O. Achmed. Boston University.

To reduce the risk of Leukotriene modifiers are used for the prevention and long-term adverse reactions from control of mild asthma generic top avana 80 mg overnight delivery. Zafirlukast’s absorption is de- creased by food order top avana 80mg with visa, so it should be given 1 hour before or 2 hours af- ter meals buy 80 mg top avana with visa. In general, this class of drugs is metabolized, induced, or inhibited by the cytochrome P450 en- zyme system, which is important for establishing drug interac- tions. Caution required Zileuton is contraindicated in the patient with active liver disease. Closely monitor the patient with liver impairment who’s taking zafirlukast for adverse reactions; he may require a dosage adjust- ment. Leukotrienes can The leukotriene receptor antagonists zafirlukast and montelukast be very trying for prevent the D4 and E4 leukotrienes from interacting with their re- asthma sufferers. The leukotriene formation Montelukast, inhibitor zileuton inhibits the production of 5-lipoxygenase, there- zafirlukast, and zileuton help to inhibit by preventing the formation of leukotrienes. Pharmacotherapeutics Leukotriene modifiers are primarily used to prevent and control asthma attacks in the patient with mild to moderate disease. If carbamazepine, pheno- barbital, phenytoin, primidone, or rifampin is used with leuko- trienes, the effectiveness of the leukotrienes could be reduced. They’re also used in an triene modifiers include: adult or child with mild to moderate persistent asthma. Drugs in • headache this class include: • dizziness • cromolyn • nausea and vomiting • nedocromil. Pharmacodynamics These drugs stabilize the mast cell membrane, possibly by inhibit- ing calcium channels, thus preventing the release of inflammatory mediators. Mast cell stabilizers are used for the prevention and long-term control of asthma symptoms. Inhaled mast cell stabi- lizers may cause these Drug interactions adverse reactions: Interactions are uncommon when using inhaled forms. Methylxanthines, also called xanthines, are used to treat respira- tory disorders. Types of methylxanthines Methylxanthines include anhydrous theophylline and its deriva- tive salt aminophylline. Pharmacokinetics The pharmacokinetics of methylxanthines vary according to which drug the patient is receiving, the dosage form, and the ad- ministration route. Absorption When theophylline is given as an oral solution or a rapid-release tablet, it’s absorbed rapidly and completely. High-fat meals can in- crease theophylline concentrations and the risk of toxicity. Gastric measures Absorption of some of theophylline’s slow-release forms depends on the gastric pH. High-fat meals can Distribution increase the Theophylline is approximately 56% protein-bound in adults and risk of 36% protein-bound in neonates. It readily crosses the placental theophylline barrier and is secreted in breast milk. In adults and children, about 10% of a dose is excreted unchanged in urine; therefore, no dosage adjustment is required in patients with renal insufficiency. Because an infant has an immature liv- er with reduced metabolic functioning, as much as one- half of a dose may be excreted unchanged in his urine. Levels must be assessed when drug therapy is initiated, when the dosage is changed, and when drugs are added or removed from the patient’s regimen. Relax and breathe deeply Methylxanthines decrease airway reactivity and relieve bron- chospasm by relaxing bronchial smooth muscle. Theophylline is believed to inhibit phosphodiesterase, resulting in smooth-muscle relaxation, bronchodilation, and decreased inflammatory media- tors (namely mast cells, T cells, and eosinophils). A stimulating conversation In nonreversible obstructive airway disease (chronic bronchitis, emphysema, and apnea), methylxanthines appear to increase the sensitivity of the brain’s respiratory center to carbon dioxide and to stimulate the respiratory drive. Pumping you up In chronic bronchitis and emphysema, these drugs reduce fatigue Memory of the diaphragm, the respiratory muscle that separates the ab- jogger domen from the thoracic cavity. They also improve ventricular function and, therefore, the heart’s pumping action. How can you remember what theo- phylline and its salts Pharmacotherapeutics are used to treat? Adverse reactions to methylxanthines Adverse reactions to methylxanthines may be transient or symptomatic of toxicity. John’s wort, and char- broiled meats) increase theophylline metabolism, thus de- creasing its serum level and possibly its effectiveness. Omalizumab Pharmacokinetics Omalizumab is slowly absorbed after subcutaneous injection. It’s metabolized by the liver, but the rate of metabolization depends on IgG clearance. Pharmacodynamics Omalizumab inhibits the binding of IgE to its receptor on the mast cell and basophils. This in turns inhibits the release of allergic substances which potentiate asthma symptoms. Pharmacotherapeutics Omalizumab is used in patients with moderate-to-severe asthma with a positive skin test and insufficient control on inhaled corti- costeroids. Adverse reactions to monoclonal antibodies Adverse reactions to monoclonal antibodies • allergic reaction. However, in rare • sinusitis cases, delayed anaphylactic reactions (occur- • headache ring more than 24 hours after administration) • pharyngitis may occur. Expectorants Expectorants thin mucus so it’s cleared more easily out of the air- ways. Pharmacodynamics By increasing production of respiratory tract fluids, expectorants reduce the thickness, adhesiveness, and surface tension of mucus, making it easier to clear from the airways. Expectorants also pro- vide a soothing effect on the mucous membranes of the respirato- ry tract. Pharmacotherapeutics Adverse Guaifenesin is used to relieve symptoms due to ineffective, pro- reactions to ductive coughs from many disorders, such as: • bronchial asthma guaifenesin • bronchitis Adverse reactions to • colds guaifenesin include: • emphysema • nausea • influenza • vomiting (if taken in • minor bronchial irritation • sinusitis. Types of antitussives Antitussives are typically used to treat dry, nonproductive coughs. The major antitussives include: • benzonatate • codeine • dextromethorphan • hydrocodone bitartrate. Removing the sensation Benzonatate acts by anesthetizing stretch receptors throughout the bronchi, alveoli, and pleurae. Taking direct action Benzonatate Codeine, dextromethorphan, and hydrocodone suppress the can be useful cough reflex by direct action on the cough center in the medulla during diagnostic procedures when of the brain, thus lowering the cough threshold. Pharmacotherapeutics The uses of these drugs vary slightly, but each treats a serious, nonproductive cough that interferes with a patient’s ability to rest or carry out activities of daily living. Put it to the test Benzonatate relieves cough caused by pneumonia, bronchitis, the common cold, and chronic pulmonary diseases such as emphyse- ma.

Major reported indications are for asthma purchase top avana cheap, No data were available to the Working Group cheap top avana 80 mg. Various forms of processed and unpro- and kaempferol order top avana on line amex, the two favonoid constituents cessed ginkgo leaf are present in dietary supple- that are present in high levels in G. It is possible that an inhib- the population was limited to people aged > 75 itory efect on topoisomerase is the underlying years and compliance in the placebo and ginkgo mechanism for quercetin- or kaempferol-associ- treatment groups was only about 60%. Summary of Data Reported risk estimates for cancers of the breast, colorectum, lung, prostate, and for urothelial cell carcinoma, 5. Increased Ginkgo biloba, also known as the “fossil tree,” risk for cancers of the breast and colorectum is the oldest living tree. Genotoxicity and/or topoisomerase inhibi- tion may be mechanisms of carcinogenicity asso- ciated with G. Tere is sufcient evidence in experimental In male mice receiving the extract, the incidence animals for the carcinogenicity of Ginkgo biloba of thyroid follicular cell adenoma exceeded the extract. In female rats, the incidences of thyroid follicular cell adenoma, thyroid follicular cell carcinoma, and nasal respiratory epithe- lium adenoma exceeded the range for historical controls in the study series. Genetic efects of the favonols quercetin, kaempferol, and galangin on Chinese hamster ovary cells in vitro. Guidelines of the Federal Committee of J Environ Sci Health C Environ Carcinog Ecotoxicol Physicians and Health Insurances on the prescrip- Rev, 25(3):211–44. Te evolution, ecology, and culti- cones in Ginkgo biloba dietary supplement crude vation of Ginkgo biloba. Quantitative determination of major active tion in vivo and by the intestinal microfora in vitro. Ginkgo biloba extract for age-related Herrschaf H, Nacu A, Likhachev S, Sholomov I, Hoerr macular degeneration. Liquid chromatography/ kidney or urinary bladder in rodents and some other atmospheric pressure chemical ionization mass spec- substances. Botanical dementia of the Alzheimer’s type or multi-infarct medicines: the desk reference for major herbal supple- dementia. Natl Toxicol dietary favonoids myricetin and fsetin act as dual Program Tech Rep Ser, 578(578):1–183. An Encyclopedia of Chemicals, Drugs, extract on lopinavir, midazolam and fexofenadine and Biologicals. Associations of herbal and specialty supple- Peters H, Kieser M, Hölscher U (1998). Cancer Epidemiol on intermittent claudication–a placebo-controlled, Biomarkers Prev, 18(5):1419–28. Detection of allergenic urushiols in afer oral administration to rats of a Ginkgo biloba Ginkgo biloba leaves. Ginkgo biloba extract for the in Alzheimer’s disease: from action mechanisms to treatment of intermittent claudication: a meta-anal- medical practice. Involvement of rat cytochrome 1A1 in the placebo controlled study of Ginkgo biloba extract biotransformation of kaempferol to quercetin: rele- (‘tanakan’) in elderly outpatients with mild to moderate vance to the genotoxicity of kaempferol. Plasma levels and distribution of use in Canada: analysis of the National Population favonoids in rat brain afer single and repeated doses Health Survey. Appl Microbiol memory enhancing efects of a Ginkgo biloba/Panax Biotechnol, 64(4):465–72. J Clin Pharmacol, Comparative pharmacokinetics and bioavailability of 46(11):1290–8. Ginkgo biloba and ovarian cancer preven- quality control of Ginkgo biloba leaves, extracts, and tion: epidemiological and biological evidence. Plant drug analysis: a thin layer Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans chromatography atlas, 2nd Ed. Te cultural history of the Intoxicating long pepper; Intoxicating pepper; use of kava has been reviewed by Singh (1992). Kao; Kava kava rhizome; Kava root; Kavapiper; In the past, traditional use of kava was Kavapyrones; Kavarod; Kavasporal forte; Kave- widespread, but, in certain cultures, custom kave; Kawa; Kawa kawa; Kawa pepper; Kawa determined who could use kava and for what Pfefer; Kew; Long pepper; Macropiper latifo- purposes. In recent years, as part of the processes lium; Malohu; Maluk; Maori kava; Meruk; Milik; of modernization, major changes have occurred Pepe kava; Piperis methystici rhizome; Rhizoma with regard to who uses kava, and where and piperis methystici; Sakaua; Sakau; Tonga; Yagona; how it is consumed. In some places, kava is now Yangona; Yaqona; Yongona being consumed much like alcohol in western countries, as a beverage that is drunk socially (b) Description (McDonald & Jowitt, 2000). Due to its (a) Nomenclature traditional use as a ritual beverage known for promoting relaxation and a sense of well-being, Chem. Name: Kava-kava resin (8Cl) in Polynesia, Melanesia, and the Federated States Botanical name: Piper methysticum G. Te leaves are heart-shaped, pointed, 8–25 cm Family: Piperaceae in length, and smooth and green on both sides. Forst between stem joints), colour of stems, intensity of leaf colour, and quality of the root. Te dried rhizome consists of irregular, transverse and longitudinal pieces, varying considerably in size and shape: 3–20 cm in length and 1–5 cm in diameter. Te outer surface is light yellowish or greyish-brown, longitudinally wrin- kled, with large, whitish, circular root scars. When dried, the rhizome consists of approximately 43% starch, 20% fbres, 12% water, 3. Te bioac- tive principles of kava rhizome are mostly, if not From Spohn (2013) entirely, contained in the lipid-soluble resin. Te © Roland Spohn compounds of greatest pharmacological interest referred to as the stump. Te stump is knotty, are the substituted α-pyrones or kavapyrones, thick, and sometimes tuberous and ofen contains commonly known as kavalactones. At least 15 holes or cracks created by partial destruction of lactones have been isolated from kava rhizome. A fringe of lateral roots up to 2–3 Te following six compounds are present in m in length extends from the pithy rhizome. Te the highest concentrations and account for roots comprise a multitude of ligneous fbres and approximately 96% of the lipid resin: kavain, consist of > 60% starch. Rhizome colour varies dihydrokavain, yangonin, desmethoxyyan- from white to dark yellow, depending upon the gonin, methysticin, and dihydromethysticin amount of kavalactones contained in the lemon- (see Fig. Te plant is usually harvested when chalcones and other favanones, and conjugated it is about 2–2. Te cultivation and selection of kava has In the past, “kavain” has been used to indi- produced numerous varieties or cultivars recog- cate a racemic mixture resulting from chem- nized by diferences in the internodes (space ical synthesis, and “kawain” for the naturally 118 Kava Fig. Singh (2004a) mentioned adulteration literature, but the term kavain has started to with sawdust, four, or soil. Kava may contamination with afatoxin B1 in four samples also be sold as an unpeeled rhizome covered of ground kava was 0. For example, the alkaloid pipermethys- tine was not detectable in some commercial kava 1. Uses described in traditional both kava and its extracts obtained by aqueous medicine, but not supported by experimental or acetone or aqueous methanol, and supercritical clinical data, are treatment of asthma, common fuid extraction – typically with carbon dioxide cold, cystis, gonorrhoea, headaches, menstrual modifed with methanol as solvent – were irregularities, urinary infections, and warts.

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It belongs to the group of 11S globulins buy top avana with visa, with sedimentation coefficients between 11S and 14S (molec- ular weight = 300–400 kDa) discount 80mg top avana free shipping. Legumin has a complex globular structure that is made up of six pairs of subunits discount 80mg top avana fast delivery, with each subunit consisting of disulphide-linked acid (molecular weight = 40 kDa) and basic (molecular weight = 20 kDa) polypeptides (41). The composition of the protein depends on the source from which it is derived and can have a signifi- cant influence on the preparation of nanoparticles. Therefore, batch-to-batch variation can have a significant influence on the nanoparticle characteristics. The batches with higher molecular weight fractions resulted in larger particle size and higher polydispersity. This can be overcome by using a two-step desolvation process to remove the large molecular weight aggregates (43). Similar to animal/human proteins, the plant proteins also contains various molecular weight fractions. In addition, the presence of pigments can also interfere with the preparation of nanoparticles. This necessitates a purification of the protein polymers before the preparation of nanoparticles (37). Protein Solubility The solubility of the protein in aqueous or organic solvent dictates the choice of the method and the nanoparticle characteristics. Protein nanoparticles are prepared by utilizing the differential solubility of the protein in aqueous and nonaqueous solvents, as proteins can fold or unfold depending on the polarity of the solvent (1). The pH value of the aqueous solution was found to have a significant influence on the size of the albumin nanoparticles (45). At a pH away from the pI, the hydrophobic interactions in the protein are reduced, result- ing in lesser aggregation (26). Type A gelatin has a pI of 7 to 9, whereas type B gelatin has a pI of 4 to 7 (Table 1). Hence, the source of gelatin can influence the size, zeta-potential, and drug loading in gelatin nanoparticles (46, 47). For type A gelatin and type B gelatin, pH 7 and pH 3, respectively, were found to be critical for the preparation of nanoparticles (48). At these pH values, the strengths of electrostatic interactions are maximized for obtaining stable particles with optimal drug loading. Furthermore, in the case of gelatin, due to its high viscosity, a preheating (40◦C) step was used to prepare smaller size nanoparticles (48). However, a higher temperature (50◦C) was found to increase the particle size, due to the excessive unfolding of the protein (48). In a comparative study between different strengths of gelatin (75, 175, and 300 bloom strength), it was found that 300 bloom strength was optimal in terms of particle size, polydispersity index, and drug encapsulation (48). Surface Properties One of the significant advantages of protein polymers is the presence of numerous surface functional groups that can be used for modifying the surface of the pro- tein nanoparticles to alter their biodistribution or biocompatibility or drug loading and/or improve their enzymatic stability (Fig. Particle size and surface proper- ties of protein nanoparticles depend on the number of disulfide bonds, number of thiol groups, degree of unfolding, electrostatic repulsion among protein molecules, pH, and ionic strength. The surface amine groups can be cross-linked using cross-linkers such as glutaraldehyde (Fig. The protonation or deprotonation of the surface amine groups can influence the degree of cross-linking (46). An increase in cross-linker concentration generally decreases the particle size of protein nanoparticles due to the formation of denser particles (48). Cross-linking helps in controlling the drug release from protein nanoparticles, as well as stabilizing the particles against prote- olytic breakdown. The surface functional groups can also be used to load drugs by electrostatic interactions (47). Kommareddy and Amiji (50) thiolated the surface amine groups to form disulfide bonds in gelatin nanoparticles. These nanoparticles can release their cargo under the highly reduc- ing environment in the tumor cells (50). Similarly, ligands have been attached to the surface of protein nanoparticles for drug targeting to specific tissues in the body (51,52). The surface functional groups in the protein can also directly interact with the biological membrane. Gliadin nanoparticles have been reported to show bioad- hesive property in the intestinal membrane, where the surface amino acids adhered to the intestinal membrane through hydrogen bonding and hydrophobic interac- tions (39). Drug Properties The physicochemical properties of the drug, such as solubility, log P, and molec- ular weight, influence the drug loading in protein nanoparticles. The drugs can be loaded through encapsulation in the nanoparticle or by the interaction of drug with the protein through covalent or noncovalent interactions. Highly hydrophobic drugs have been found to interact with cysteine residues in the albumin through hydrophobic interactions (19). For example, paclitaxel a highly hydrophobic drug is loaded in albumin nanoparticles by mixing albumin and paclitaxel in a high pressure homogenizer (53). A large number of drugs are known to bind to serum albumin, and hence albumin appears to be a promising carrier (19). In the case of gelatin nanoparticles, higher encapsulation efficiency was reported for hydrophilic drugs than for hydrophobic drugs (46). Doxorubicin was adsorbed onto gelatin- coated iron oxide nanoparticles for targeting using magnetic field (47). It was found that the adsorption of cationic doxorubicin onto gelatin nanoparticles increased with increasing pH due to the negative charge of gelatin at higher pH. On the other hand, the encapsulation of doxorubicin in gelatin-coated iron oxide nanopar- ticles showed a slower drug release than surface-adsorbed nanoparticles (47). The release of hydrophilic drugs from gelatin nanoparticles was found to occur by zero- order kinetics, whereas hydrophobic drugs were released by pseudo zero-order kinetics (46). It was found that hydrophobic drugs are slowly released because of their higher affinity to hydrophobic gliadin. On the other hand, hydrophilic drugs showed a burst release followed by slower drug diffusion from the nanoparticle matrix. High encapsulation efficiency (90%) of bone mor- phogenetic protein was reported with albumin nanoparticles (55). Unlike synthetic polymers, macromolecular drugs can be loaded in protein nanoparticles under milder conditions. It is generally recognized that increasing pro- tein unfolding and decreasing intramolecular hydrophobic interactions are criti- cal determinants for nanoparticle formation (26). During nanoparticle formation, the protein undergoes conformational changes depending on its composition, con- centration, preparation conditions (such as pH, ionic strength, solvent), and cross- linking methods. Usually, surfactants are required to stabilize the nanoparticles of water-insoluble proteins such as gliadin (40). The unfolding of the proteins dur- ing the preparation process exposes interactive groups such as disulfides and thi- ols. Subsequent thermal or chemical cross-linking leads to the formation of cross- linked nanoparticles with entrapped drug molecules.

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Beta-blockers may precipitate asthma and should not be used in patents with asthma or a history of obstructve airways disease discount top avana 80mg online. Some generic top avana 80mg on-line, including atenolol order genuine top avana, have less efect on β2 (bronchial) receptors and are therefore relatvely cardioselec- tve. Although they have less efect on airways resistance they are not free of this efect and should be avoided. Beta-blockers slow the heart and may induce myocardial depres- sion, rarely, precipitatng heart failure. They should not be given to patents who have incipient ventricular failure, second-or third- degree atrioventricular block, or peripheral vascular disease. Beta-blockers should be used with cauton in diabetes since they may mask the symptoms of hypoglycaemia, such as rapid heart rate. Beta-blockers enhance the hypoglycaemic efect of insulin and may precipitate hypoglycaemia. Calcium-Channel Blockers: A calcium-channel blocker, such as verapamil, is used as an alternatve to a beta-blocker to treat stable angina. Calcium- channel blockers interfere with the inward movement of calcium ions through the slow channels in heart and vascular smooth muscle cell membranes, leading to relaxaton of vascular smooth muscle. Myocardial contractlity may be reduced, the formaton and propagaton of electrical impulses within the heart may be depressed and coronary or systemic vascular tone may be diminished. Calcium-channel blockers are used to improve exercise tolerance in patents with chronic stable angina due to coronary atherosclerosis or with abnor- mally small coronary arteries and limited vasodilator reserve. Calcium-channel blockers can also be used in patents with unstable angina with a vasospastc origin, such as Prinzmetal’s angina and in patents in whom alteratons in cardiac tone may infuence the angina threshold. Unstable Angina: Unstable angina requires prompt aggressive treatment to prevent progression to myocardial infarcton. Inital treatment is with acetylsalicylic acid to inhibit platelet aggregaton, followed by heparin. Prinzmetal’s Angina: Treatment is similar to that for unstable angina, except that a calcium-channel blocker is used instead of a beta-blocker. Atenolol* Pregnancy Category-D Schedule H Indicatons Angina and myocardial infarcton; arrhythmias; hypertension; migraine prophylaxis. Dose Oral Adult- 50 mg once daily, increased if neces- sary to 50 mg twice daily or 100 mg once dai- ly. Angina: 50 mg daily administered alone or with a diuretc, dose can be increased to 100 mg (over 100 mg has no added advantage). Contraindicatons Asthma or history of obstructve airways disease (unless no alternatve, then with extreme cauton and under specialist supervision); uncontrolled heart failure, Prinzmetal angina, marked bradycardia, hypotension, sick sinus syndrome, second- and third-degree atrioventricular block, cardiogenic shock; metabolic acidosis; severe peripheral arterial disease; pheochromocytoma (unless used with alpha- blocker). Adverse Efects Gastrointestnal disturbances (nausea, vomitng, diarrhoea, constpaton, abdominal cramp); fatgue; cold hands and feet; exacerbaton of intermitent claudicaton and Raynaud phenomenon; bronchospasm; bradycardia, heart failure, conducton disorders, hypotension; sleep disturbances, including nightmares; depression, confusion; hypoglycaemia or hyperglycaemia; exacerbaton of psoriasis; rare reports of rashes and dry eyes (oculomucocutaneous syndrome-reversible on withdrawal). Diltazem Pregnancy Category-C Schedule H Indicatons Angina pectoris due to coronary artery spasm; chronic stable angina; cardiac arrhythmia. Dose Oral Adult-30 mg 2 to 5 tmes a day before food and at night (bed tme), increase gradually to 240 mg in 3 to 4 divided doses daily. They should therefore be dispensed in glass or stainless steel containers and closed with a foil-lined cap which contains no wadding. No more than 100 tablets should be dispensed at one tme and any unused tablets should be discarded 8 weeks afer opening the container. Contraindicatons Hypersensitvity to nitrates; hypotension; hypovolaemia; raised intracranial pressure; hypertrophic obstructve cardiomyopathy, aortc stenosis, cardiac tamponade, constrictve pericardits, mitral stenosis; marked anaemia; head trauma; cerebral haemorrhage; angle-closure glaucoma. Adverse Efects Throbbing headache; fushing; dizziness, postural hypotension; tachycardia (paradoxical bradycardia also reported); abdominal pain; collapse; neurological defcit. Storage Store protected from light and moisture in glass container of not more than 100 tablets at a temperature not exceeding 30⁰C. The container should be closed by means of screw cap lined with aluminium or tn foil. Coton, wool wadding or other additonal packing that absorbs glyceryl trinitrate should be avoided. Isosorbide-5-Mononitrate* Pregnancy Category-C Schedule H Indicatons Prophylaxis and treatment of angina, congestve heart failure. Dose Oral 20 mg 2 to 3 tmes a day initally, or 40 mg twice daily (max 120 mg daily individual dose). Contraindicatons Hypersensitvity to nitrates; hypotensive conditons and hypovolaemia; hypertrophic cardiomyopathy; aortc stenosis; cardiac tamponade; constrictve pericardits; mitral stenosis; marked anaemia; glaucoma; obstructve cardiomyopathy; raised intracranial pressure. Precautons Hypothyroidism; malnutriton; hypothermia; head trauma; cerebral haemorrhage; gastrointestnal disease; recent history of myocardial infarcton; hypoxaemia or other ventlaton and perfusion abnormalites; susceptbility to angle-closure glaucoma; metal-containing transdermal systems should be removed before cardioversion or diathermy; avoid abrupt withdrawal; tolerance; severe hepatc impairment; severe renal impairment; pregnancy (Appendix 7c); lactaton; interactons (Appendix 6a). Specifc side-efects following injecton (partcularly if given too rapidly) include severe hypotension, diaphoresis, apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitaton, abdominal pain, syncope; prolonged administraton has been associated with methaemoglobinaemia. Isosorbide Dinitrate* Pregnancy Category-C Schedule H Indicatons Prophylaxis and treatment of angina; heart failure. Contraindicatons Hypersensitvity to nitrates; hypotension; hypovolaemia; myocardial infarcton; hypertrophic obstructve cardiomyopathy, aortc stenosis, cardiac tamponade, constrictve pericardits, mitral stenosis; marked anaemia; head trauma; cerebral haemorrhage; angle-closure glaucoma. Precautons Severe hepatc or renal impairment; hypothyroidism; malnutriton; hypothermia; recent history of myocardial infarcton; interactons (Appendix 6a, 6b, 6c, 6d); pregnancy (Appendix 7c). Patents taking isosorbide dinitrate for the long-term management of angina may ofen develop tolerance to the antanginal efect; this can be avoided by giving the second of 2 daily doses of longer-actng oral presentatons afer an 8-h rather than a 12-h interval, thus ensuring a nitrate-free interval each day. Metoprolol* Pregnancy Category-C Schedule H Indicatons Supraventricular arrhythmia, angina pectoris, hypertension, myocardial infarcton; migraine prophylaxis; hyperthyroidism, heart failure. Intravenous injecton Arrhythmia: up to 5 mg at a rate of 1 to 2 mg per min, repeated afer 5 min if necessary (max dose 10 to 15 mg). Beta-blockers, including those considered to be cardioselectve, should not be given to patents with a history of asthma or bronchospasm. However, in rare situatons where there is no alternatve a cardioselectve beta-blocker is given to these patents with extreme cauton and under specialist supervision. Adverse Efects Gastro-intestnal disturbances; bradycardia, heart failure, hypotension, conducton disorders; peripheral vasoconstricton (including exacerbaton of intermitent claudicaton and Raynaud’s phenomenon); bronchospasm; dyspnoea; headache; fatgue; sleep disturbances; paraesthesia; dizziness; vertgo; psychosis; sexual dysfuncton; purpura; thrombocytopenia; visual disturbances; exacerbaton of psoriasis; alopecia; rarely, rashes and dry eyes (reversible on withdrawal); on infusion venous irritaton and thrombophlebits; agranulocytosis; hyperglycemia; myocardial depression. Dose Oral Adult- Hypertension: initally 40 mg twice a day or 80 mg once a day; increased at weekly intervals as required, maintenance 160 to 320 mg in three divided doses. Prophylaxis of variceal bleeding in portal hypertension: 40 mg twice daily, increased to 80 mg twice daily according to heart rate (max. Prophylaxis afer myocardial infarcton: 40 mg 4 tmes daily for 2 to 3 days, then 80 mg twice daily beginning 5 to 21 days afer infarcton. Beta-blockers, including those considered to be cardioselectve, should not be given to patents with a history of asthma or bronchospasm. However, in rare situatons where there is no alternatve a cardioselectve beta-blocker is given to these patents with extreme cauton and under specialist supervision. Adverse Efects Gastro-intestnal disturbances; bradycardia; heart failure, hypotension, conducton disor- ders; peripheral vasoconstricton (including exacerbaton of intermitent claudicaton and Raynaud’s phenomenon); bronchospasm; dyspnoea; headache; fatgue; sleep distur- bances; paraesthesia; dizziness; vertgo; psychosis; sexual dysfuncton; purpura; thrombocytopenia; visual disturbances; exacerbaton of psoriasis; alopecia; rarely, rashes and dry eyes (reversible on withdraw- al); on infusion venous irritaton and throm- bophlebts; eosinophilia; hyperglycemia; cardiogenic shock; visual hallucinatons. A proposal to include such a product in a natonal list of essental drugs should be supported by adequate documentaton Dose Oral Adult- 80 to 120 mg 3 tmes daily (120 mg 3 tmes daily usually required in Prinzmetal angina). Elderly- Paroxysmal tachyarrhythmias: 5 to 10 mg over 3 min, further 5 mg may be given afer 5 to 10 min if required. Contraindicatons Hypotension, bradycardia, second- and third-degree atrioventricular block, sinoatrial block, sick sinus syndrome; cardiogenic shock; history of heart failure or signifcantly impaired lef ventricular functon (even if controlled by therapy); atrial futer or fbrillaton complicatng Wolf-Parkinson- White syndrome; porphyria; platelet dysfuncton.