihydroxyphenylpropionic acid). These two metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30 of the total urinary excretion. No drug interactions have been described. MAO...

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...

Products

Sildenafil, citrate (Viagra), is a potent inhibitor of PDE5. It was initially studied for use in hypertension and angina pectoris because of its ability to increase intracellular levels of cyclic nucleotides. However, during phase I clinical trials, it was noted that the drug had little effect on angina and was unpredictable in managing hypertension. However, patients noted that there were improved effects in their sexual dysfunction. Therefore, the manufacturer decided to...

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...

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

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...

Oh

Long-term use is justified if the drug significantly reduces the severity of asthma symptoms permits a significant reduction in, or elimination of, steroid dosage or improves management of those who have intolerable side effects to sympathomimetic agents or methylxan-thines. For cromolyn to be effective, it must be administered at least 30 minutes prior to antigen challenge and administered at regular intervals (see dosing information that follows). When inhaled,...

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...

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...

W

Enantiomers of, 109 metabolism of, 48 R(+)-Warfarin, metabolism of, 80, 82 Warfarin potassium, 658 Warfarin sodium, 658 Water-soluble contrast agents, 432 Water-soluble vitamins, 916, 916t, 935-956 vitamin B1, 935-938 vitamin B2, 938-942 vitamin B3, 939-942 vitamin B5, 942-944 vitamin B6, 944-947 vitamin B7, 947-948 vitamin B9, 948-951 vitamin B12, 951-954 vitamin C, 954-956 WelChol. See Colesevelam Wellbutrin. See Bupropion Wernicke-Korsakoff syndrome, 938 West African sleeping sickness, 221,...

Dnach3

Scheme 10.14 Metabolic and chemical activation of dacarbazine and temozolomide. MECHLORETHAMINE HYDROCHLORIDE (NH2, MUSTARGEN) Mechlorethamine is available in 10-mg vials for intravenous (IV) administration in the treatment of Hodgkin's lymphoma. It is part of the MOPP regimen used in treating this condition, which is comprised of mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone. The agent is also used topically in the treatment of mycosis fun-goides, a rare type of cancer...

N O

Cefpodoxime is a broad-spectrum cephalosporin with useful activity against a relatively wide range of Grampositive and Gram-negative bacteria. It is also resistant to many jS-lactamases. Its spectrum of activity includes S. pneumoniae, Streptococcus pyogenes, S. aureus, H. influenzae, M. catarrhalis, and Neisseria spp. Cefpodoxime is also active against members of the Enterobacteriaceae family, including E. coli, K. pneumoniae, and P. mirabilis. It thus finds use in the treatment of upper and...

Mcv Pharmaceutical

Figure 5.11 Recommended immunization schedule for persons aged 0 to 6 years United States, 2009. (Available at Accessed January 23, 2009.) Adsorbed Tetanus and Diphtheria Toxoid for Adults Adsorbed tetanus and diphtheria toxoid for adults (designated Td) is for children older than 7 years and for adults. It has a lower level of diphtheria toxoid (1 15) because older children are much more sensitive to D. It is used for immunization of schoolchildren.

Hypersensitivity Reaction Of Phenytoin

Hypersensitivity reactions (idiosyncratic toxicity) to phenyt-oin and other aromatic AEDs in susceptible individuals are believed to stem from the reactions of these reactive intermediates (i.e., arene oxide, catechol, or o-quinone) with hepatic enzymes or other cellular proteins forming covalently bonded haptens.45 The reactive intermediate, arene oxide, is deactivated by either epoxide hydrolase to dihydrodiol (a major urinary metabolite) or by the action of GSH and glu-tathione transferase....

Phenothiazines

Beginning in the mid-l940s, several antihistaminic drugs were been discovered as a result of bridging the aryl units of agents related to the ethylenediamines. The search for effective antimalarials led to the investigation of phenothiazine derivatives in which the bridging entity is sulfur. Subsequent testing found that the phenothiazine class of drugs had not only anti-histaminic activity but also a pharmacological profile of its own, considerably different from that of the ethylenediamines...

N

Figure 20.28 Structures of DPP-4 inhibitors on the global market or in advanced stages of clinical development. binding ( 38 ), a relatively large volume of distribution (198 L), and a terminal elimination half-life of 12 hours. About 79 of a 100-mg oral dose is excreted unchanged in urine, the balance as trace-level metabolites (CYP3A4, lesser contribution by CYP2C8) in urine or feces 87 of administered radioactivity is excreted in urine, and 13 in feces. Active tubular excretion is reported...

O Eicosanoid Biosynthesis

Prostaglandins and other eicosanoids are produced by the oxidative metabolism of free arachidonic acid. Under normal circumstances, arachidonic acid is not available for metabolism as it is present as a conjugated component of the phospholipid matrix of most cellular membranes. Release of free arachidonic acid, which subsequently may be oxidatively metabolized, occurs by stimulation of phospholipase (PLA2) enzyme activity in response to some traumatic event (e.g., tissue damage, toxin exposure,...

Detoxify The Phosphothioate By Phosphatase

Echothiophate iodide is a long-lasting cholinesterase inhibitor of the irreversible type, as is isofluorphate. Unlike the latter, however, it is a quaternary salt, and when applied locally, its distribution in tissues is limited, which can be very desirable. It is used as a long-acting anticholinesterase agent in the treatment of glaucoma. Hexaethyltetraphosphate (HETP) and Tetraethyl pyrophosphate (TEPP). HETP and TEPP are compounds that also show anticholinesterase activity. HETP was...

O New Biological Targets For Drug Development

One of the outcomes of the progress that has been made in the identification and cloning of genes is that many proteins encoded by these genes represent entirely new targets for drug development. In some cases, the genes themselves may represent the ultimate target for the treatment of a disease in the form of gene therapy. The cloning of the CF gene is an example of both a new drug target and a gene that could potentially be used to treat the disease. The protein encoded by this gene, CFTR, is...

Chapter Overview

Modern drug design as compared with the classical approach let's make a change on an existing compound or synthesize a new structure and see what happens continues to evolve rapidly as an approach to solving a drug design problem. The combination of increasing power and decreasing cost of desktop computing has had a major impact on solving drug design problems. Although drug design increasingly is based on modern computational chemical techniques, it also uses sophisticated knowledge of disease...

Innate Immunity

Innate immunity is the most basic form of immunity and includes immune systems that are present in a human from birth. A clear distinction must be made between innate immunity and acquired (adaptive) immunity, which develops after birth, and then only after an antigenic challenge (Table 5.2). Innate immunity is the first line of defense against invasion by microbes and can be characterized as fast in response, nonspecific, and lacking in memory of the challenge. Acquired immunity develops...

Insulin

One of the major triumphs of the 20th century occurred in 1922, when Banting and Best34 extracted insulin from dog pancreas. Advances in the biochemistry of insulin have been reviewed with emphasis on proinsulin biosynthesis, conversion of proinsulin to insulin, insulin secretion, insulin receptors, metabolism, effects by sulfonylureas, and so on.35-38 Insulin is synthesized by the islet jS-cells from a single-chain, 86-amino-acid polypeptide precursor, proinsulin.39 Proinsulin itself is...

Amides And Imides

Glutethimide, 2-ethyl-2-phenyl-glutarimide (Doriden), is one of the most active nonbarbitu-rate hypnotics that is structurally similar to the barbiturates, especially phenobarbital. Because of glutethimide's low aqueous solubility, its dissolution and absorption from the GI track is somewhat erratic. Consistent with its high lipophilicity, it undergoes extensive oxidative metabolism in the liver with a half-life of approximately 10 hours. Glutethimide is used as a racemic...

Nh3

Hypersensitivity reactions is initiated by the interaction of an antigen-IgE complex with the membrane of a histamine storage cell. This interaction triggers activation of intracellular phosphokinase C (PKC), leading to accumulation of inositol phosphates, diacylglycerol, and calcium. Exocytotic release of histamine follows the degranulation of histamine storage cells.10 Degranulation also results in the release of other mediators of inflammation including prostaglandins, leukotrienes,...

Xray Crystallography And Steroid Fit At The Receptor

The x-ray structures have now been solved for the ligand-binding domains of all the steroid hormone receptors (ERa and ER3,18-20 PR,21 AR,22 GR,23'24 and MR25). The x-ray crystal structures of the ER, PR, and AR have revealed a key difference that leads to the unique ligand specificity of the ERs.19,26 In the region of the ligand-binding domain, where the A ring of steroids binds, are key residues that bind to either the phenolic A ring of estrogens or the enone A ring of progesterone or...

Thiotepa

The early success of the nitrogen mustards led researchers to investigate other compounds that contained a preformed aziri-dine ring, and thiotepa resulted from this work. Thiotepa containing the thiophosphoramide functionality was found to be more stable than the oxa-analog (TEPA) but is metabolically converted to TEPA by desulfuration in vivo.15 Thiotepa incorporates a less reactive aziridine ring compared with that formed in mechlorethamine. The adjacent thiophosphoryl is electron...

S

Dosage forms Tablets (20 and 40 mg), oral disintegrating tablets (20 and 40 mg), gelcaps (10 mg), oral suspension (40 mg 5 mL), injection (10 mg mL and Benign gastric ulcer 40 mg once daily (bedtime) Duodenal ulcer Treatment dose, 40 mg once to twice a day at bedtime maintenance dose, 20 mg once daily at bedtime Gastroesophageal reflux disease 20 mg twice a day Heartburn 10 to 20 mg for relief or 1 hour before a meal for prevention Esophagitis, including erosions and ulcerations 20 or 40 mg...

Therapeutic Uses

Pyridoxine is indicated in the treatment and prevention of known or suspected vitamin B6 deficiency, which is most likely to occur in the setting of alcoholism in developed countries. Vitamin B6 deficiency-related conditions have been reviewed by Spinneker et al.184 A hypochromic, microcytic, iron-refractory anemia, a form of sideroblastic anemia, develops because of decreased hemoglobin synthesis. Cognitive defects also develop with impairment in memory function, especially in the elderly....

Jtp

Although muscarinic receptors have been cloned and the amino acid sequences are known, their three-dimensional structures remain unresolved. Thus, it is not possible to use this information alone to design specific drug molecules. Scientists still use pharmacological and biochemical tests to determine optimal structural requirements for activity. ACh is a relatively simple molecule. The chemistry and ease of testing for ACh biological activity have allowed numerous chemical derivatives to be...

O Aceinhibitor Prodrugs

Many new ACE inhibitors became available for the treatment of hypertension following the clinical effectiveness of enalapril. Enalapril is a non-thiol-containing ACE inhibitor devoid of the side effects of rash and loss of the sense of taste characteristic of the thiol-containing compound captopril. With the exception of the phosphorus-containing fosinopril, these antihypertensive agents have a 2-(s)-aminophenylbutyric acid ethyl ester moiety differing only in the substituents on the amino...

Ord

Figure 20.34 Full structure of ganirelix. Figure 20.34 Full structure of ganirelix. residue a derivatized lysine at position 6 the diacetate salt endows the drug with excellent water solubility for preparation of an aqueous solution (0.5 mg mL, pH 5.0) for parenteral administration (sc injection) the solution stability at pH 5.0 is such that ganirelix can be marketed as a sterile solution rather than a powder requiring reconstitution. An overview of key structure-activity aspects for pep-tidic...

Newer Carbapenems

The extended spectrum of antibacterial activity associated with the carbapenems together with their resistance to inac-tivation by most S-lactamases make this class of S-lactams an attractive target for drug development. In the design of new carbapenems, structural variations are being investigated with the objective of developing analogs with advantages over imipenem. Improvements that are particularly desired include stability to hydrolysis catalyzed by DHP-I,62 stability to bacterial...

ODRUG classes

The alkylating agents are a class of drugs that are capable of forming covalent bonds with important biomolecules. The major targets of drug action are nucleophilic groups present on DNA (especially the 7-position of guanine) however, proteins and RNA among others may also be alkylated. Alkylation of DNA is thought to lead to cell death, although the exact mechanism is uncertain. Potential mechanisms of cell death include activation of apoptosis caused by p53 activation and disruption of the...

X

CH3O oh 0,0-Dimethyl Phosphorothioate Figure 17.18 Comparison of metabolism of malathion by mammals and insects. however, enzymes present in liver microsomes and insect tissues convert parathion (p 50 < 4) to paraoxon, a more potent inhibitor of cholinesterase (pi50 > 8).64 Parathion is also metabolized by liver microsomes to yield -nitrophenol and diethylphosphate the latter is inactive as an irreversible cholinesterase inhibitor.65 Schradan. Schradan, octamethyl pyrophosphoramide (OMPA),...

For A Virus

Despite their simplicity relative to bacteria, viruses still possess various biochemical targets for potential attack by chemotherapeutic agents. An appropriate chemical compound may interrupt each of these. Hence, a thorough understanding of the specific biochemical events that occur during viral infection of the host cell should guide the discovery of site-specific antiviral agents. The process of viral infection can be sequenced in seven stages 1. Adsorption, attachment7 of the virus to...

Ch3

Platelet activation and platelet aggregation play an important role in the pathogenesis of thromboses. These, in turn, play an important role in unstable angina, myocardial infarction, stroke, and peripheral vascular thromboses. Because many cardiovascular diseases are associated with platelet activation, many agents possessing antiplatelet or antithrombotic effects have been investigated. This has revolutionized cardiovascular medicine, in which vascular stenting or angioplasty can be used...

Ch2ch3

Procaine was synthesized in 1904 to address the chemical instability of cocaine and the local irritation it produced. The pKa of procaine is 8.9 it has low lipid solubility and the ester group is unstable in basic solutions. Procaine is available in concentrations ranging from 0.25 to 10 with pHs adjusted to 5.5 to 6.0 for chemical stability. Procaine is also included in some formulations of penicillin G to decrease the pain of intramuscular injection. Procaine is very quickly metabolized in...

C7 Oh

Scheme 10.30 Alkylation of DNA by mitomycin C. Scheme 10.30 Alkylation of DNA by mitomycin C. It was realized early on that the growth and proliferation of many tissues was under the control of the endocrine system, in which endocrine glands secreted hormones and that hormones or their antagonists were useful in controlling the overgrowth of these tissues. It was found later that other growth factors, many of which were secreted by nearby cells, were also involved in controlling the growth and...

AxNValence Example 151l8

Where X is the symbol of the chemical element to which the nuclide belongs, A represents the atomic mass (number of neutrons plus the number of protons), and Z represents the atomic number (number of protons). The right side of the element is reserved for the oxidation state (valence), and N represents the number of neutrons. In most medical references, various notations indicating the element and mass number are used (e.g., 131I, I-131, or iodine-131). The nuclide at the beginning of the decay...

Glucocorticoids With Very Little Or No Salt Retention

Cortisone and hydrocortisone, and even prednisone and prednisolone, have too much salt-retaining activity in the doses needed for some therapeutic purposes. Over the past several decades, several substituents have been discovered that greatly decrease salt retention. They include 16a-hy-droxy, 16a,17a-ketal, 6a-methyl, and 16a- and 16 -methyl. Other substituents have been found to increase both GC and MC activities 9a-fluoro, 9a-chloro, and 21-hydroxy. As a result of the great economic benefit...

O Sympathomimetic Agents

Sympathomimetic agents produce effects resembling those produced by stimulation of the sympathetic nervous system. They may be classified as agents that produce effects by a direct, indirect, or mixed mechanism of action. Direct-acting agents elicit a sympathomimetic response by interacting directly with adrenergic receptors. Indirect-acting agents produce effects primarily by causing the release of NE from adrenergic nerve terminals the NE that is released by the indirect-acting agent...

Structureactivity Relationships

The SAR of phenothiazines is relatively simple because only position 2 (ring A) and the side chain afford active antipsychotic molecules. Conformational studies on chlor-promazine reveal that tilting of the side chain toward ring A allows favorable van der Waals interactions of the side chain with the chlorine substituent.78 The resulting conformation permits the superimposition of DA. Substitution at the 1-position sterically hinders the ability of the side chain to approach ring A. On the...

Oxycodone

Oxycodone is synthesized from the natural opium alkaloid thebaine. Oxycodone is the 14 beta-hydroxyl version of hy-drocodone. This additional functional group gives oxycodone greater potency (1.5 times orally) than hydrocodone presumably by increasing receptor affinity. The oral bioavailability of oxycodone is 65 to 87 .65 The metabolism of oxy-codone follows the similar pattern of opioid metabolism with N-demethylation, O-demethylation, and their glucuronides all identified. Per the...

Hq0

Figure 6.6 ionization equilibria in the quinolone antibacterial drugs. Figure 6.7 A 2 1 chelate of a Mg24 ciprofloxacin. powder that is sparingly soluble in water and ether but soluble in most polar organic solvents. Figure 6.7 A 2 1 chelate of a Mg24 ciprofloxacin. Nalidixic acid is useful in the treatment of urinary tract infections in which Gram-negative bacteria predominate. The activity against indole-positive Proteus spp. is particularly noteworthy, and nalidixic acid and its congeners...

Ept

Drug has significant sedative and hypotensive properties, possibly reflecting central and peripheral -adrenergic blocking activity, respectively. As with the other phenothiazines, the effects of the other CNS-depressant drugs, such as sedatives and anesthetics, can be potentiated.90 Chlorpromazine is a minor substrate of CYP1A2 and 3A4 and a major substrate of CYP2D6.91 Chlorpromazine also is a strong inhibitor of CYP2D6 and a weak inhibitor of CYP2E1. Inhibitors of the CYP2D6 enzyme may...

Biochemical Effects Of Muscarinic Receptor Stimulation

Transmission at the synapse involving second messengers is much slower, about 100 ms, compared with the few milliseconds at synapses where ion channels are activated directly. The delayed reaction to receptor stimulation is caused by a cascade of biochemical events that must occur to cause the pharmacological response (Fig. 17.4). The sequence of events in these second-messenger systems begins with activation of the receptors by an agonist and involves the activation of G proteins that are...

Jks

Figure 13.8 Metabolic pathway of clozapine. following a single 75-mg dose is 8 hours. Because of several adverse effects, clozapine is only used in refractory cases of schizophrenia. Individuals with a history of seizures or predisposed to seizures should be cautioned when taking clozapine. Similar to other atypical antipsychotic agents, clozapine causes an increased risk of mortality in elderly individuals with dementia-related psychoses.23 Olanzapine. Olanzapine, benzodiazepine (Zyprexa), is...

Fatty Acids

Adults have an acidic, fatty substance in and on the skin called sebum. Sebum functions as a natural antifungal agent, part of the innate immune system. Fatty acids have been used for years with the idea that if a substance similar to sebum could be applied to the infected area, the effect of the sebum would be augmented and fungi could be eradicated. The application of fatty acids or their salts does in fact have an antifungal effect, albeit a feeble one. The higher-molecular-weight fatty...