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He passed a catheter as far down as possible purchase super p-force oral jelly 160mg otc, and then combined one part of echinacea with six parts of sterilized water purchase 160 mg super p-force oral jelly. Relaxation took place probably from the local anesthetic influence of the remedy in a few minutes super p-force oral jelly 160mg discount. Rounseville reported to the Wisconsin State Medical Society that he had used echinacea with excellent results in both diabetes mellitus, and diabetes insipidus, and also in some forms of albuminuria, and in each of the cases he obtained results that confirmed his opinion that the agent was one that would be a material assistance combined with other measures. He made a strong solution and Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 192 combined with it agents that would assist in stimulating the nutritive functions of the hair follicles. A directly curative influence from this agent alone has been secured, where from vaccination a general infection has been induced. I am confident that no other single medicine will accomplish as much in these cases, immediately and as satisfactorily as this remedy. I am convinced that it would be good practice to use collinsonia, hamamelis or aesculus in conjunction with this remedy, Dr. Yates treated an eruptive disease with purulent discharge which we call nettle rash with echinacea internally, and permanganate of potassium solution externally. Many cases of tibial ulcer treated with echinacea with curative results, are reported. The agent is used both internally and externally, associated often with other successful measures. Ono doctor had an opportunity to observe the action of echinacea in some fowl that had taken strychnine which was used to poison animals. This is simply a suggestion in favor of trying echinacea as an antidote for strychnine poisoning. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 193 Specific Symptomatology—This agent should be freely employed where there is excess of uric acid; where the “brick dust” deposit is marked; where the extreme and nauseating backache suggests that the crystalline constituents of the urine are not well dissolved and washed out of the tubules; or where there is renal sand or gravel in the bladder; where the urine is dark and heavy, and there is irritation, causing congestion of the kidneys, which in some cases induces hemorrhage; where precipitated solids irritate the bladder, and induce cystitis with thickening of the walls, and formation of pus. An infusion of epigaea freely drunk in these cases will relieve the entire train of symptoms, inducing a grateful sense of relief from irritation and distress. Any of the preparations in sufficient doses will accomplish satisfactory results in the above conditions, but the infusion is more immediately active. Fifteen drops of specific Epigaea in an ounce of hot water, drunk hot, will act most promptly. If the patient is closely confined and constipated, with dark, sallow skin, and inactive liver, add thirty grains of sodium phosphate and note the most gratifying results. Its specific influence upon the liver greatly facilitates its effects on the kidneys when there is a fault in the hepatic conversion of the nitrogenous waste. In addition to its influence upon the kidneys, epigaea is a carminative of much value. It will quickly relieve persistent eructations of gas, and will cure many chronic cases that have resisted other treatment. When there is noisy rumbling in the bowels so distressing to ladies, when present, this agent may be successfully administered. Fluid Extract of Epilobium Dose, from five to sixty minims Specific Medicine Epilobium. Physiological Action—The several species of epilobium are astringent, tonic, emollient, and demulcent, and have a specific influence on the Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 194 intestinal mucous membrane. The epilobium palustre has a well established reputation as a remedy in intractable cases of camp dysentery and diarrhea, cases having been cured by it when other means had failed. Specific Symptomatology—Chronic diarrhoea with general emaciation, and a persistent enfeebled condition with dry, dingy, rough, harsh skin. If no great structural change, and no tubercular or cancerous conditions are present, this agent is the most satisfactory remedy we have. It is suggested where the abdomen is contracted, and where the diarrhea is feculent in character with sharp colicky pains. Therapy—It will be curative also in general relaxed, subacute or acute cases of diarrhea, after the stage of inflammation has passed, but is not as reliable a remedy at that time as geranium. In muco-enteritis it is of some service in conjunction with the indicated remedies. It exercises an apparent tonic influence upon the mucous and glandular structures of the entire intestinal canal, overcoming ulceration, and being of material benefit in the more speedy restoration of normal function. In the treatment of chronic eczema, epilobium was strongly advocated by one of our best physicians. In that class of inveterate cases that was at first papular and finally squamous, he got excellent results. He gave it in doses from fifteen to twenty minims, and in persistent cases he would make all infusion of the herb, having the patient drink it freely. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 195 Therapy—A diuretic useful in suppression of urine from any cause. Useful in dropsy and in lithemic conditions, where the urine is scanty, of high specific gravity, and dark-colored. In cases of irritable bladder with much tenesmus, it is soothing in its influence. It is valuable in the treatment of nocturnal incontinence of urine in children, and in incontinence induced by cystic irritation. An infusion made from the green stalks of the plant, is sometimes of more service than other forms, a fact which is true of a large number of diuretics. Some authorities have advised the powdered ashes of this agent in the treatment of certain forms of acid dyspepsia. This influence is probably due to the presence of the potassium or sodium hydrate, or their compounds, in these, ashes, and these substances are readily supplied from more available sources. Equisetum is used where there is suppression of urine or scanty urine, or where there is irritability of the mucous surface of the urinary tract. There is pain at the base of bladder and in the prostate, and there is irritability of the nervous system. Jedlicka of Wisconsin thinks that it influences morbid enlargements within the urinary apparatus. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 196 Ergot is prepared by special processes of purification for hypodermic injection. So used it is immediate in its action and can be so administered when impossible to give it by the stomach. Ergotine in solution in water and glycerine, is excellent for hypodermic administration. Physiological Action—Ergot causes both acute and chronic poisoning when taken in toxic closes. Acute ergotism is characterized by vomiting, purging, headache, dizziness, drowsiness, slowing of the pulse, dilatation of the pupils, dyspnea, pain in the chest and loins, confusion of the senses, formication, coldness, anesthesia, convulsions, swelling of the face. Chronic ergotism is characterized by neuralgic pains, formication and numbness of the extremities, opisthotonos, violent delirium succeeded by exhaustion, death occurring in coma or in convulsions; or the drug may affect nutrition; muscular weakness is followed by gangrene of the limbs or superficial parts, which become blackened, shriveled and hard—a dry gangrene, generally ending fatally. Ergot is classed as a motor excitant by most writers, and yet the evidences, as above described, of its depressing influence upon the nervous system and upon the circulation are most conspicuous. In its influence upon the circulation of the brain and spinal cord, it may be given in sufficient doses to produce anemia, and that it does greatly reduce the excitability of the nervous system, under certain circumstances, none will deny. It acts in perfect harmony with the bromides when there is acute cerebral engorgement with great nervous excitability. There is no doubt that it produces contraction of the arterioles, although there are many evidences to prove that it may permit the venous capillaries to dilate freely. It acts upon the muscular structure of the womb, producing extreme tonic or tetanic spasm of the fibrillae, causing a marked reduction in the size of the organ if enlarged, and rapid emptying of its blood vessels, and consequent anemia. Many prominent writers believe the anemia induced, causes the profound muscular contraction. It is more plainly apparent that a peculiar irritating influence of the agent upon such muscular structure induces its contraction, and that such contraction, assisted by the influence of the agent upon the coats of the arterioles, causes them to become emptied to a marked extent, and thus Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 197 the anemia. Ergot acts upon the heart muscle in much the same manner as upon the muscular structure of the womb, although much less violently. Because of the profound irritation of muscular fibrillae and consequent almost immediate contraction induced by Ergot, it is a most active agent in inducing expulsive pains in labor, in overcoming uterine inertia and in controlling uterine hemorrhage. Specific Symptomatology—Extreme fullness of the circulation of the brain, flushed face, headache, bright, sharp eyes, great restlessness.
No differences in major or minor anomaly frequencies between the tretinoin and control groups were found (Loureiro et al discount super p-force oral jelly 160mg without a prescription. Tretinoin administered to pregnant animals during embryogenesis in doses up to 50 times those used in humans was not associated with congenital anomalies or adverse fetal effects buy cheap super p-force oral jelly 160 mg. In summary super p-force oral jelly 160 mg amex, tretinoin does not appear to be associated with an increased risk of congenital anomalies in infants born to women who used the drug as directed during pregnancy. It is unlikely that absorption of topical antibiotics through the skin results in significant serum concentration, or would be associated with an increased risk of con- genital anomalies. Unlike oral or parenteral tetracycline, topical preparations are not associated with yellow-brown discoloration of the teeth. Other topical antimicrobial agents are used to treat minor skin infections and include neomycin (usually in combination with polymixin B, bacitracin, gramicidin, and/or hydrocortisone). The fre- quency of congenital anomalies was not increased among 30 or 61 infants whose moth- ers took neomycin or gramicidin, respectively, during early pregnancy (Heinonen et al. Other topical antimicrobials used to treat local skin infections include chlorampheni- col, gentamicin, and metronidazole. When applied topically, physiologically significant amounts of these agents are not likely to be absorbed systemically. These agents are dis- cussed in other chapters, and do not increase the risk of congenital anomalies. Mupirocin (Bactroban) is a topical antibacterial used to treat skin infections and fol- liculitis. Mupirocin was not teratogenic in several animal studies, but no human studies of this drug have been published. No studies are published of the use of this drug during human or animal pregnancy. According to its manu- facturer, silver sulfadiazine was not teratogenic in animal studies (unpublished). Some systemic preparations are also used for vaginitis: amphotericin B, griseofulvin, and ketoconazole. Systemic antifungals are not associated with an increased risk of birth defects, except for griseofulvin (conjoined twinning is hypothesized with griseoful- vin; see Chapter 2). Topical application of these agents on parts of the body is not asso- ciated with an increased frequency of congenital anomalies or other medical complica- tions. Ciclopirox, haloprogin, naftifine, and tolnaftate are antifungals used to treat tinea corpus, cruris, pedis, and versicolor. No human studies of these drugs during pregnancy have been published, but their manufacturers report that these antifungal agents were not teratogenic in several animal studies. Applied topically, it is used to treat tinea captis, corporis, cruris, versicolor, pedis, and barbae. No human reproduction studies for any of these agents have been published and the same is true for animal data. Benzoyl peroxide, resorcinol, and salicylic acid have significant potential for systemic absorption, but no cases of adverse fetal effects are documented related to the topical route of delivery. Manufacturer data on salicylic acid was reported to be ter- atogenic in animals when used in large doses, several times that used in humans. It is very unlikely that these agents have any effect on prenatal development because they are not absorbed systemically. Coal tar and sali- cylic acid are often used in combination with other agents, such as sulfa, and in combi- nation with one another to treat seborrhea and seborrheic dermatitis. According to the manufacturer, however, several of these agents may be teratogenic in laboratory animals. Topical steroids are very unlikely to be associated with significant risk to the human fetus, except triamcinolone (see below). Systemic adrenocorticosteroids are sometimes indicated to treat dermatologic diseases and there is a small collection of these agents (Box 13. The frequency of con- genital anomalies was not increased among 43 infants born to women who took pred- nisone during early pregnancy (Heinonen et al. Perinatal deaths were increased in frequency among infants born to women who took this steroid throughout preg- nancy, but the disease being treated (e. Fetal growth retardation was associated with prednisone use during gestation by one research group (Reinisch et al. Prednisone and prednisolone Prednisone and prednisolone are active adrenoglucocorticoids. Numerous animal studies reported an increase in the fre- quency of cleft palate with prednisolone (as well as other steroids) when given in large doses (e. The association between oral clefts and prednisone exposure was assessed among humans using data from well-regarded case–control studies (Carmichael and Shaw, 1999; Rodriguez-Pinilla and Martinez-Frias, 1998) and it was concluded that the risk of nonsyndromic cleft palate may be associated with prednisone/prednisolone and other glucocorticoid exposure during embryogenesis. Note that most oral clefts can be surgically corrected and this isolated defect is not associated with other physical or mental abnor- malities. Hydrocortisone Hydrocortisone, another glucocorticoid, is the main steroid produced by the adrenal glands. The frequency of congenital anomalies was not increased among infants whose mothers took hydrocortisone during early pregnancy, including the first trimester (Heinonen et al. As with prednisone/prednisolone, an increased frequency of cleft palate was found among the offspring of experimental animals whose mothers were given hydrocortisone during embryogenesis (Chaudhry and Shah, 1973; Harris et al. It is possible that a small risk for cleft palate in humans exists with hydrocortisone use during embryogenesis, but it is likely that the risk is small at less than 1 percent (Shepard et al. Adrenocorticosteroids 247 Dexamethasone and betamethasone These agents (dexamethasone and betamethasone) are glucocorticoids that are closely related to prednisone (see Prednisone and prednisolone above). No human teratology studies of dexamethasone or betamethasone have been published. These drugs are com- monly used in the late second and early third trimesters to promote fetal lung maturity, preventing respiratory distress syndrome (Collaborative Group on Antenatal Steroid Therapy, 1984; Liggins, 1976; Liggins and Howie, 1974). Consistent with other corti- costeroids, dexamethasone and betamethasone are reported to be associated with an increased frequency of cleft palate in the offspring of pregnant animals that received these agents during embryogenesis (Mosier et al. Fetal body and organ weight were decreased in several animal studies with exposure to these glucocorticoids during pregnancy (Barrada et al. As with other glucocorticoids, it is possible that a small risk for cleft palate in humans exists with dexamethasone and betametha- sone use during early pregnancy. Triamcinolone No human epidemiological studies of triamcinolone use during early pregnancy have been published. The published case–control studies are confounded and it is not possi- ble to interpret them for triamcinolone exposures. The cause of concern for triamci- nolone exposure during embryogenesis is an increased frequency of congenital anom- alies found in offspring of three species of nonhuman primates that received this corti- costeroid during embryogenesis (Bacher and Michejda, 1988; Hendrickx and Tarara, 1990; Hendrickx et al. The collection of congenital anomalies included neural tube defects, craniofacial malformations, and skeletal anomalies. Therefore, triamcinolone should be avoided dur- ing pregnancy, especially during the first trimester (Friedman and Polifka, 2006). Triamcinolone will most probably be associated with an increased risk of birth defects in humans when these studies are reported. This warning is issued to attempt a reduc- tion of the number of infants who will be damaged, i. Cortisone The risk of congenital anomalies among women who used cortisone during pregnancy and its possible adverse fetal effects cannot be assessed with the available published data. Among only 34 infants exposed to cortisone during early pregnancy, the frequency of congenital anomalies was not increased (Heinonen et al. Cortisone is in the drug class (glucocorticoids) noted above to be associated with an increased frequency of cleft palate in several animal models, including nonhuman primates (Biddle and Fraser, 1976; Walker, 1971). The nonhuman primate association, even with small sample sizes, is an ominous indicator. Based mostly on primate data, these agents will predictably be shown to be associated with an increased frequency of isolated cleft palate in human 248 Use of dermatologics during pregnancy infants exposed to glucocorticoids during embryogenesis. Glucocorticoids summary In summary, limited human data are published of adrenocorticosteroid use during early human pregnancy and possible association with congenital anomalies or other possible adverse fetal effects. Although these agents were used for many years in pregnant women without apparent adverse effects, no systematic studies are available. Recent analyses based upon reputable case–control studies indicate that a low risk (< 1 percent) for cleft palate may be associated with glucocorticoid exposure during the first trimester.
The clinical “usefulness” of these pyrimidine and purine drugs depends directly on their ability to selectively block synthesis of viral nucleic acids while not stopping the synthesis of “host” cell nucleic acid discount super p-force oral jelly 160mg mastercard. Interacting this with acetonitrile in a Ritter reaction conditions gives 1-acetylaminoadaman- tane (36 super p-force oral jelly 160mg visa. It has a very narrow spectrum of action and is used only for treating and preventing influenza A super p-force oral jelly 160 mg fast delivery. The exact mech- anism of antiviral action of amantadine is not completely understood. It has also been suggested that amantadine inhibits absorption of viral par- ticles into the host cell, which is expressed in the breakdown of diffusion of the virus into the cell, or inhibition of the “stripping process” of the virus. The hydroxyl and amino groups of guanine are previously protected with a trimethylsilyl group by being treated with hexamethyldisilazane. After hydrolysis the result- ing product with water, 9-(2-benzoyloxymethoxymethyl)guanine (36. Treating this with a methanol solution of ammonia removes the benzoyl protecting group from the hydroxyethoxymethyl fragment, giving acyclovir. Antiviral Drugs Another way of preparing acyclovir begins with 2,6-dichloropurine, which is alkylated with the same 1-benzoyloxy-2-chloromethoxyethane, but in a triethylamine—dimethyl- formamide system to make 2,6-dichloro-9-(2-benzoyloxyethoxymethyl)purine (36. Treating this with a methanol solution of ammonia replaces both chlorine atoms with amino groups, and subsequent diazotization using sodium nitrite in dilute acetic acid selec- tively replaces one of the two amino groups for a hydroxyl group, in particular the amino group at position C6 of the purine system. Finally, treating the product with a methanol solution of ammonia removes the benzoyl protection from the synthesized 9-(2-benzoy- loxyethoxymethyl)guanine (36. Acyclovir possesses antiviral activity with respect to types 1 and 2 of herpes simplex, shingles virus, Epstein–Barr virus, and cytomegalovirus. Acyclovir dif- fuses into the cell infected by a virus and phosphorylates thymidine kinase of herpes sim- plex to a monophosphate. Acyclovir is used for herpes simplex that has attacked the eyes and genetilia, for herpes in other locations, shingles, and chicken pox. It is synthesized from the acetonide-β-D–xylofuranoside of adenine—9-(3 ,5 -O-isopropyliden-β-D–xylofuranoside)adenine, which is reacted with methanesulfonyl chloride to make the mesylate 9-(3 ,5 -O-isopropyliden-2 -O-methansul- fonyl-β-D-xydlofuranoside)adenine (36. Prolonged heating in 90% acetic acid removes the acetonyl protective group from the resulting compound, giving the product (36. Antiviral Drugs 553 Reacting this with sodium methoxide leads to the formation of an epoxide— 9-(2 ,3 -anhydro-β-luxofuranosyl)adenine (36. Finally, heating this epoxide with sodium acetate or benzoate opens the epoxide ring in the dimethylformamide–water system to make the corresponding dihydroxy derivative, vidarabine [12,13]. This simultaneously N-debenzylates the sixth position of the purine sys- tem and fulfil O-debenzylation of hydroxyl groups of the furanosyl fragment of the molu- cule, giving vidarabine . This analog of a purine nucleoside exhibits selective activity against the herpes virus. It is easily metab- olized to a less active, yet nonetheless antiviral compound—arabinosylhypoxanthine. It has been successfully used for herpetic encephalitis, and for complicated shingles. Hydrolysis of the tosyl groups using sodium hydroxide and subsequent treatment of the resulting substance with acetic acid gives the desired product idoxuridine [15–19]. Since this drug also affects mammalian cells and also possess theratogenic, mutagenic, and immunosuppressive action, its use is limited to external use. It is used primarily for ophthalmology for herpetic infections of the eye (keratitis). Adding to this dry hydrogen bromide in methanol solution in a process of which methanolysis of the nitrile group takes place the bromide 36. Brominating of the obtained dihydropy- rimidine with molecular bromine and subsequent dehydrobromination of the resulting prod- uct 36. This is reacted with 2-deoxy-D-ribos-1-phosphate using the nucleoside phosphorylase enzyme, or by treating it with hyxamethyldisylazane and then with trichloromethylsilane to make 2,4- trimethylsilyloxy-5-trifluoromethyl pyrimidine (36. Hexamethyldisilazane, which itself does not form trimethylsilyl ethers, is used because using a combination of two reagents leads to optimal yield of trimethylsilyl ethers. The resulting product undergoes preliminary purification by chromatography, and then is treated with a methanol solution of diisopropylamine to remove the 4-nitrobenzoyl protection from the furanosyl part, giving the desired trifluridine [20–23]. Replacing the methyl group with an azide group using lithium azide in dimethylformamaide makes the product 36. Heating this in 80% acetic acid removes the trityl protection, giving zidovudine [24–28]. It also turned into mono-, di-, and triphosphates by the same cel- lular enzymes that catalyze phosphorylation of thymidine and thymidine nucleosides. It significantly pro- longs the life of the patient, although it has a number of toxic effects. All types of protozoa are single-cell organisms that can adapt to various conditions. These forms require different approaches when treat- ing patients that have protozoan infections. Protozoa are typical parasites that occupy host cells, multiply in them, and then destroy them. Prevention of protozoan diseases consists of controlling the spread of the disease, improv- ing sanitarial-hygenic conditions of life, receiving vaccinations, and treatment. It should be kept in mind that malaria is spread by mosquitoes, in particular by the bite of (female) Anopheles mosquito; leishmaniasis is spread through infected gerbils; trypanosome is spread by the tsetse fly; amibiasis and giardia are spread through food and water; and toxoplasmo- sis is spread through meat products and infected cats. Antimalarial drugs currently used for treatment for prophylaxis are mefloquine, primaquine, chloroquine, pyrimethamine, amodiaquin, quinine/quinidine, chloroguanide. The causative agents of malaria are plasmodia (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale). Malarial plasmodia have two developmental cycles; an asexual cycle, which takes in the body of an infected person (schizogony); and a sexual cycle, which takes place in the body of the mosquito (sporogony). When a person is bit by a mos- quito, sporocytes that were formed in the blood of the mosquito (from male and female hematocytes) enter the body. These enter liver cells, where they form primary tissue sch- izonts, which grow, divide, and transform into merozoites. Merozoites then enter the blood of the person and diffuse into erythrocytes, where they develop further. After maturing in ery- throcytes, schizonts again divide and transform into merozoites. These merozoites are peri- odically released from the occupied erythrocyte cells and attack a new group of erythrocytes, starting the process over. Drugs for Treating Protozoan Infections destroyed and the merozoites enter the blood is expressed by an onset of malarial fever, which is referred to as the perierythrocytic form of malaria. This is when parasites in the mero- zoite stage of development remain in or enter the liver cells again. This restarts the erythrocytic cycle of development of plasmodia and the onset of relapse. Chemotherapy of malaria consists of affecting various stages of the life cycle of the par- asite. Antimalarial drugs are subdivided into three corresponding groups: those that have an effect on erythrocyte stage of the life cycle, those that destroy exoerythrocytic (or hepatic stage), and those that affect both stages simultaneously. Currently, aminoquinolines such as chloroquine and its analog (primarily for affecting the parasite during the erythrocyte stage), and pri- maquine (for affecting the parasite during the exoerythrocyte stage) are used to treat malaria. Recently, mefloquine, and a natural compound quinghaosu, as well as various antibiotics in combination with antimalarial drugs have begun to be used. Their most important structural character- istic is the type of substituent at C7 and C4 of the quinoline ring. It has been shown that an amine substituent is necessary at C4 of the quinoline ring, which can vary while retaining antimalarial activity of the compound; however, the necessary conditions for expression of antimalarial activity is the presence of a chlorine atom at C7 of the quinoline ring. The second group of drugs used during the erythrocyte stage of malarial infections is quinolinmethanol derivatives. This group includes mefloquine, pyranobenzodioxepin derivative isolated from the plant—quing- haosu, as well as cinchona alkaloids that are made from the bark of the cinchona tree, of which only quinine is still used for treating malaria. One of these ways consists of reacting 3-chloroaniline with ethoxymethylenmalonic ester to make (3-choroanilino)-methylenemalonic ester (37. Hydrolyzing this with sodium hydroxide gives 7-chloro-4-hydroxyquinolin-3-decarboxylic acid (37. Treating this with phosphorus oxychloride gives one of the desired components for synthe- sis of chloroquine – 4,7-dichloroquinoline (37. Alkaline hydrolysis of the ethyl ester of the 7-chloro-4-hydroxyquinolin-2-carboxylic acid (37.
In- creasedplasmabinding during stress canprolong the elimination half-life from 1or2 hours to as long as 4 hours super p-force oral jelly 160mg without prescription, and thus cancause lidocaine levels to increase evenduring a constant infusion discount super p-force oral jelly 160mg mastercard. When lidocaine is given acutely 160mg super p-force oral jelly with visa, it israpidly distributed to the target or- gans(phase 1 distribution), but within 20 minutes, it is distributed throughout the rest of the body(phase 2distribution); the initial immediate efﬁcacy of the drug falls off during phase 2. Thus, twoor three additional boluses are usually given at 10-minute intervals af- ter the original bolus; the dosage of the additional boluses is usually half that of the initial bolus. However, at fast heart rates or during ischemia, hypokalemia, or acidosis, lidocaine can substantially slowdepolarization and conduc- tion velocity. The duration of the actionpotential and the refractory period are shortened by lidocaine in ventricular tissuebut not in atrial tissue. Lidocaine can suppress both normal and abnormal au- tomaticity, which can lead to asystole when lidocaine is giveninthe setting ofaventricular escape rhythm. Class I antiarrhythmic drugs 67 Hemodynamic effects Lidocaine has little or nohemodynamic effect. Therapeutic uses Lidocaine is effective for ventricular tachyarrhythmias and is often the drug of choice for the emergent therapy of these arrhythmias because therapeutic plasma levels can be obtained rapidly. The drug has been shown to decrease the incidenceofventricular ﬁbrillation in the setting of acute myocardial infarction but does not improve mortality. Adverse effects and interactions The predominantside effects relate to the central nervous sys- tem. Slurred speech, dizziness, perioral numbness and paresthesias, seizures, and respiratory arrest can all occurand are generally asso- ciatedwith toxic plasma levels. Propranolol, metoprolol, and cimetidine(but not ranitidine) decrease hepatic blood ﬂow and result in increased levels of lidocaine. Clinical pharmacology Mexiletine is nearly completely absorbed from the gutand displays minimal ﬁrst-pass hepatic clearance. Peak plasma levels occur in 4–6 hours, and the drug isapproximately 70% protein bound. The drug is mainly metabolized by the liver, and the elimination half-life is from 8to16hours. Dosage Because of the variable metabolism and because therapeutic and toxic doses of mexiletinetend to overlap, dosage must be individu- alized. If there is no response after several days (at least 3 days) and if toxicity is not present, dosage can be increased to 200 mg every 8 hours. Dosage can be further increased after several 68 Chapter 3 more days unless toxicity is present, but rarely canmore than 750 mg/day be administeredwithoutsigniﬁcantside effects. Electrophysiologic effects The electrophysiologic effects of mexiletine are virtually identical to those of lidocaine. Hemodynamic effects Mexiletine has little or no effecton bloodpressure or cardiac func- tion. Therapeutic uses The therapeutic proﬁle of mexiletine issimilar to that of lidocaine; that is, it effectively suppresses ventricular arrhythmias. Unlike lido- caine, however, mexiletine is not particularly suitable for the treat- mentofemergentoracute arrhythmias because titrating the drug to an effective dose may take many days. Although mexiletine is effective in suppressing premature ventricular complexes and non- sustained ventricular tachycardia, these arrhythmias shouldgener- ally not be treatedunless they are producing signiﬁcantsymptoms. On the basis of serial drug testing in the electrophysiology laboratory, mexiletine rarely suppresses inducible sustained ventricular tachy- cardia; the drug is estimated to be effective for suchsuppressionin only 5–10% of patients tested. Adverse effects and interactions As with lidocaine, central nervous system side effects predominate; tremor, blurred vision,and ataxia are the most common effects. While the drug generally has nohemodynamic effects, it has been reported to worsen heart failure in patients with severe cardiomyopathy. Mexiletine levels can be increased by cimetidine, chlo- ramphenicol, and isoniazid. Theophylline levels can be increased substantially when the drug is givenwith mexiletine. Class I antiarrhythmic drugs 69 Tocainide Tocainide isanother oral analog of lidocaine. Its properties are very similar to mexiletine, except that it iseliminated from the system by both the liver and the kidneys. The drug enjoyed brief popularity as an antiarrhythmic agent in the early 1960s but was almost entirely supplantedwhen lidocaineand procainamide came into widespreaduse. Clinical pharmacology Phenytoin’s oral absorptionis relatively slow and highly variable. The drug is 90% protein bound and is metabolized by the liver to inactive compounds. At higher plasma levels, eliminationis dose dependent, and plasma levels increase disproportionately as dosage is increased. Dosage A drug-loading regimenis usually recommendedwith oral admin- istration of phenytoin,especially if therapeutic levels are desired within 24 hours. Chronic dosage shouldnot be changedmore often than at 10- to 14-day intervals because of the dose-dependentelimination of the drug. Phenytoin can also be administeredintravenously, preferably throughacentral intravenouslinebecause of the tendencyto 70 Chapter 3 produce phlebitis. Monitoring for the appearanceof lateral gaze nystagmus during administration of the drug can be a useful indicator of therapeutic serum levels (10–20 µg/mL). Electrophysiologic effects The electrophysiologic proﬁle of phenytoin issimilar to that of lido- caine;it displays a rate-dependent effecton the sodium channel with rapid binding-unbinding characteristics. Thus, conduction velocity is minimally affectedinnormal tissueand at normal heart rates. Delayed afterdepolarizations of the type seenwith digitalis toxicity are suppressed by phenytoin. Hemodynamic effects With rapid intravenous loading,hypotensioncan occurbut can be controlled by titrating the rate of drug administration. Therapeutic uses Phenytoin is effective for ventricular tachyarrhythmias caused by digitalis toxicity, most likely because itsuppresses delayed afterde- polarizations. Adverse effects and interactions The most common side effects involve the gastrointestinal and cen- tral nervous systems. Central nervous system symptoms(mainly ataxiaand nystagmus) are related to plasma levels. Other less com- mon side effects include osteomalacia (frominterference with vita- min D metabolism), megaloblastic anemia (frominterference with folate metabolism), and hypersensitivity reactionssuchaslupus, hepatic necrosis, hematologic disorders, and pseudolymphoma. Gin- gival hyperplasia, said to occur in up to 20% of children taking phenytoin,appears to be relatively rare in adults. Class I antiarrhythmic drugs 71 Several drug interactions have been seenwith phenytoin. Pheny- toin increases plasma levels of theophylline, quinidine, disopyra- mide, lidocaine, and mexiletine. Phenytoin levels are increased by cimetidine, isoniazid,sulfonamides, and amiodarone. Clinical pharmacology Flecainide is well absorbed from the gastrointestinal tract, and peak plasma levels are reached2–4 hours after an oral dose. The drug is mainly metabolized by the liver (70%), but 30% isexcreted unchanged by the kidneys. Flecainidehasalong elimination half-life (12–24 h), so a steady state is not reached for 3–5 days after a change in oral dosage. Dosage can be increased by 50 mg/dose (at 3- to 5-day intervals) to a maximal dosageof200 mg every 12 hours. Electrophysiologic effects The major electrophysiologic feature of ﬂecainide isasubstantial slowing in conduction velocity. The prolonged slowing is directly related to the prolonged binding-unbinding time(i. Thus, ﬂecainide isvirtually continuously bound to the sodium channel, and therefore produces slowconduction even at low heart rates (i. Hemodynamic effects Flecainide has a pronouncednegative inotropic effectsimilar to that of disopyramide. The drug shouldnot be given to patients with a history of congestive heart failure or with signiﬁcantly depressed left ventricular ejection fraction. Therapeutic uses As one might predict from the universal nature of the drug’s elec- trophysiologic properties, ﬂecainide has an effecton both atrial and ventricular tachyarrhythmias. It has been shown to be effective for terminating and preventing atrial ﬁbrillation and atrial ﬂutter;if the arrhythmias recur, ﬂecainide can slow the ventricular response.
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