By P. Bernado. Smith Chapel Bible College.
Automatic ventricular arrhythmias are most often seen in patients with acute myocardial ischemiaorinfarction order 50 mg sildenafil with mastercard erectile dysfunction doctor in phoenix,orsome other acute medical illness purchase sildenafil 75 mg without a prescription erectile dysfunction q and a. Most arrhythmias occurring within the ﬁrst few hours of an acute myocardial infarction are thought to be automatic purchase sildenafil 100mg amex erectile dysfunction doctor specialty. Once the ischemic tissue dies or stabilizes generic sildenafil 25mg on line erectile dysfunction medicine pakistan, however, the substrate for automaticity is nolonger present. Ingeneral, the treatmentofautomatic ventricular arrhythmias consists of treating the underlying illness. Reentrant ventricular tachyarrhythmias Most ventricular arrhythmias are reentrant in mechanism. While the conditions producing automatic ventricular arrhythmias are usually temporary in nature (e. Because the intra- atrial reentrant circuit can be located anywhere within the atria, the P-wave morphology can have any conﬁguration. Reentrant circuits within the ventricular myocardium usually arise after scar tissue develops, a conditionmost commonly seenin patients who have myocardial infarctionsorcardiomyopathy. Once the scar tissue gives rise to a reentrant circuit, the circuit persists, and the potential for a ventricular arrhythmiaalways exists. Reentrantventricular arrhythmias are seen only rarely in individuals who have normal ventricles. Most antiarrhythmic drugs affect the ventricular myocardium and,accordingly, most are used to treat ventricular tachyarrhyth- mias. Channelopathic ventricular tachyarrhythmias Channelopathies probably account for several distinctive types of ventricular tachyarrhythmias, at least twoofwhich have now been Mechanismsofcardiac tachyarrhythmias 29 well characterized. These are the ventricular arrhythmias dueto triggered activity and Brugadasyndrome. Triggered activity in the ventricles Because ventricular tachyarrhythmias duetotriggered activity are reasonably common,and because the managementoftriggered ven- tricular arrhythmias is very different from the managementofmore typical ventricular arrhythmias, it is importanttorecognize their characteristics. Twofairly distinct clinical syndromes are caused by ventricular triggered activity:catechol-dependent arrhythmias and pause-dependent arrhythmias. They are the classically polymor- phic ventricular tachyarrhythmias generally referred to as torsades de pointes. Patients with catechol-dependenttriggered activity therefore expe- rience arrhythmias (oftenmanifested by syncopeorcardiac arrest) in times of severe emotional stress or during exercise. Pause-dependenttriggered arrhythmias are caused by afterdepolarizations that occur during 30 Chapter 1 Delayed afterdepolarization (a) Early afterdepolarization (b) Figure 1. These patients, from available evidence, have one of several channelopathies that become clinically manifest only when theiractionpotential durations are increased by drugs or electrolyte abnormalities. The T-U abnormalities tend to be dynamic; that is, they wax and wane from beat to beat, mainly depending on beat- to-beat variations in heart rate. The slower the heart rate, the more exaggerated the T-U abnormality; hence, this conditionissaid to be pause dependent. In thisﬁgure, eachburst of polymorphic ventricular tachycardia causes a compensatory pause, and the pause causes the ensuing normal beat to be associatedwith pronounced U-wave abnormalities (i. The acute treatmentofpause-dependenttriggered activity con- sists of attempting to reduce the duration of the actionpotential, to eliminate the pauses, or both. Intravenous magnesium often ameliorates the arrhythmias evenwhen serum magnesium levels are in the normal range. The mainstay of emergent treatmentof the arrhythmias, however, istoeliminate the pauses that trigger the arrhythmias—that is, to increase the heart rate. This is most often ac- complished by pacing the atrium or the ventricles (usually, at rates of 100–120 beats/min)or,occasionally, by using anisoproterenol infusion. The top two strips show the typical pattern—eachburst of polymorphic ventricular tachycardia is followed by a compensatory pause; the pause, in turn, causes the ensuing sinus beat to be followed by another burst of ventricular tachycardia. The bottom strip shows the sustainedpolymorphic ventricular tachycardia that followed after sev- eral minutes of ventricular tachycardiabigeminy. Brugadasyndrome is usually seeninmales and is probably the same disorder as the suddenunexpectednocturnal death syndrome seeninAsianmales. Patients with Brugadasyndrome have genetic abnormalities in the rapid sodium channel. Several varieties of sodium channelopathies have beenidentiﬁed, probably accounting for the several clinical varieties seenwith Brugadasyndrome. The implantable deﬁbrillator is the mainstay of therapy for patients with Brugadasyndrome. Mechanismsofcardiac tachyarrhythmias 35 Miscellaneous ventricular arrhythmias Several clinical syndromes have beendescribedinvolving unusual ventricular arrhythmias that do not ﬁt clearly into any of these cate- gories. Nomenclature for these arrhythmias is unsettledinthe litera- ture, reﬂecting the lackofunderstanding of their mechanisms. It islikely that at least some of these will eventually prove to be duetochannelopathies. Thus, it should not be surprising that drugs that alter the actionpotential might have important effects oncardiac arrhythmias. How antiarrhythmic drugs work Thinking of an antiarrhythmic drug as a soothing balm that sup- presses an“irritation of the heart”is more thanmerely naive;it is dangerous. If this ishow one imagines antiarrhythmic drugsto work, thenwhen an arrhythmiafails to respond to a chosendrug, the natural response istoeither increase the dosage of the drug or, worse, add additional drugs(in afutile attempttosufﬁciently soothe the irritation). Effect on cardiac action potential What antiarrhythmic drugsactually do—the characteristic that makes them“antiarrhythmic”—istochange the shapeofthecar- diac actionpotential. Antiarrhythmic drugs dothis, in general, by altering the channels that control the ﬂow of ionsacross the cardiac cell membrane. When an appro- priate stimulusoccurs, the mgate opens, which allows positively charged sodium ionstopour into the cell very rapidly, thus causing the cell to depolarize(phase 0 of the actionpotential). Panels (a) through(c) display the function of the two controlling gates in the baseline(drug-free) state. Panels (d)and (e) display the effectofadding a Class I antiarrhythmic drug (opencircles). Consequently, reaching the end of phase 0 takes longer; the slopeofphase 0 and the conduction velocity are decreased. Class I antiarrhythmic drugs work by binding to the h gate, mak- ing it behave as if it is partially closed. When the mgate opens, the opening through whichsodium enters the cell isfunctionally much narrower; thus, it takes longer to depolarize the cell (i. Because the speed of depolarization determines how quickly adjacent cells depolarize(and therefore af- fects the speed of conduction of the electrical impulse), Class I drugs decrease the conduction velocity of cardiac tissue. In so doing, these drugs change the shapeof the cardiac actionpotential, and thus change the three basic electro- physiologic properties of cardiac tissue:conduction velocity, refrac- toriness, and automaticity. Effect on cardiac arrhythmias Tachyarrhythmias are mediated by changes in the cardiac actionpo- tential, whether the mechanismisautomaticity, reentry, or a chan- nelopathy. It is not difﬁcult to imagine, then,howdrugs that change the shape of the actionpotential might be useful in treating cardiac tachyarrhythmias. Inpractice, the drugs commonly referred to as antiarrhythmic are relatively ineffective in treating automatic arrhythmias or chan- nelopathies. Instead, the potential beneﬁt of these drugs isalmost exclusive to the treatment of reentrant arrhythmias, whichaccount for most cardiac arrhythmias. Nonetheless, drugs that change the shape of the actionpotential canpotentially affect all three mecha- nisms of arrhythmias. Automatic arrhythmias Abnormal automaticity, whether atrial or ventricular, is generally seeninpatients who are acutely ill and as a result have signiﬁ- cant metabolic abnormalities.
With the exception of oxmetidine buy sildenafil 50 mg with visa impotence 24, for which only a single clinical study was performed order 50mg sildenafil otc erectile dysfunction kaiser, these in vitro findings will favorably describe the interactions seen between the H2-receptor antagonists and benzodiazepines that rely upon P450-mediated metabolism for their elimination discount 50 mg sildenafil free shipping stress and erectile dysfunction causes. Coadministration of multiple doses of cimetidine has been found to diminish the elimination of a number of benzodiazepines (Table 20) 50mg sildenafil with amex causes of erectile dysfunction and premature ejaculation, that include: adinazolam (156), alprazolam (157,158), bromazepam (159), chlordiazepoxide (160), clobazam (161), clorazepate (162), diazepam (149,163–168), flurazepam (169), midazolam (140,170), nitrazepam (171), nordiazepam (172), and triazolam (157,158,173). Single doses of cimetidine seem to have milder effect, but have been found to diminsih the elimination of diazepam (174) and midazolam (154,175,176) in a dose-dependent fashion (Table 20). In all studies, but one, that monitored pharmacodynamic effects these were mildly diminished also (Table 20). Lorazepam (166,169,174,177) and oxazepam (169,172,177), which are exclusively glucuronidated, and temazepam (140,178), which can be glucuronidated without further metabolism, were resistant to the effects of cimetidine. The outlier in this scheme is clotiazepam, which appears to require P450-dependent metabolism, but was unaffected by cimet- idine. Multidose ranitidine inhibited the elimination of oral diazepam (179), midazolam (140,170,180), and triazolam (181), but was inaffective against intravenous doses of these benzodiazepines (179,181–183), intravenous lorazepam (182), and oral tem- azepam (140). A single dose of ranitidine had no effect on oral adinazolam (184), oral midazolam (154), or infused midazolam (175). Multidose famotidine (155,185,186), oxmetidine (155), and nizatidine (155) had no effect on the pharmacokinetics of intra- venous diazepam. They hypothesized that the increase in pH caused by ranitidine was responsible for the diminished elimination of oral triazolam. The basis of their hypothesis was that at acidic pH triazolam is in equilibrium with its more poorly absorbed benzophenone (Fig. With increased pH, less benzophenone is formed and more triazolam is absorbed (181). This appears to be limited to first-pass metabolism within either the gastrointestinal tract or the liver. Omeprazole has been best characterized as an inhibitor of P450 2C19, and can cause drug interactions with drugs that are 2C19 substrates. In vitro, both omeprazole and lansoprazole inhibit 2C19 with K s 10-fold lower than those fori inhibition of other P450s (Fig. As the benzophenone would not be absorbed as effectively as triazolam, it was postulated that agents that increase stomach pH would decrease the amount of the benzophenone and thereby increase the absorption of the benzodiazepine. Whereas this conversion is useful for the gas chromatographic detec- tion of many benzodiazepines, as explained in the text, it does not appear to impact drug interactions involving agents that change stomach pH. In four different studies, omeprazole was found to inhibit elimination of either intravenous or oral diazepam (168,191–193). Lansoprazole (194) and pantoprazole (195) had no effect on the pharmacokinetics of diazepam (Table 21). Interactions with Imidazole Antifungal Agents The imidazole antifungal agents are well known for their ability to inhibit P450- mediated drug metabolism (196). Most studies comparing the effects of the imidazole antifugal agents on different P450s have utilized ketoconazole (21–23,197). These demonstrate that ketoconazole can inhibit many P450s, but that its ability to inhibit 3A4 at concen- trations of »1 µM make it 10–100 times more specific for this P450 gene product (Fig. Studies comparing the inhibitory ability of the other imidazole antifungal agents are limited. When studying the inhibitioni of 2C9 using tolbutamide as the substrate, Back et al. Whereas fluconazole, itraconazole, and ketoconazole were without effect, miconazole, bifonazole, clotrimazole, and econazole inhibited the activ- ity with K s of 4, 7, 12, and 25 µi M (not shown). In clinical studies on drug interactions between benzodiazepines and the imida- zole antifungal agents, the responses appear to follow inhibition of P450 3A4 poten- cies (Table 22). Ketoconazole has been found to inhibit the elimination of alprazolam (202,203), chlordiazepoxide (204), midazolam (205), and triazolam (202,206,207; Table 22). Fluconazole has been found to inhibit the elimination of midazolam (208, 209) and triazolam (210), but not bromazepam (211). Itraconazole has been found to inhibit the elimination of alprazolam (212), diazepam (213), midazolam (205,208,214), 1. Metronidazole had no effect on the elimination of alprazolam (216), diazepam (217), lorazepam (216), or midazolam (218). The same was true for the nonimidazole antifungal agent, terbinafine, on midazolam (214) and triazolam (219; Table 21). Their ability to do this followed the same potency ranking as with their effects on the pharma- cokinetics, ketoconazole > itraconazole > fluconazole. Indeed, multiple doses of keto- conazole strongly enhanced the pharmacodynamic effects of triazolam and midazolam; 1. Drug Interactions with Benzodiazepines 47 triazolam was also strongly enhanced by itraconazole and fluconazole. These imida- zole antifungals were some of the most potent inhibitors found during the research for this review. They are most active against P450 2D6, where they have relative potency of paroxetine > flouxetine > sertraline, fluvoxamine > citalopram > venlafaxine, nefazodone, with K s ranging from 0. P450 3A4–dependent metabolism of alprazolam is inhibited with K s ranging from 10 to 83 µi M (fluvoxamine > nefazodone, sertraline > paroxetine > fluoxetine); 2C19 metabolism of mephenytoin with K s ranging from 1. Of particular importance for this class of drugs is that the initial metabolite often has equal inhibitory potency to the parent drug (Fig. This is seen with midazolam where the substrate inhibition constant for a-hydroxyla- tion was 1. Pharmacokinetically significant drug interactions have, however, been identified (Table 23). Fluoxetine was found to inhibit the elimination of alprazolam (225,226) and diazepam (227), but was reported as without effect on clonazepam (226) and triazolam (228). Subjects were randomly allocated to either the placebo-fluoxetine or fluoxetine-placebo order of study, with a 14-d washout period between sessions. For subjects that took placebo first, the inhibition of alprazolam elimination was significant; for those that took fluoxetine first, it was not. The reason for this was that in subjects that took fluoxetine first, norfluoxetine plasma concentrations were still quite high (226). During the 8 d of active treatment with fluoxetine, mean norfluoxetine concentrations rose from 25 to 80 ng/mL. During the 14 to 31 d after sessation of treatment they went from 55 to 45 ng/mL (226). Fluvoxamine was found to inhibit the elimination of diazepam (229) and midazo- lam (230). Nefazodone was found to inhibit the elimination of alprazolam and triazolam (231–233), but not lorazepam (231,234). Venlafaxine actually enhanced the elimination of alprazolam (237) and diazepam (238; Table 23). Nefazodone had greater inhibitory effect on alprazolam than did fluoxetine, and in turn enhanced the phar- macokinetics of alprazolam to a greater extent (225,231,232). The pharmacodynamics of lorazepam and clonazepam were not effected by nefazodone or sertraline, respec- tively; nor were their pharmacokinetics (231,234,235). The 1A2, 2C19, and 3A4 (except nefazodone and metabolites) data are from Brosen et al. An exception was the study on diazepam and fluoxetine, where a pharmaco- kinetic interaction was found, but there was no effect on the pharmacodynamic measures in the study (227; Table 23).
Various ways of synthesizing emetine have been suggested cheap 50mg sildenafil with mastercard testosterone associations with erectile dysfunction diabetes and the metabolic syndrome, all of which begin with homoveratrylamine – 2-(3 cheap sildenafil 50 mg without prescription impotence restriction rings,4-dimethoxyphenyl)ethylamine [44–48] discount 100 mg sildenafil with amex experimental erectile dysfunction drugs. Upon a combined catalytic hydrogenation of the ethyl ester of β–(α′-cyano)propylglu- taric acid and homoveratrilamine trusted 25 mg sildenafil erectile dysfunction drugs new, a reductive amination reaction takes place, in which ammonia is released and an intermediate amine (37. Reacting the resulting lactam with phosphorus oxychloride causes heterocyclization into the derivative of benzoquino- lizine (37. Subsequent reaction of the product with homoveratrylamine makes the cor- responding amide. Upon reaction with phosphorus oxychloride, this compound cyclizes to an isoquinoline derivative, and the pyridine ring is then hydrogenated by hydrogen to a racemic mixture of products, from which the desired emetine is isolated. The mechanism of action of emetine consists of the blockage of protein synthesis in eukaryotic (but not in prokaryotic) cells. Protein synthesis is inhibited in parasite and mammalian cells, but not in bacteria. Emetine is currently only used as a drug for treating amebiasis in cases of resistance to other drugs. It suppresses the development of trichmonad, giardia, ameba, lambliosis, bacteriods, fusobacteria, and a few other diseases. Metronidazole easily diffuses through the membrane of both aerobic and anaerobic bacteria. Further acti- vation and effects of the drug require it to pass through certain reductive processes, which exist in anaerobic organisms and a few bacteria in anaerobic conditions. This reaction lowers the concen- tration of unchanged metronidazole, and makes a gradient that allows a large amount of the drug to pass into the bacteria. Metronidazole exhibits high bactericidal activity with respect to most anaerobes (Protococcus, Peptostreptococcus, Clostridium Bacteroides and Fusobacterium), as well as a few non-spore forming Gram-positive organisms (Actinomyces, Eubacterium, Bifido- bacterium, Propionibacterium). It is highly active against anaerobic protozoan infections, including Trichomonas vaginalis, E. Metronidazole is the drug of choice for amebiases, vaginal trichomonasis and trichlomonadic urethritis in men, lambliosis, amebic dysentery, and anaerobic infections caused by microorganisms that are sensitive to the drug. It is also effective against amebas, trichomonad, lambliosis, acute ulcera- tive gingivitis, and post-operational anaerobic infections. This disease is mainly found in the tropics and subtropics, and it is transmitted by specific blood-sucking insects. There is cutaneous leishmaniasis (causative agent—Leishmania tropica), and visceral leishmaniasis (causative agent Leishmania dono- vani). A pentavalent antimony derivative—sodium stibogluconate is widely used to treat vis- ceral leishmaniasis (kala azar). It should be noted that organic salts of trivalent antimony (antiomalin, the lithium salt of antimonylmalic acid; antimosan, a derivative of arylsul- fonic acid; stibamin, a derivative of p-aminophenylstylbonic acid, and others) have long been the traditional and effective drugs for treating leishmaniasis. It was recently shown that pentavalent antimony salts were more convenient to use. It is believed, however, that pentavalent antimony is reduced to trivalent antimony in the body. Amfotericin B, metron- idazole, and pentamidin are also used to treat leishmaniasis. Sodium stibogluconate:Sodium stibogluconate, D-gluconic acid, 2,4:2′,4′-O-[oxybis (oxidostibylidyne)] bis-, trisodium salt, (37. Drugs for Treating Protozoan Infections Sodium stibiogluconate is the drug of choice for treating leishmaniasis. It is believed that it inhibits the glycotic enzyme phosphofructokinase (which plays a role in the Kreb’s cycle) in parasites of the family Leishmania. As a result, the parasitic microorganisms cease to produce the energy necessary to stay alive, and die. It is expressed as chronic sleepiness, headaches, impaired motor coordination, apathy, loss of intellect, and when not treated, death. In Africa, trypanosomiasis is transmitted by the tsetse fly that has been infected with trypanosomiasis (Trypanosoma gambience and Trypanosoma rhodesience). Subsequent reaction of this with an ethanol solution of hydrogen chloride with the intermediate formation of an iminoester, and then with an ethanol solution of ammonia gives the desired pentamidine [55–57]. Interaction of 2-mercaptoethanol with propylene oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsul- fide) (37. Oxidation of this using hydrogen peroxide gives 2-methyl-1,4-oxithian-4,4-dioxide (37. Reacting this with 5-nitro- furfurol gives the corresponding hydrazone—the desired nifurtimox [58,59]. It is believed that the drug acts by forming a reactive radical (superoxide, hydroperoxide, hydroxyl) in the parasite, which leads to a loss of catalysis and glutathione peroxidase, and an increase in sensitivity to hydrogen perox- ide, which alters its normal vital activities. Suramin: Suramin, a hexasodium salt of [8,8’ carbonyl-bis-[imino-3,1-phenylencar- bonylimino(4-methyl-3,1-phenylen)carbonylimino]]-bis-1,3,5-naphthalintrisulfonic acid (37. The nitro group in this compound is reduced by activated iron to an amino derivative (37. Reacting the resulting product with phosgene makes [8,8′-carbonyl-bis-[imino-3,1-phenylencar- bonylimino(4-methyl-3,1-phenylen]-carbonylimino]-bis-1,3,5-naphthalenetrisulfonic acid (37. However, it is believed that suramin is absorbed in trypanosomes, where it is possible that it reversibly binds with proteins. Metronidazole and tinidazole are used for treating trypchomonadiasis, another communicable protozoan infection. Depending on the type and localization of the causative agent of helminthosis, it can run asymptomatic, or it can be the cause of anemia, or damaged blood vessels, liver, or eyes. Most nematode infec- tions are localized in the intestinal tract, although a few of them can pass into other organs, including the heart, liver, lungs, muscles, and so on, from which removal is significantly harder. Cestode infections are usually localized in the gastrointestinal tract, but there have been cases of them passing into the circulatory system. Trematodes cause chronic infection, called schistosomiasis, in which the blood vessels are attacked and various organ structures (liver, intestines, urinary tract) are damaged. Antihelmintic drugs are intended for exterminating helminthes and removing them from the host organism. Examples include albendazole, diethylcarbamazine, mebendazole, nicolsamide (against tapeworms), suramin, and thiabendazole. Natural antihelmintics include black walnut, wormwood (Artemisia absynthium), clove (Syzygium aromaticum), tansy tea (Tanacetum vulgare), and the male fern (Dryopteris filix-mas). They are subdivided into drugs that damage neuromuscular coordination of helminthes, drugs that have an effect on the energetic processes of helminthes (in particular on the metabolism of glucose), and drugs that affect the enzymatic system, laying of eggs by helminthes, and so on. Historically, halo- genated carbohydrates, naphthoquinones, phenothiazine, a number of natural compounds isolated from leaves of sagebrush and ferns, ether oils (derivatives of pinene), alkaloids (arecoline group), alkaloids of the emetine group, and many others were used to treat helminthosis. However, the currently essential drugs for treating helminthosis are those described below. Nitration of 4-chlorobenzo- phenone with nitric acid at a temperature lower than 5°C gives 4-chloro-3-nitrobenzophenone (38. Reducing the nitro groups in this compound with hydrogen using a palladium on carbon cata- lyst gives 3,4-diaminobenzophenone (38. Mebendazole is used for treatment of enterobiasis, ascariasis, ankylo- stomiasis, strongyloidiasis, trichocephaliasis, trichuriasis, and mixed helminthoses. It is used twice a day over the course of 3 days in doses of 100 mg, resulting in complete recov- ery in 90–100% of patients. In order to do that, 3-chloro-6-nitroacetanylide is reacted with propylmercaptane to make 3-propylthio-6-nitroacetanylide (38. Reducing the nitro group in this compound with hydrogen using a palladium on carbon catalyst gives 4-(propylthio)-o-phenylenediamine (38. Reacting the resulting derivative of o-phenylenediamine with cyanamide and then with the methyl chloroformate gives the desired albendazole . It exhibits an antihelmintic effect against sensitive cestodes and nematodes by blocking the process of glucose uptake by the parasites, which is expressed in the depletion of glyco- gen reserves and subsequent reduction in the level of adenosintriphophate.