By B. Mannig. Cedar Crest College. 2019.

Maternal hypotension and resultant decreased uterine blood flow are the major risks from the use of this agent order avana 100mg on line. Consistent reduction in uterine activity during the infusion of atosiban has been observed (Goodwin et al avana 100 mg visa. No studies regarding the safety of this agent have been published quality 100mg avana, but a review is available (Shubert avana 50 mg otc, 1995). No difference in tocolytic efficacy was noted in a randomized investigation compar- ing intravenous nitroglycerin with magnesium sulfate (Clavin et al. Parenteral nitroglycerin is associated with severe maternal hypotension, which suggests that pla- cental hypoperfusion may be a serious risk. Concern includes efficacy of specific agents and whether these agents can effectively delay labor for greater than 48 h, i. Tocolytics do appear to be effective for delaying labor for short intervals (24–48 h) and possibly for relieving hypertonic contractions. This may be of benefit with regard to corticosteroid therapy in an attempt to accelerate fetal lung maturation. Magnesium sulfate treatment is an initial loading intravenous dose of 4 g of a 20 per- cent solution, followed by an infusion of 2–3 g/h until uterine contractions stop (Cox et al. If ritodrine is chosen, a dose of 1–3 mg intravenously over 2 min should be used (Fernandez et al. Three primary indications for immunosuppressant use during pregnancy are: (1) organ transplant main- tenance; (2) treatment of autoimmune disease; and (3) systemic lupus. Most posttrans- plantation immunosuppressive regimens include prednisone with either azathioprine or cyclosporine. This raises the issue of the possible small risk of cleft palate associated with prednisone during pregnancy (see Chapter 13, Use of dermatologics during pregnancy). Neonates are at high risk for a transiently compromised immune system when exposed to the effects of immunosuppressant drug(s). Hence, risk of opportunistic infection is a danger until the infant’s immune system recovers following exposure to immunosuppressant therapy. Chronic long-term use of immunosuppressants has been associated with a higher inci- dence of neoplastic disease. Dose-dependent maternal side effects include bone marrow suppression, increased susceptibility to infection, alopecia, rash, gastrointestinal disturbances, arthralgias, hypersensitivity, pancreatitis, and toxic hepatitis (Berkowitz et al. Among 154 infants born to renal transplant recipients treated with azathioprine and prednisone throughout gestation, congenital anomalies occurred among 9 percent (four of 44) and 6. It is not possible to determine whether this rate of congenital anomalies is higher than expected because these mothers took other drugs in addition to azathioprine, and were ill. Prematurity and fetal growth retardation are increased in frequency among infants born to renal transplant recipients treated with azathioprine compared to infants born to healthy untreated women (Penn et al. Conditions result- ing in chronic renal failure, such as hypertension, diabetes, and other vascular diseases, are also associated with an increased frequency of prematurity and/or growth retarda- tion. An increased frequency of congenital anomalies (limb defects, ocular anomalies, and cleft palate) occurred among the offspring of experimental animals born to mothers treated with azathioprine in doses similar to those used medically in humans (Davison, 1994; Rosenkrantz et al. A case report of fatal neonatal pancytopenia was published of an infant born to a renal transplant recipient treated with azathioprine and prednisone during pregnancy (DeWitte et al. Neonatal lymphopenia and thrombocytopenia were reported in several other children born to women who received similar therapy (Davidson et al. Frequencies of acquired chromosomal breaks and rearrangements were increased in somatic cells of renal transplant recipients receiving azathioprine therapy and, tran- siently, in the infants of women who were given such treatment during pregnancy (Price et al. One child with two separate de novo constitutional chromosomal anomalies was born to a woman treated before and during pregnancy Immunosuppressants during pregnancy 289 with azathioprine and prednisone (Ostrer et al. Importantly, chromosome abnormalities in somatic cells cannot be extrapolated to interpret possible gonadal effects. It acts on cell- mediated immunity and T-cell-dependent humoral immunity (Hou, 1989). Cyclosporine, > 1000 in molecular weight, metabolizes to several amino acids ranging from 300 to 500 in molecular weight, that easily cross the placenta, resulting in detectable fetal levels (Claris et al. Maternal risks of cyclosporine use include hyper- tension, nephrotoxicity, hepatotoxicity, tremor, hirsutism, paresthesias, seizures, gout, and gingival hypertrophy (Berkowitz et al. Doses of cyclosporine need not be increased during pregnancy to maintain therapeutic levels although body weight and blood volume increase during pregnancy. One study found that cyclosporine doses needed to be lowered during the later stages of pregnancy (Flechner et al. Cyclosporine has been detected in breast milk, with breastfeeding contraindicated in patients who remain on cyclosporine (Flechner et al. Blood levels of cyclosporine decline to 50 percent at 48 h postpartum and should be undetectable at 1 week (Berkowitz et al. Thus, suppression of the infant’s immune system should be short-lived (Rose et al. One report found persistent (1–3 months) hematologic abnormalities in newborns from renal transplant mothers receiving cyclosporine A, aza- thioprine, and methylprednisolone (Takahashi et al. There have been no studies of the frequency of congenital anomalies among infants born to women treated with cyclosporine during pregnancy. The frequency of abortions (spontaneous and induced) and preterm deliveries was higher among cyclosporine- exposed pregnancies (Haugen et al. The frequency of malformations was not increased among rats and rabbits whose mothers were treated with doses within several multiples of the usual human therapeutic doses of cyclosporine. Maternal toxicity, fetal growth retardation, and intrauterine death were increased in frequency in both species at doses at or just above the maximum used therapeutically in humans (Brown et al. It decreases T-cell production by inhibiting enzymes essential to T-cell proliferation. Several small case series or case reports of the use of tacrolimus during pregnancies of transplant patients have been pub- lished (Jain et al. There were no mal- formations and pregnancy outcome was uneventful except for slightly reduced birth weight and transient immunocompromise. Among 100 pregnancies in women treated with tacrolimus, 71 infants were born and four (5. Another clinical series reported favorable outcomes in pregnancies maintained on tacrolimus (Garcia-Donaire et al. The frequency of congenital anomalies was not increased among mice exposed to the drug during embryogenesis, although litter weights were slightly reduced (Farley et al. Use of both prednisone, which is metabolized to prednisolone, and prednisolone during pregnancy has been studied intensively (see Chapter 13, Use of dermatologics during pregnancy). Acute rejection reactions to organ transplantation can be treated acutely and prophylactically with monoclonal antibodies. Untoward maternal effects include increased vulnerability to infection and neoplasm. Other side effects include tremor, headache, anaphylactic shock, chest pain, hypotension, neurospasm, pulmonary edema, gastrointestinal upset, rash, and allograft vascular thrombosis.

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Finally avana 100mg sale, the District Court in the Magic Secret case determined that the product was a cosmetic avana 200mg without prescription, not a drug proven 50mg avana, based on the conclusion that the claims were less exaggerated than in the other two cases buy avana 200 mg. The court held that the claim that the product caused an ‘‘astringent sensation’’ would not be regarded by consumers as doing anything other than altering their appearance (30). The advisory committee reports, together with a proposed monograph, were published in the Federal Register for public comment. Thus, in many of the advisory committee meetings and subsequent reports (33), as well as in the preambles to the tentative final (34) and final (35) monographs, there has been substantial discussion about the dividing line between a drug claim and a cosmetic claim for a cosmetic drug. It has proposed to reclassify ‘‘kills germs that cause odor’’ from the cosmetic category to drug status (39). It has proposed to set a limit on cosmetic use of hormone ingredients, above which they would automatically become drugs (40). Based upon new product technology and the conclusion that the consuming public was becoming increasingly sophisticated about skin-care products and their claims, the cosmetic industry gradually became more aggressive with cell rejuvenation and other antiaging promotional claims. As a result of research and development in the intervening years, new and more effective products were now on the market. First, in 1986 the well- known South African heart surgeon, Christiaan Barnard, made a tour of the United States on behalf of a cosmetic company to promote its skin care product, Glycel. Such a claim constitutes a representation that the product is intended to affect the structure or function of the body and thus makes the product a drug under 21 U. Therefore, we consider most of the anti-aging and skin physiology claims that you outline in your letter to be drug claims. For example, claims that a product ‘‘counteracts,’’ ‘‘retards,’’ or ‘‘controls’’ aging or the aging process, as well as claims that a product will ‘‘rejuvenate,’’ ‘‘repair,’’ or ‘‘renew’’ the skin, are drug claims because they can be fairly understood as claims that a function of the body, or that the structure of the body, will be affected by the product. For this reason also, all of the examples that you use to allege an effect within the epidermis as the basis for a tempo- rary beneficial effect on wrinkles, lines, or fine lines are unacceptable. The Associate Commissioner did offer some guidelines for cosmetic claims: While we agree with your statements that wrinkles will not be reversed or removed by these products... The label of such products should state that the product is intended to cover up the signs of aging, to improve the appearance by adding color or a luster to skin, or otherwise to affect the appearance through physical means.... However, we would consider a product that claims to improve or to maintain temporarily the appearance or the feel of the skin to be a cosmetic. For example, a product that claims to moisturize or soften the skin is a cos- metic. As a result, they have become extremely popular with consumers and gained substantial media and regulatory attention. First, the Review included only those products on the market prior to the final procedural regulations, published in June 1972. Second, the Review included only products marketed in the United States, and excluded those marketed abroad. As a result, it was impossible to market in the United States any nonprescription drug that had been sold abroad before the cutoff date or that was developed at any time, anywhere in the world, after the cutoff date. A number of products that are marketed as cosmetic drugs in the United States are classified solely as cosmetics in Europe. Cosmetic drugs can also be marketed in Europe with less restrictions than apply in the United States. Once a cosmetic drug is on the market in Europe, entry into the United States could become easier based upon international harmonization and mutual recognition principles. The second notice consisted of an analysis sup- porting the agency’s decision on the matter. Normally, regulation of cigarettes would have little or nothing to do with regulation of cosmetics. In a divided decision, the majority of the Court of Appeals agreed with the District Court that ‘‘no court has ever found that a product is ‘intended for use’ or ‘in- tended to affect’ within the meaning of the [Act] absent manufacturer claims as to that product’s use,’’ but then went on to decide the case on completely different grounds. Because of the inexorable impact of inflation, this has been tantamount to a substantial reduction in available resources. Virtually every option has been considered, from making no change at all to modest or even substantial legislative changes. Legal Distinction in the United States Between a Cosmetic and a Drug 237 Advocates of leaving the statute unchanged contend that, in general, there is already sufficient flexibility in the law to permit valid cosmetic claims and that any attempt to change the legislation might well result in a worse situation rather than a better one. Advocates of moderate change contend that all that would be needed is to insert the two words ‘‘and cosmetics’’ in the parenthetical exclusion that cur- rently exists in the structure/function prong of the drug definition—the approach taken by the Senate in April 1935 (68)—with the result that both food and cos- metics would be excluded from this portion of the definition. This would allow cosmetics to make structure/function claims comparable to the structure/function claims available to dietary supplements and conventional food (69). Advocates for a more extensive legislative approach offer a wide variety of potential statutory changes. Some advocate creating an entire new category of cosmetic drugs that would have its own separate regulatory requirements and prohibitions, halfway between those for drugs and those for cosmetics. Others argue for imposing the same premarket safety requirements for cosmetic drugs as for other drugs, but excluding claims from premarket review or approval. In the more than 30 years that this subject has been debated, no new legisla- tion has been proposed to address the matter. Even with legislation, whatever new statutory definitions or standards that might be enacted would inev- 238 Hutt itably raise close questions of judgment that would continue to evolve over time. Accordingly, legislation will not eliminate the uncertainty inherent in the cosmetic/drug distinction and thus is not the only or even the preferred solution to this matter. By assuring the safety of cosmetic ingredients through the Cosmetic Ingredient Review program (71), the cosmetic industry has substantially reduced concern about the safety of marketed cosmetic products. It is thus more likely that a reasonable approach to the cosmetic/drug distinction will be found through ad- ministrative and international action rather than through legislation. The legislative history of this prong of the drug definition is reviewed exhaustively in American Health Products Co. In Japan, there are also regulations covering cosmetic prod- ucts with pharmacological action, called quasidrugs, which are ranked between cosmetics and drugs (1). Each definition of drugs, cosmetics, and quasidrugs in the regulations of The Pharmaceutical Affairs Law (2) reads as follows: Drugs are articles as defined below. Articles (other than quasidrugs) that are intended for use in the diagno- sis, cure, or prevention of disease in humans or animals, and that are not equipment or instruments (including dental materials, medical sup- plies, and sanitary materials). Articles (other than quasidrugs and cosmetics) that are intended to af- fect the structure or any function of the body of humans or animals, and that are not equipment or instruments (paragraph 1, article 2 of the law). Quasidrugs are articles that have the purposes given below and exert mild actions on the human body, or similar articles designated by the Minister of Health and Welfare. They exclude not only equipment and instruments but also any article intended, in addition to the following purposes, for the use of drugs described in 2 and 3 above. Prevention of nausea or other discomfort, or prevention of foul breath or body odor. The term ‘‘cosmetic’’ means any article intended to be used by means of rubbing, sprinkling, or by similar application to the human body for cleaning, beautifying, promoting attractiveness, altering the appearance of the human body, and for keeping the skin and hair healthy, provided that the action of the article on the human body is mild. Such articles exclude the articles intended, besides the above purposes, for the use of drugs described in 2 or 3 above, and quasidrugs (paragraph 3, article 2 of the law). Cosmeceuticals in Japan A current definition of cosmeceuticals would cover those products ‘‘that will achieve cosmetic results by means of some degree of physiological action’’ (3). It is a well-known fact that Japan is ahead of most other countries in coping with the legal issues.

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See Cannabis sativa alcohol-related aggression and buy generic avana 100mg, 363 Federal Trade Commission Ethanol cheap avana 200 mg with amex. See Vision Festival of Life generic 50mg avana with visa, 1369 racial profiling and order avana 100 mg without prescription, 947–949 Fetal alcohol syndrome, 73, 297, 533–537 Ethinamate, 502 acetaldehyde and, 307 Ethiopia and coffee, 210, 279, 874–875 F characteristics of, 317–318 Ethnicity, 507–510. See also Cannabis sativa cocaethylene and, 267 Abuse Prevention and Control Act Gap junctions, 777 cocaine and, 898–899 of 1970 Garagiola, Joe, 1105 drugs effect on, 537–543 Forfeiture of assets. See Block grants Gas chromatography methods, 456, 457, tobacco and, 302 Forth Worth, Texas, Public Health Service 584 Fifth Amendment. Public Health Gasoline as inhalant, 644 Fiji, 677 Service Hospitals Gastrointestinal disorders Filipino Americans and alcohol, 254 Fourteenth Amendment. See Exclusionary alcohol and, 219–220, 304–308, 322 Fillmore, Kaye Middleton, 672 rule caffeine-related, 213, 214 Financial Action Task Force, 740–741 Fourth Amendment. See Metronidazole wine use in, 79 Gautier, Theophile, 592–593 Flashbacks, 293, 693, 1024 Franklin, Benjamin, 101–102 Gaviria, Cesar, 285, 286, 658–660 Flay, Brian R. See also Women and Fleming, Robert, 1124 of methamphetamines, 118–119 Florida substance abuse Freon. See Federal Trade Commission Fluorescence polarization immunoassays, Gene regulation, 577 Functional tolerance, 25 General Accounting Office, 190 626, 628–629 Funding. See also Government funding Fluorodeoxyglucose, 623–624 General Assistance welfare program, 1337 of parent prevention groups, 838 Generalized anxiety disorder, 139 Fluoxetine, 1026, 1027 for research, 964–965 alcohol and, 970, 1156, 1251 Genes, 577. See Pure Food assessment of, 551–555 vulnerability and, 232–234, 1316, 1318, and Drugs Act of 1906 epidemiology of, 555–559 1322–1324 Food and Drug Administration progression of, 554 Genome project, 578 alcohol advertising and, 39 Gaming industry. See Gamma-hydroxybutyrate on tobacco, 684, 685, 1204–1205 memory and, 710, 711 Gin, 407–408 Ford, Gerald R. See Corticosteroids anabolic steroids and, 126–127 opioids and, 816–817, 1122 Glucose metabolism Harvard University, 409, 980–981 imaging techniques and, 623–625 Hashish, 592–593, 593. See also Cannabis limbic system and, 688–689 H sativa opioids and, 297 Habit, defined, 22. See also Dependence Hawaii methamphetamine epidemic, Glucuronic acid, 448 syndrome 118–119 Glue, 644 Habitrol. See Patches (Nicotine) Hayyah, Jabir ibn, 406 Glutamate, 578–579 Habituation, 22, 399–400. See also Hazelden Foundation, 1134, 1244, alcohol effects on, 75 Dependence syndrome 1245–1246 neuronal network hypothesis and, 196 Haggard, Howard W. Glutathione, 448 International Opium Convention of 1912, Department of Health and Human Glutethimide, 59, 579, 579 198 Services Glycine Mexico and, 726–727 Health care professionals. See also drug metabolism and, 448 Haight-Ashbury district, methamphetamines Physicians neurotransmission and, 777–779, and, 116 addiction in, 629–633 780–781 Haight-Ashbury Free Clinics, Inc. See Cardiovascular Goodlett, Douglas, 914 antipsychotics for, 137 disorders Gordon S. See Prevention yippies and, 1369–1370 methadone treatment and, 720 Great Awakening, 1077–1078 Hammurabi’s code, 78 needle exchange programs and, 763, 766, Greece, ancient Handsome Lake (Religion), 81 767 betel nut use in, 183 Hansen, William B. See Genetics Growing Healthy, 478–479 in the Netherlands, 769–771 Herodotus, 144 Guanosine triphosphate-binding proteins. State of Michigan (1991), 697 Heroin, 441, 594–596, 595 Guarana seeds, 210 Harmful use addiction to, 809, 810–811, 1173–1174 Guatemala criteria for, 388, 389 from Afghanistan, 655 crop control in, 664 defined, 654–655 allergic response to, 105 as opium source, 655–656, 657, Harmine, 157 barbiturates with, 162–163 660–661, 664, 1054 Harrison, Francis B. See Terrorism and drugs Harrison Narcotics Act of 1914, 349, Britain Gum (Nicotine), 785–786, 788, 1088, 591–592 abuse in, 199–204, 599 1203–1204, 1255 Anslinger, Harry J. See Comprehensive Alcohol health risks of, 15, 881 subgroups of, 508–509 Abuse and Alcoholism Prevention, ibogaine and, 622 vulnerability and, 1325 Treatment and Rehabilitation Act interdiction of, 441 Histamine of 1970 introduction of, 815 barbiturates and, 105 Human immunodeficiency virus. See Clinical research legalization of, 881, 881–882 neurotransmission and, 777–779 Huss, Magnus, 101–102, 103, 398 memory and, 712 History Hutchison, Sir Robert, 336 from Mexico, 655, 656–657 of alcohol, 77–86 Hydromorphone, 618, 618, 832 from the Middle East, 655 alcoholism term, 101–104 5-hydroxytryptamine. See Henbane in Netherlands, 769–770 of drug policies, 885–886 Hyothalamic pituitary adrenal axis, from Pakistan, 655 of heroin treatments, 1181 1331–1332 during pregnancy, 893–897 of opioids, 813–820 Hyperactivity. See Allergies treatment for abuse (See Heroin addiction Hypertension, 321, 1351–1352 History taking. See Diagnosis of substance treatment) Hypnosis, 1089, 1200, 1242–1243 from Turkey, 655 abuse Hypnotics. See Methamphetamines vulnerability and, 1326–1327 Addicts Index, 199, 201–204, 1011–1012 High School Senior Survey, 36, 496, 498, Iceland and alcohol, 83 British policy and, 198–199, 1010 Icelandic Model, 1246 600–610, 602–607 heroin treatment and, 597–598 alcohol, 497 Ifex. See Ifosfamide Rolleston Committee and, 1010, Ifosfamide, 220 cannabis, 498 1011–1012 cocaine, 499 IgE. See Mate´ decriminalization and, 701–702, 905 614, 890–891 dropouts and, 422–423 I’ll Quit Tomorrow, 273 Hong Kong and methamphetamines, 119 Illegal Immigration Reform and Immigrant drug risks and, 878 Hoover, Herbert C. See Inpatient treatment alcohol pharmacotherapy and, 1155–1156 Hinduism and alcohol beliefs, 80 House of Lords (Britain), 200 for cocaine addiction, 1254–1255 Hippocampus, 194–195, 687–688 House of Refuge, 566 Immediate hypersensitivity, 104–105 Hirsch, Amy E. See Congress Immigration Hispanic Americans, 610–613 Housing, alcohol- and drug-free, 67–70, 585 border management and, 190–191 adolescent substance abuse and, 34, How to Form a Families in Action Group in from China, 253 608–609 YourCommunity, 924 inebriate asylums and, 1119–1120 cultural considerations for, 506 Hubbard, L. Ron, 379 from Latin America, 610–611 gangs among, 566–567, 567, 568, 571, Hughes, Harold E. See Addicted babies International Certification Reciprocity Border Patrol (See Border Patrol) Infectious diseases. See Economic conditions purposes of, 386 allergic responses and, 104–106 Information Agency, 1274, 1277–1278 substance abuse definition, 400 tobacco and, 302 Information regulation, 683, 685 International drug control. See also Source Impaired control and dependence syndrome, Informed consent (Clinical testing), 966–967 countries for illicit drugs 391 Ingersoll, John E. See International Narcotics Control Intravenous route of administration International drug trafficking. See Source Strategy Board complications from, 342–344 countries for illicit drugs Incentive motivation. See Social Security pharmacokinetics and, 849 286 programs; Welfare viral hepatitis and, 313 International Narcotics Control Strategy Independent reinforcers and behavioral Injuries. See Accidents and injuries Board, 943 economics, 168–170 ‘‘Inner child’’ concept, 272 report, 659–660, 1055 India Inner City Families in Action, 924–925 Single Convention on Narcotic Drugs and, alcohol use in, 80, 145 Inpatient treatment, 1216. See also 1033, 1034, 1035 betel nut use in, 183 Therapeutic communities International sources of illicit drugs. See cannabis use in, 144, 185, 575, 592 Betty Ford Center, 1139 Source countries for illicit drugs as opium source, 660–661, 821, 833, for cocaine addiction, 1159–1160, 1162 International Students in Action, 925 875–876 group therapy and, 1238 International Symposium on the Economic opium use in, 143 health insurance and, 1129 and Social Costs of Substance as tea source, 1076 vs. See Diagnosis of Industry and workplace, 633–640 1138–1139 substance abuse alcohol-related accidents, 9 Institutional accreditation. See also Overdose drug testing and, 450, 455 and accreditation from alcohol, 70–71 drug user data, 634 Institutional Review Board, 966 from cannabis, 704 homelessness and, 614 Insufflation, complications from, 341 defined, 22 productivity and substance abuse, Insulin, opioids and, 297 phencyclidine, 868–869 932–933 Interferon-a, 295 public (See Public intoxication) solvents and, 335 Internal Revenue Service. Intra-arterial injection, 342 zero tolerance and, 1372 Department of Treasury Intracranial hemorrhages. MacArthur Kubacki, Raymond, 584 pharmacokinetics and, 849 Foundation, 450 Ku¨mmelvasser, 407–408 Investment in Treatment for Alcohol and Johns Hopkins University, 1257 Kumys (Beverage), 145 Other Drug Problems: It Pays Johnson, Ben, 123–124 (Report), 757–758 Johnson, C. See Clinical research, Iran Joint Inter-Agency Task Forces, 442 laboratory studies ancient, alcohol use in, 78, 164–165 Jones, Ernest, 549 Lactation, methadone and, 807 as opium source, 660–661, 663, Jones, Jim, 379 Lager beers, 165–166 665–666, 1054 Joplin, Janis, 435 LaGuardia, Fiorello, 287 Ireland, 166–167, 490, 1307 Journal of Addiction and Mental Health, 246 Lamivudine, 1061 Irreversible antagonists, 135 Journal of Addictive Diseases, 108 Lancet, 533 Islam, 377, 813 Journal of Community Psychology, 481 Laos Isocarboxazid, 136 Journal of Studies on Alcohol, 1012–1013 as opium source, 143, 144, 579–581, Isopropyl alcohol.

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The use of benzodiazepines listed in Martindale avana 100 mg online, along with their half-life buy avana 200 mg fast delivery, route(s) of administration purchase 50mg avana otc, and normal range of doses generic avana 50mg with visa, is presented in Table 3. Depression (2) aThe number in parentheses represents the number of benzo- diazepines listed in Martindale that are used to treat this disorder. Drowsiness, sedation, and ataxia are the most frequent adverse effects of benzodi- azepine use. Less common adverse effects include ver- tigo, headache, mental depression, confusion, slurred speech, tremor, changes in libido, visual disturbances, urinary retention, gastrointestinal disturbances, changes in saliva- tion, and amnesia. Rare events include paradoxical excitation leading to hostility and aggression, hypersensitivity reactions, jaundice, and blood disorders. With very high doses, hypotension, respiratory depression, coma, and occasionally death may occur. Daily benzodiazepine use has been associated with dependence, tolerance, and after discontinuation, withdrawal symptoms in many individuals. The likelihood of dependence appears higher in individuals with a history of drug or alcohol dependence and personality disorders. Because devel- opment of dependence cannot be easily predicted, abrupt discontinuation of use is not recommended. Symptoms of withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances, nausea, vomit- ing, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and ortho- static hypotension. If long-term use of benzodiazepines occurs, professional assisted withdrawal is recommended. Within the class, however, lipophilicity measured as the oil:water coefficient can differ over a 50-fold range. Due to their lipophilicity the benzodiazepines have relatively high plasma protein binding (70–99%) and relatively large volumes of distribution (0. In gen- eral, the percent plasma protein binding and volume of distribution increase as does the oil:water partition coefficient. The differences in lipophilicity can have a major impact on the pharmacokinetics of the benzodiazepine. When diazepam is given as a single dose, however, it rapidly redistributes to nonplasma (lipid) compartments, the a elimination phase. It then slowly distributes back into the plasma compartment at subtherapeutic concentrations with a long terminal elimination half- life. Therefore, single doses of diazepam can be used as a short-term preanesthesia med- ication, whereas daily dosing will result in accumulation during the terminal elimination phase and provide long-acting therapy. Drug Interactions with Benzodiazepines 7 Table 3 Uses of Benzodiazepines Listed in Martindale Half-Life Route(s) of Usual Generic Name (h)a Administration Dose (mg) Usesb Adinazolam short — — 1, 8 Alprazolam 11–15 oral 0. The benzodiazepines are well absorbed from the gastrointestinal tract, which allows for oral dosing of benzodiazepines (Table 3). The plasma concentration benzodiazepines, or their primary phar- macodynamically active metabolites, correlates well with the dose of benzodiazepine administered (Fig. There are structural differ- ences between them, and these differences will affect the manner in which the benzo- diazepine is metabolized, and thereby have an impact on their individual susceptibility to drug interactions. In all but two of the commercially avail- able benzodiazepines, the nitrogens in the diazepine ring are in the 1,4 position. Cloba- zam has nitrogens in the 1,5 position of the diazepine ring; tofisopam has nitrogens in the 2,3 position of the diazepine ring (Fig. The range of (A) therapeutic doses and (B) plasma concentrations of selected ben- zodiazepines. Therefore, with the exception of clobazam and tofisopam, these are 5-aryl-1,4- benzodiazepines. Following the initial synthesis of chlordiazepoxide by Sternbach in 1957, and its introduction as a therapeutic agent in 1961, a number of benzodiazepines have been introduced onto the market. The initial modifications involved changes in the substit- uents on the diazepine ring. Modifications along this line first led to the development of diazepam, flurazepam, and oxazepam. Substitution of the benzene with a thieno group produced the 1,4-thienodiazepines (Figs. While most benzodiazepines have a phenyl substituent at the 5 position of the diazepine ring, bromazepam has a 2- pyridinyl substituent, and tetrazepam has a 1-cyclohexen-1-yl substituent at this posi- tion (Fig. Bentazepam, with a benzylthieno group fused to the diazepine ring, and brotizolam with both the thieno and triazolo groups are unique 1,4-thieno- diazepines (Fig. An electron-withdrawing group is required at the 7 position of the benzene (or thieno) group (R10 for oxazolo and R8 for triazolo or imidazo). These are generally the halides chloride, and occasionally bromide, or a nitroso group. Basic Metabolism of Benzodiazepines Most of the 5-aryl-1,4-benzodiazepines are metabolized by N-dealkylation at the N-1 position and hydroxylation at the 3 position (Fig. Structure of “odd” benzodiazepines that could not easily be described in Tables 5 or 6. In many cases the N-dealkyl metabolite is nordiazepam (N-desmethyldiazepam, nordiazam) (Fig. The 3-hydroxyl group is then conjugated, usually with glucuronide, resulting in an inactive metabolite. Clorazepate is nonenzymatically decarboxylated to nordiazepam at the low pH of the stomach. The 4,5-oxazolo-benzodiazepines, such as ketazolam, oxazolam, and mexazolam, have the 4,5-oxazolo cleaved. Adinazolam is successively N-demethylated at the1-dimethylaminomethyl constituent to N-desmethyladinazolam and didesmethyladinazolam. The first N-demethyl product has a higher area under the curve than the parent drug and higher affinity for the central benzodiazepine receptors. Deamination of N-desmethyladinazolam with eventual 1-hydroxylation to 1-hydroxy- alprazolam or side chain cleavage to estazoalm have been described in the mouse, but does not appear important in humans (10,11). Although both metabolites have minor activity, they are not formed in sufficient amounts to contribute to the pharmacologic activity of estazolam. The 7-nitroso-benzodiazepines, clonazepam, flunitrazepam, and nitrazepam, are metabolized by successive reduction of the nitroso-group to the amine and subsequent N-acetylation of the amine to the corresponding acetamido-group (Fig. N-Dealkylation at the 1 position of the diazo-ring is also a prominent route of metabolism for flunitrazepam. Clonazepam and flunitrazepam can also be hydroxylated at the 3 position of the diazoring. With nitrazepam, oxidative metab- olism at the diazo ring results in ring cleavage; this can be followed by hydroxylation of the phenyl (B) ring (Fig. The routes of metabolism of other benzodiazepines, bromazepam (ring cleavage and 3-hydroxylation), clobazam (N-dealkylation and c-ring hydroxylation), clotiazepam (N-dealkylation and side chain hydroxylation), and loprazolam (N-dealkylation and spontaneous hydrolysis to polar compounds) have been described (Fig.

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