Mark Corson

By R. Anog. Johnson State College. 2018.

An antiarrhythmic drug that might be effective against automatic tachyarrhythmias islikely to reduceone or both effects generic bactroban 5gm line. Unfortu- nately buy bactroban 5 gm on-line, no drug has been shown to reliably improve abnormal au- tomaticity in cardiac tissue buy cheap bactroban 5gm line. Therefore, the mainstay of therapy isto treat the underlying illness and reverse the metabolic abnormalities causing abnormal automaticity. A logical treatment, therefore, istoadminis- ter a drug that reduces the duration of the actionpotential. Treating the arrhythmias most ofteninvolves discontinuing digitalisand administering beta blockers. Brugada syndrome Thissyndrome is caused by abnormalities in the rapid sodium chan- nel. Antiarrhythmic drugs that further block the sodium channel (Class I drugs) seem to potentiate the abnormalities associatedwith Brugadasyndromeand should be avoided. Other drugs, including 40 Chapter 2 beta blockers and amiodarone, have at best provenineffective in treating thissyndrome. Reentrant arrhythmias Incontrast to the limitedusefulness of antiarrhythmic drugs in treat- ing automatic arrhythmias and channelopathies, these drugs, at least in theory, directly address the mechanism responsible for reentrant arrhythmias. Afunctioning reentrant circuit requires a series of prerequisites— an anatomic or functional circuit must be present, onelimbofthe circuit must display slowconduction,and asecond limb must display a prolonged refractory period (to produce unidirectional block). One can immediately grasp the potential benefit of a drug that, by chang- ing the shape of the cardiac actionpotential, alters the conductivity and refractoriness of the tissues forming the reentrant circuit. A drug that increases the duration of the cardiac actionpotential (thereby increasing refractory periods) fur- ther lengthens the alreadylong refractory period of one pathway, and thus may convert unidirectional blocktobidirectional block, which chemically amputates oneofthepathways of the reentrant circuit. Alternatively, a drug that has the opposite effecton refrac- tory periods—one that reduces the duration of the actionpotential and shortens refractory periods—may shorten the refractory period of one pathway so that the refractory periods of both pathways are relatively equal. Withoutadifference between the refractory periods of the twolimbs of the circuit, reentry cannot be initiated. The key point in understanding howdrugs affect reentrantar- rhythmias is that reentry requires a critical relationship between the refractory periodsand the conduction velocities of the twolimbs of the reentrant circuit. Because antiarrhythmic drugs canchange these refractory periodsand conduction velocities, the drugs can make reentrant arrhythmias less likely to occur. Proarrhythmia The manner in whichantiarrhythmic drugs work against reentrant arrhythmias has an obvious negative implication. For example, if a patient with a previous myocardial infarction and asymptomatic, nonsustained ventricular tachycardiahad an occult reentrant cir- cuit whose electrophysiologic properties were not able to support a reentrant arrhythmia, such as the circuit shown in Figure 2. With suchadrug, the refractory period of pathway B may be sufficiently prolonged to prevent reentry from being initiated. The refractory pe- riod of pathway B may be shortened to the extent that the refractory periods of pathwaysAand Bbecome nearly equal. A premature impulse islikely to either conduct or block both pathways and thus prevent initiation of reentry. Although it is possible that the drug will suppress the ambientectopy, it is also possible that it might selectively reduce the refractory period of the pathway with the longer refractory period,thus giving this circuit the characteristics shown in Figure 2. In other words, the drug might make a reentrant arrhythmia much more likely to occur. Anytimean antiarrhythmic drug is given to a patient with a po- tential reentrant circuit, the drug may change the electrophysiologic characteristics of the circuit in suchaway as to makeasustained ar- rhythmiaeither less likely or more likely to occur. Unfortunately, it is the very same mechanism that produces an antiarrhythmic effect that causes antiarrhythmic drugs to also produceaproarrhythmic effect. Proar- rhythmia is therefore not a bizarre, inexplicable, idiosyncratic,or rare side effectofantiarrhythmic drugs. Proarrhythmia isan en- tirely predictable, inherent property of antiarrhythmic drugs. Since antiarrhythmiaand proarrhythmiaoccur by the same mechanism, one cannot have one effect without the other. Proarrhythmia isafairly common occurrence, but it was only poorly recognizeduntil the late 1980s. The failure to recognize that drug therapy may worsen arrhythmias often leadstoinappropriate therapy(suchasincreasing or adding to the offending drug)and sometimes to death. Therefore, proarrhythmia isapossibility for whichone must be vigilant whenever these drugs are prescribed. Classification of antiarrhythmic drugs For any set of entities, a useful classification systemisone that pro- vides a relatively simple, logical framework that facilitates teaching and learning,aids in communication, allows practical generaliza- tions, and offers insights into the essential nature of these entities. Two general classification schemes have been set forth for antiar- rhythmic drugs—the Vaughan-Williamsscheme, initially proposed in 1971, and the so-called Sicilian Gambit, proposed about 20 years later. For the vast majority of clinicians, the older Vaughan-Williams systemmore nearly fulfills the essential purpose of a classification system. Introduction to antiarrhythmic drugs 43 Vaughan-Williams scheme Until the late 1960s, so few antiarrhythmic drugs were available that no classification systemwas needed. Whennewdrugsbegan to arrive with increasing frequency, however, several classification systems were proposed; the Vaughan-Williamsscheme is the one proved to have the greatest practical value. By attempting to classify drugsaccording to their major membrane effects, the Vaughan-Williamsschemefacilitates thinking aboutan- tiarrhythmic drugs in terms of their electrophysiologic properties. The prototypical electrophysiologic effects of the various classes of drugs are depictedinFigure 2.

The line represents a function of the form y ¼ BxA determined by nonlinear regression order 5 gm bactroban. Human cytochromes and some newer antidepressants: kinetics buy discount bactroban 5 gm, metabolism purchase bactroban 5gm with amex, and drug interactions. Effects of the antifungal agents on oxidative drug metabolism in humans: clinical relevance. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. Drug metabolism and drug interactions: application and clinical value of in vitro models. In vitro cytochrome P450 inhi- bition data and the prediction of drug-drug interactions: qualitative relationships, quantitative predictions, and the rank-order approach. Prediction of in vivo drug-drug interactions from in vitro data: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. Inhibition-based metabolic drug-drug interactions: predictions from in vitro data. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. Database analyses for the prediction of in vivo drug- drug interactions from in vitro data. Predicting inhibitory drug-drug interactions and evalu- ating drug interaction reports using inhibition constants. Inhibition constants, inhibitor concentrations and the prediction of inhibitory drug drug interactions: pitfalls, progress and promise. The effects of ketoconazole on triazolam pharmacokinetics, pharmacodynamics and benzodiazepine receptor bind- ing in mice. Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. Mechanism-based inactivation and reversibility: is there a new trend in the inactivation of cytochrome P450 enzymes? Fluvoxamine-theophylline interaction: gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2. Fluvoxamine impairs single- dose caffeine clearance without altering caffeine pharmacodynamics. Urinary excretion of 6 beta-hydrox- ycortisol and the time course measurement of enzyme induction in man. Receptor-dependent transcriptional activa- tion of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man. Molecular mechanisms of cytochrome P-450 induction by xenobiotics: an expanded role for nuclear hormone receptors. Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. Expression and regulation of cytochrome P450 enzymes in primary cultures of human hepatocytes. The use of adult human hepatocytes in primary culture and other in vitro systems to investigate drug metabolism in man. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with rito- navir. Drug interactions in primary care: impact of a new algorithm on risk determination. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors, and clinical con- firmation of a predicted interaction with ketoconazole. Ketoconazole inhibition of tri- azolam and alprazolam clearance: differential kinetic and dynamic consequences. Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Time-course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.

Protection of elastic fibers (collagens cheap bactroban 5 gm fast delivery, elastin) is promoted by extracts hav- ing free-radical scavenging properties discount bactroban 5 gm visa, activating the synthesis of these proteins or inhibiting the enzymes responsible for their degradation: streptomyces cheap 5 gm bactroban with amex, black currant, Centella asiatica (rich in asiatic acid), Rudbeckia purpurea, Coleus, Areca,... Apigenin, extracted from Chamomile and its derivatives, and rutin from Fagopyrum have anti-inflammatory properties (by inhibiting histamine release), but they are also β-glucuronidase inhibitors. Other extracts rich in polyphenols—tanins—also have antihy- aluronidase activity (16–18). Recent studies show the importance of amino acids in protecting the skin barrier function. This hormone is very important to many biological processes and decreases rapidly with age. They con- tribute to the elimination of dead cells from the skin surface, hydration, as well as cell renewal. Selenium (Astrogalus) is said to play an important role in antiaging (immu- nity, inflammation, free radical scavenging), zinc (Taraxacum) in hair growth (action on testosterone) (24), and mother of pearl from shellfish in wound healing or tissue repair. Saponins, a huge family of compounds, whether of a steroidal or triterpenic structure, are known for their detergent activity. Constant research shows that saponins, present in botanical extracts, have tremendous pharmacological and metabolic properties. Centella asiatica (asiaticosides)—stimulates synthesis of collagen and fi- bronectin. Sterols from sabal, serenoa as well as ∆7 sterols are inhibitors of 5-α- reductase, an enzyme involved in androgenic alopecia, hyperseborrhea of the scalp or the skin, as well as acne. Glycyrrhizin from glycyrrhiza and harpagosides from harpagophytum are broadly used for their anti-inflammatory properties. Saponins have also been shown to increase stress resistance by increasing cortisol and prostaglandins, to protect membranes (Eleutherococcus), to increase metabolic efficacy (Medicago), to stimulate cells (Ginseng, bupleurum). Extracts from ganodema are immunostimulating, immunoregulating, pro- long all life in culture, and act on endocrine functions. Extracts from arctophylos uva-ursi, coactis, and adenotricha rich in arbutin and methylarbutin are used for their depigmenting effect. The main difference between the two is really the intention of the manufacturer (i. Most cosmetic products today address both the rational and the emotional aspects that characterize their need in society, while they are often still considered as a ‘‘dream in a bottle’’ (Charles Revson). Botanicals are playing an increasingly important role in the activity and safety of cosmetics; they allow for a renewal of the source of active ingredients in drugs. Oriental herbs in cosmetics: Plant extracts are reviewed for their potential as cosmetic ingredients. The effect on rhino mouse skin of agents which influ- ence keratinization and exfoliation. New raw materials and new technologies in cosmetics: Chouji and Gennoshouko extracts as a useful scavenger of reactive oxygen species for cosmetics. Prevention of second primary tumors by an acyclic retinoid, polypre- noic acid, in patients with hepatocellular carcinoma. Inhibitory effects of some natural products on the activation of hyaluronidase and their antiallergic actions. Arginine supple- mented diets inhibit endotoxin—induced bacterial translocation in mice Nutrition 1995; 11:371–374. Colloidal silicic acid for oral and topical treatment of aged skin, fragile hair and brittle nails in females. Vitamin A generically encompasses retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (vitamin A acid) (Fig. In clinical use, retinoids have established their effectiveness in treating acneiform eruptions (e. Additional retinoids are currently being investigated, as are novel uses of retinoids already established in clinical practice. The main focus of retinoid usage in cosmeceuticals has been its role as the mythical ‘‘fountain of youth’’ (i. Retinoids, like all drugs, have adverse effects, the most infamous one being teratogenicity. Over 2000 derivatives have been developed in the hope of finding retinoids with increased therapeutic efficacy coupled with diminished local and systemic toxicity. The recent focus of retinoids has been on topical delivery systems, as this route not only provides a safer adverse effect profile, but also delivers a higher dose to a targeted area (i. Oral retinoids with no significant cosmeceutical activity, such as acitretin, will not be covered. Note that the defini- tion of drug versus cosmeceutical for this class is regulatory (man made) and not biological. However, it was not until the early twentieth century that definitive knowledge of this substance was discovered. In Table 2 The Roles of Naturally Existing Retinoids Retinoid Role Retinol Growth promotion Differentiation/maintenance of epithelia Reproduction Retinal Vision Retinoic acid Growth promotion Differentiation/maintenance of epithelia Topical Retinoids 109 Figure 1 Structure of retinoids. This substance, initially termed ‘‘fat-soluble A’’ (3) and later named ‘‘vitamin A’’ (4), was also found in butter fat and fish oils, demonstrating growth-promoting activity (5). Synthesis of vitamin A was achieved in the 1940s and from then on an upsurge of interest in the therapeutic uses of vitamin A became apparent. Topical tretinoin was first used successfully by Stuttgen¨ to treat disorders of epidermal keratinization in the 1960s (6).

Among 104 labetolol- versus methyldopa-treated women with pregnancy-induced hypertension order 5 gm bactroban mastercard, labetolol caused fewer side effects than methyldopa (el-Qarmalawi et al discount 5 gm bactroban with visa. Labetolol is the agent of choice to blunt the hypertensive response to endotracheal intubation discount bactroban 5gm visa, with few maternal, fetal or neonatal side effects (Cheek and Samuels, 1996). No studies on the use of these agents during the first trimester of pregnancy are published. No increase in adverse maternal or fetal effects, includ- ing no significant differences in birth weight, were reported in 120 women treated with atenolol or placebo during pregnancy (Rubin et al. Similarly, no adverse fetal effects or pregnancy outcomes associated with metoprolol or metprolol/hydralazine treat- ment in second and third trimesters of pregnancy were noted (Sundstrom, 1978). Breastfeeding is allowed during maternal therapy with either metoprolol or atenolol (American Academy of Pediatrics, 1994), despite a case report of toxicity in a neonate whose mother was receiving atenolol while breastfeeding (Schmimmel et al. Neonatal hemodynamic adaptation failure occurred in five of 11 infants whose mothers were treated with aceb- utolol during pregnancy (Yassen et al. It seems unlikely that this drug is associ- ated with an increased risk of congenital anomalies. Among 51 women with pregnancy-induced hypertension randomized to Antihypertensives 61 hydralazine, hydralazine and propranolol, or hydralazine and pindolol, pindolol was associated with fewer maternal and fetal side effects (Paran et al. However, infants born to mothers who received propranolol had smaller birth weights. In a com- parative study of atenolol or pindolol on uterine/fetal hemodynamics and fetal cardiac function, investigators found that pindolol was preferable to atenolol for the treatment of pregnancy-induced hypertension based upon maternal and fetal cardiovascular func- tion (Rasanen and Jouppila, 1995). No increase in congenital malformations was noted in the offspring of pregnant mice who received up to 150 mg/kg. Also, no increase in the frequency of malformations was found among the offspring of rats, rabbits, and hamsters that had received nadolol in doses several times higher than the usual human dose (Sibley et al. No increased frequency of adverse fetal effects was found in the offspring of mice treated with penbutolol (Sugisaki et al. No epidemiologic studies of the frequency of congenital anomalies and cloni- dine use during early pregnancy have been published. Anecdotal case reports of clonidine use during pregnancy suggest no adverse fetal effects (Horvath et al. Head size and neurologic examination of 22 children whose mothers received clonidine during pregnancy were normal (Huisjes et al. One rat teratology study found no increased frequency of birth defects (Angelova et al. Clonidine is probably not associated with an increased risk of congenital anomalies when used therapeutically. An oral form of this drug (Proglycem) is also used to treat hypoglycemia secondary to hyperinsulin- ism. An anecdotal case report of abnormalities of body and scalp hair, including alopecia, in four neonates of women who received oral diazoxide during the last trimester of pregnancy has been published (Milner and Chonskey, 1972). Maternal diazoxide therapy was also reportedly associated with hyperglycemia in the neonate (Milsap and Auld, 1980). Pancreatic islet cell damage was found in the offspring of sheep and goats treated with intravenous diazoxide (Boulos et al. It is also used to induce hypotension during certain types of 62 Cardiovascular drugs during pregnancy Box 3. No epidemiological studies of congenital anomalies in association with nitroprusside use during pregnancy have been published. Nitroprusside was reported to be associated with cyanide toxicity in animals (Lewis et al. Nonetheless, it is prudent to avoid use of nitroprusside during pregnancy because of the theoretical accumulation of cyanide in the fetal liver. Chronic use of sodium nitroprus- side is logically associated with a much higher risk than acute usage. Three basic categories of diuretics are: (1) loop diuretics; (2) potassium-sparing diuretics; and (3) thiazide diuretics. Loop diuretics Loop diuretics act primarily by inhibiting sodium and water reabsorption by the loop of Henle. No increase in malformations was found in offspring of animals receiving several times the usual adult human dose of bumetanide (McClain and Dammers, 1981). Diuretics given after the first trimester of pregnancy may inter- fere with normal plasma volume expansion. An adverse effect on plasma volume, no improvement in perinatal outcome (Sibai et al. Furosemide also displaces bilirubin from albumin, increasing the risk for fetal hyper- bilirubinemia (Turmen et al. In animal studies, furosemide exposure in preg- nancy was associated with an increase in fetal loss and skeletal anomalies in offspring (Godde and Grote, 1975; Mallie et al. Furosemide crosses the placenta and assists in assessing fetal urinary tract obstruction and fetal urine production (Barrett et al. Potassium-sparing diuretics Potassium-sparing diuretics include amiloride, spironolactone, and triamterene, and result in sodium and water loss while sparing potassium. Spironolactone is a competi- tive inhibitor of aldosterone, while ameloride and triamterene function at the level of the collecting tubules.