Metoclopramide

U. Ingvar. Messiah College.

Color adjustments are made cheap 10 mg metoclopramide mastercard, if necessary purchase metoclopramide with amex, in the ribbon blender and the batch is repulverized discount metoclopramide 10mg with amex. Pressed Face Powders Pressed face powders are more popular than loose powders because of their ease of application and portability buy 10 mg metoclopramide. The basic raw materials are the same as loose powder except that a binder must be used to press the cake into a tin-plate godet. If water-based binders are used, aluminum godets should be considered to prevent corrosion. The properties of a binder are is follows: provides creaminess to the powder, aids in compression and adhesion, develops colorants, enhances water- resistance and pick-up and deposit. If the binder level is too high, it may be difficult to remove the powder with a puff. Also, high levels may lead to glazing of the powder surface, making it waxy looking, with little or no pay-off. Fatty soaps, kaolin, polyethylene, teflon synthetic wax and calcium silicate are some of the binder systems used. Silicone-treated pigments have given rise to pressed face powders that may be used wet or dry. When a wet sponge is applied to the cake, no water penetrates the cake; the water is repelled. When formulating pressed powders, care must be taken so that the raw materials used do not corrode the godets or attack the plastic packaging materials. The manufacture of pressed pow- ders, including the mixing and color-matching process, is similar to loose pow- ders. Sometimes the powder mix is pulverized without binder and then again 294 Schlossman after its addition. Pearls are usually added during the blending process and prefer- ably without the milling operation, which can damage the pearl. If milling a batch containing pearl becomes necessary, it should be done with the mill screen removed. Powder pressing is often more successful if the powder is kept for a few days to allow the binder system to fully spread, especially when pearls are present. The pressures used and the speed of pressing depends on the characteris- tics of the individual formulation and the size of the godet. Powder Blushers The attributes of blushers are as follows: (1) add color to the face; (2) give more dimension to the cheekbones; (3) harmonize the face-balance between eye makeup and lipstick; (4) create subtle changes in the foundation look when lightly dusted over the face. Pressed powder blushers are similar to face powder formula- tions, except that a greater range of color pigments are used. The three basic iron oxides and one or more of the lakes are used to achieve various blusher shades. Care should be taken than only nonbleeding pigments be used to avoid skin staining. Pressed powder rouges were once popular and contained high levels of colorants (10–30%). Usually they are applied from the godet with the finger so that glazing may frequently occur if the rouge is improperly formulated. Pressed Powder Eyeshadows Eye shadows in general have the following functions: (1) Add color and personal- ity to the face; (2) sharpen or soften the eyeball itself; (3) create the illusion of depth or bring out deep-set eyes; (4) create light and dark illusions for subtle character changes; and (5) can be used wet or dry for different illusions. The technology is similar to other pressed powder products but the permitted color range is limited. Problems of poor adherence to the skin, color matching, and creasing in the eyelid is common when the binder formulation is ineffective with the type and level of pearls used. In manufacture, formu- las with high pearl content should be allowed to settle to remove entrapped air before pressing. Decorative Products 295 Quality Assurance on Powder Products Color testing is done, where production batch and standard are placed side by side on white paper and pressed flat with a palette-knife. Bulk density is carried out on loose powder to ensure that no entrapped air is present so that incorrect filling weights are minimized. A penetrome- ter is used to determine the accuracy of the pressure used during filling. Normally, the godet is dropped onto a wooden floor or rubber matte (1–3 times) at a height of 2 to 3 ft to note damage to the cake. Glazing and payoff is done where the pressed cake is rubbed through to the base of the godet with a puff and any signs of glazing is noted. Payoff must be sufficient and the powder should spread evenly without losing adhesion to the skin. Foundation In general, foundation makeup’s chief functions are to hide skin flaws, even out various color tones in the skin, act as a protectant from the environment, and makes the skin surface appear smoother. Requirements for an ideal makeup foun- dation’s application are as follows: (1) moderately fast drying to allow for an even application; (2) should be nonsettling, easy pourability, stable in storage; (3) no tacky, greasy, or dry feel; (4) improve appearance, not artificially; (5) have proper ‘‘play time’’ and slip. Depending on the formulations, several contain treated pigments and volatile silicones to add water-resistance properties. Coverage or capacity will vary with skin types; finish on the skin may by matte, shiny, or ‘‘dewy. Water-in-oil became more popular for water/proofness and contains volatile sili- cone, hydrocarbons, mineral oil, and light esters. Emulsified Foundations Composition can vary widely depending on degree of coverage and emolliency desired. Although nonionic (usually not stable), cationic (difficult to make, not 296 Schlossman on market), and water-in-oil systems have been marketed, most emulsified foun- dations are anionic oil-in-water emulsions due to ease of formulation. Anionics possess the following properties: emulsion stability; pigment wetting and disper- sion; easy spreading and blending; good skin feel; slippery (soaplike) feeling. In the direct pigment method, the pigments are weighed directly into the aqueous phase and dispersed or colloid milled, then the emulsion is formed in the usual manner. The major problem is that there are too many color adjustments needed and accurate color matching is difficult. With the pigment dispersion method, the pigment is mixed with talc as a 50:50 dispersion and pulverized to match a standard. This reduces the number of color corrections needed, but storage may be a problem as well as the time taken to make these dispersions. During the mixed pigment blender method the pigments and extenders are premixed, pulverized and matched to a standard. It is then dispersed in the aqueous phase of the emulsion and the emul- sion is formed in the normal way. In the last method, the mono- chromatic color solutions require color concentrates of each pigment to be made in a finished formula. It is easy to color match by blending finished base, but much storage space is needed and the possibility for contamination is increased. Emollients, waxes, and wetting agent(s) are introduced into a jacketed kettle and heated until phase is clear and uniform. Pigments and texturizing agents are slowly introduced into the oil phase with higher shear mixing. Continue high shear mixing until dis- persion is uniform and colorants are completely ‘‘extended. Brings out the contrast between the iris and the white of the eye, sharp- ens white of the eye. Mascara’s performance is usually judged by application, appearance, wear, and ease of removal. Generally, mascara and eyeliners consist of one or more film formers, pigment, and the vehicle that mostly evaporates to allow the film to set. This was basically a wax base with a soap or nonionic emulsifier present so that that color could be applied with a wetted brush. Mascara and eyeliners consist or one or more film formers, pigment, and the vehicle that mostly evaporates to allow the film to set. Anhydrous solvent-based suspension: waterproof but not smudge- proof and difficult to remove. Water-in-oil emulsion: waterproof but not smudge-proof and can be removed with soap and water. Oil-in-water emulsion: ‘‘water-based’’ if the film is sufficiently flexi- ble, can be flake-proof and smudge-proof. Additional film former: solution polyacrylate (improves flake resistance); emulsion polyacrylate; polyurethane; polyvinyl acetate; rosin derivatives; di- methiconol; proteins: wheat, soy, corn, keratin, oat, silk. Manufacturing: procedure is general oil-in-water emulsification procedure except that iron oxides are first wet and milled in the water phase prior to emulsi- fication and final product goes through a colloid mill, roller mill, or homogenizer.

After incubating the hepatocytes with test com- pounds 10 mg metoclopramide sale, the reaction was terminated by separating the cells from the medium by passing through the layer of a mixture of silicone and mineral oil (density: 1 order metoclopramide mastercard. The hepatic uptake of peptidic endothelin antagonists by freshly isolated rat hepatocytes was extrapolated to give the in vivo uptake clearance based on the assumption of a well-stirred model; they were very close to those obtained by in vivo integration plot analysis (Fig order 10mg metoclopramide otc. Thus order metoclopramide overnight delivery, isolated hepatocytes are a good model for evaluating hepatic uptake clearance. Because of progress in cryopreservation techniques, cryopreserved human hepatocytes are now available from several commercial sources for transport studies. Cry- opreserved hepatocytes are now frequently used for the characterization of hepatic uptake of drugs in human. Since there is a large interbatch difference, it is recommended to prescreen the cryopreserved human hepatocytes with high Drug-Drug Interactions Involving the Membrane Transport Process 149 Figure 2 Comparison between the uptake clearance obtained in vivo and that extrapo- lated from the in vitro transport study of endothelin antagonists. In vitro hepatic uptake clearance was measured using isolated rat hepatocytes and was extrapolated to the in vivo uptake clearance assuming the well-stirred model. Since they attach to the cell culture dish, it can be washed several times to remove extracellular compounds. The disadvantage of this system is that the expression levels of transporters decrease during culture: a saturable com- ponent for the uptake of pravastatin into cultured rat hepatocytes is reduced to 70% by a 6-hour culture, and to 33% by a 24-hour culture, although the non- saturable component remained constant during culture (8). The time of culture should be no more than four to six hours, the minimum time for cell attachment. The transport activity was retained to some extent even in 96-hour cultured rat hepatocytes (10). Incubating the hepatocytes in the absence of Ca for 10 min disrupts the bile canaliculi (11). The cumulative biliary excretion of drug in this system is 150 Kusuhara and Sugiyama obtained by comparing the cumulative accumulation of drugs with or without 2þ preincubation of Ca free butter. In sandwich-cultured rat hepatocytes, the P-glycoprotein (P-gp) expression was increased during six days of incubation, while their uptake transporters (Oatp1a1 and Oatp1a4) were similar or rather decreased during incubation (12). Human hepatocytes also form canalicular network following a four-day incubation in sandwich culture (12). Membrane Vesicles The methods for preparing brush border membrane vesicles from intestine, kidney, and choroid plexus, basolateral membrane vesicles from kidney, sinus- oidal and canalicular membrane vesicles from liver and luminal and abluminal membrane of the brain capillary endothelial cells are readily available in the literature (13–21). It is important to characterize the preparation of membrane vesicles in terms of purity and ori- entation. Purity can be estimated by the enrichment of the relative activity of marker enzymes for the target plasma membrane (13–21). Generally speaking, as far as sec- ondary or tertiary active transporters are concerned, orientation is not important, because the transport mediated by these transporters is bidirectional. The extra- cellular marker compounds, such as methoxyinulin and sucrose, were below the limit of detection in the luminal space of the proximal tubules, while they could Drug-Drug Interactions Involving the Membrane Transport Process 151 be detected in the extracellular space (23). Therefore, the kidney slices allow only a limited access of drugs from the luminal space in the kidney slices, but free access from the basolateral side. In vitro studies using kidney slices have proved its usefulness for examining uptake mechanisms of drugs. Everted Sac This method is used to measure drug absorption from the mucosal to serosal side (29). A segment of intestine is everted and, thus, the mucosal side is turned to the outside. Drug absorption is evaluated by measuring the amount of drug that appears inside the sac when the everted sac is incubated in the presence of test compound. Since a segment of intestine is used for the assay, not only transport but also metabolism should be taken into consideration. Ussing Chamber Method A segment of small intestine is opened along the mesenteric border to expose the epithelial cells and is mounted on the diffusion cell chamber after the longitudinal muscle fibers have been carefully stripped from the serosal side. The transcellular transport of test compound from the mucosal to serosal side, and vice versa, is measured to evaluate the drug absorption. Ussing chamber method allows the determination of electrophysical parameters such as membrane electroresistance, membrane potential and short circuit current, and the transport via the transcellular and paracellular routes can be evaluated separately (31,32). The transport of ionized drug via the paracellular route is sensitive to the potential difference, while that via the transcellular route is not, because of the high electrical resistance of plasma membrane. By measuring the transport rate at different potential difference (the voltage clamp method), the contribution of 152 Kusuhara and Sugiyama transport via the paracellular route can be evaluated. Caco-2 Cells Caco-2 cells, which are derived from human colorectal tumor, are used as an in vitro system for the intestine (33–35). Caco-2 cells retain the specific features of intestinal epithelial cells and differentiate to form tight junction and microvilli, but without a mutin layer. When Caco-2 cells are cultivated on a porous filter, they differentiate and form tight junctions and microvilli (36), and the membrane electroresistance and the permeability of mannitol (a marker for paracellular leakage) reach a plateau 15 days after seeding (36). Absorption can be evaluated by measuring transcellular transport across a monolayer of Caco-2 cells cultured on a porous filter. Papp represents the membrane permeability of following 20 compounds, and was obtained by measuring the transcellular transport from the apical-to-basal side in Caco- 2 cells. Drug-Drug Interactions Involving the Membrane Transport Process 153 Figure 4 Time profiles of the transcellular transport of vinblastine in Caco-2 cells and the effect of verapamil on this transport. The transcellular transport of vinblastine in the presence (þverapamil) and absence of verapamil (100 mM) was measured across a monolayer of Caco-2 cells cultured on a porous filter for 14 to 15 days. For instance, the per- meability of P-gp substrates from the apical-to-basal side is lower than that in the opposite direction due to active efflux on the apical side (44), which was diminished in the presence of P-gp inhibitors (verapamil in Fig. Therefore, the Caco-2 cell is a useful model for evaluating drug-drug interactions where these transporters are involved. The activity of g-glutamyl transpeptidase and alkaline phos- phatase, specific marker enzymes for brain capillary endothelial cells, was half that in the brain capillary (45). The expression level of Mdr1b increases in primary cultured rat brain capillary endothelial cells, while that of mdr1a decreases (47). In addition, immortalization and culture increase the expression of multidrug resistance associated protein 1 (Mrp1) (48,49). Gene Expression Systems The advantage of using a gene expression system is that the kinetic parameters for the target transporter can be obtained. Once the responsible transporters are iden- tified, the possibility of drug-drug interactions can be examined using gene expression systems comprehensively. This will save time and materials, otherwise the uptake or excretion needs to be examined in vivo with many possible combi- nations of drugs. According to our prediction method, the maximum unbound concentration and Ki are needed to determine the degree of inhibition for each transporter under clinical conditions. They can be obtained from the pharmacoki- netic data in clinical trials and from in vitro transport studies, respectively. As mentioned previously, when a drug is transported by several transporters, the con- tribution of each needs to be estimated to predict the degree of overall drug-drug interaction. To determine the contribution, gene deficient/knockout animals are helpful compared with normal/wild-type animals, according to the pharmacokinetic profile of both. Thus, comparing the predicted transport activity among candidate trans- porters will allow the rough estimation of the contribution of each transporter. Oatp1a1 and Ntcp, respectively, and found that they account for the part of the hepatic uptake. Double Transfectants Hepatobiliary and tubular secretions in the kidney are characterized by vectorial transport across the epithelial cells from blood side to the luminal side. Except lipophilic compounds, uptake and efflux transporters coordinately form this vectorial transport (Fig. Considering the scaling factor, the clearance values for in vitro transcellular transport across the monolayers of Oatp1b2/Mrp2 cells correlated well with those for in vivo biliary clearance (Fig. There is great interspecies difference in the number of genes forming the subfamily ‘‘a’’ and ‘‘b’’ between human and rodents. Oatp1a1 was isolated from rat liver as a candidate for sodium-independent uptake of organic anions (65). Oatp1a1 is localized to the sinusoidal membrane in the rat liver and the brush border membrane in the male kidney (66).

Coadministration of multiple doses of cimetidine has been found to diminish the elimination of a number of benzodiazepines (Table 20) purchase 10mg metoclopramide otc, that include: adinazolam (156) order metoclopramide 10mg line, alprazolam (157 purchase metoclopramide amex,158) buy genuine metoclopramide on-line, 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). Interactions with Oral Contraceptives The oral contraceptives are known to interfere with the elimination of a number of drugs (239). Oral contraceptives vary in their composition, but in general they con- tain an estrogen and a progestin. A number of progesterones are used includ- ing, norethindrone, norgestrel, levonorgestrel, ethynodiol diacetate, norethisterone, desogestrel, 3-keto-desogestrel, gestodene, and norgestmate. In combination with the inhi- bition of P450-mediated reactions, oral contraceptives are also inducers of glucuronidation. A number of studies compared the pharmacokinetics of benzodiazepines in woman who did vs woman who did not use oral contraceptives (Table 24). The values shown are the % of control after use of the highest concentration of the progestogen. The substrates and concentration of progestogens were: 3A4 (ee), ethinyl- estradiol, 100 µM; 3A4 (diaz), diazepam hydroxylation, 100 µM; 3A4 (cyc), cyclosporin hydroxylation, 50 µM; 2C19 (diaz), diazepam N-demethylation, 100 µM; and 2C9 (tol), tolbutamide, 25 µM. No effect was found in another study on alprazolam (249), for bromazepam (159), with intramuscular mid- azolam (250), or in a study that compared unlabeled intravenous midazolam to N3- 13 labeled oral midazolam (251). In contrast, the elimination of benzodiazepines depending primarily on glucuronidation was enhanced as found for lorazepam (242,244,252), oxazepam (244,252), and temazepam (242). In a study on conjugated estrogens and medroxyprogesterone at doses used for estrogen replacement therapy, no or minimal effect was found on the pharmacokinetics of midazolam (253; Table 23).

Moreover purchase generic metoclopramide, prospective studies have found that the use of b-blockers during pregnancy may lead to fetal growth retardation cheap metoclopramide 10mg. When a b-blocker is discontinued order metoclopramide amex, angina pectoris and myocardial infarction may occur 10mg metoclopramide for sale. Therefore, patients with ischemic heart disease must be warned not to rapidly dis- continue treatment, since this can lead to a withdrawal syndrome characterized by accel- erated angina, myocardial infarction, and even death. These findings, which can occur even in patients without previously known coronary disease, probably result from upreg- ulation of the beta receptors following chronic b-blockade. This will decrease both the first-pass and systemic elimination of propranolol, causing plasma concentrations to increase as much as fourfold. Other drugs are also potent inhibitors of this cytochrome isoenzyme and decrease 238 Auer the metabolism of propranolol, including quinidine, propafenone, chlorpromazine, fle- cainide, fluoxetine (and its metabolite norfluoxetine), paroxetine, fluvoxamine, and tri- cyclic antidepressants. On the other hand, propranolol can inhibit the hepatic metabolism and raise the plasma levels of certain drugs by decreasing hepatic blood flow rather than enzyme activity. Among the drugs that can be affected are flecainide, lidocaine, nifedi- pine, and nisoldipine. Nitroprusside Nitroprusside (41,42) is an arteriolar and venous dilator, given as an intravenous infusion. Its effects are evident within 60–90 s after initiation of the infusion and should an adverse effect such as symptomatic hypotension occur, the vasodilating properties usually abate within 20–30 min after discontinuation. Thus, hypotension can be easily reversed by temporarily discontinuing the infusion. Nitroprusside is metabolized to cyanide (45), which rarely causes toxicity because it is converted to thiocyanate by the enzyme rhodonase, which is a thiosulfate-cyanide transferase. Thiocyanate can accumulate, and its levels should be monitored in patients with decreased renal function. Nitroprusside is a powerful vasodilator with potent afterload-reducing properties. It is the agent most frequently used early in the treatment of acute heart failure, particu- larly when a rapid and substantial reduction in systemic vascular resistance is neces- sary. Common clinical conditions would include complications of myocardial infarction such as acute mitral regurgitation secondary to papillary muscle dysfunction or rupture, ventricular septal defect, and acute aortic regurgitation. Nitroprusside relaxes arterial and venous smooth muscle via the production of nitric oxide and nitrosothiols leading to an increase in cyclic guanosine monophosphate and smooth muscle relaxation. Simi- lar to nitroglycerin, nitroprusside causes preload reduction by diminishing heightened venous tone and increasing venous capacitance with a concomitant shift in central blood volume to the periphery. This agent reduces the major components of aortic impedance (mean and hydraulic vascular load) resulting in an improved and often dramatic increase in forward stroke volume and cardiac output with reductions in left ventricular filling pressure, volume, and valvular regurgitation. In most patients with heart failure, judicious titration of nitroprusside can result in a fall in aortic impedance, increased cardiac output, and reduced ventricular filling pressures without the undesirable effects of a decrease in systemic blood pres- 7. The combined balanced vasodilator effect of nitroprusside can therefore rapidly improve the hemodynamic abnormalities associated with acute heart failure when preload and afterload reduction is desired. Generally, by improving ventricular wall stress and reducing myocardial oxygen consumption, nitroprusside will have a favorable effect on myocardial energetics. Nitroprusside may also improve coronary blood flow and myocardial perfusion by directly reducing coronary vascular resistance and by increasing coronary perfusion pressure. The latter will occur as long as there is a reduction in ventricular diastolic pressure that is greater than aortic coro- nary diastolic pressure. In patients with occlusive coronary artery disease, care must be taken to avoid excessive reductions in systemic pressure or elevations in heart rate that would reduce coronary perfusion and increase myocardial oxygen demand. Unlike nitroglycerin, nitroprusside may cause “coronary steal” whereby arteriolar dilatation in nonischemic zones diverts coronary flow away from areas of ischemia. Continuous monitoring of central hemodynamics with an indwelling flow-directed thermodilution pulmonary artery catheter is mandatory to safely and effectively target the optimal dose. In acute heart failure, an arterial catheter for continuous systemic blood pressure recording and monitoring and frequent blood gas determinations is also recommended. It should be recognized, however, that during nitroprusside infusion, the pressure measured in a peripheral artery (usually radial artery) may not reflect a reduction in central aortic pressure because of nitroprusside-induced changes in the amplitude and timing of reflected waves within the central aorta. One must remain cog- nizant of this when the clinical findings are consistent with systemic hypoperfusion despite a seemingly acceptable peripheral arterial pressure. Nitroprusside can be rapidly titrated to achieve the desired clinical and hemodynamic end points including a reduc- tion in pulmonary capillary wedge pressure to 18–20 mmHg, a decrease in systemic vascular resistance to 1000 to 1200 dynes/s/cm5, reduction in valvular regurgitation, and an improvement in stroke volume, cardiac output, and systemic perfusion while avoiding significant hypotension and tachycardia. Although the target blood pressure is variable depending on the individual patient, a systolic blood pressure of 80 mmHg or greater is usually acceptable. A higher systolic blood pressure may be required in the elderly or in patients with a recent history of hypertension or cerebrovascular dis- ease. The target pulmonary capillary-wedge pressure is usually higher in acute heart failure than in patients with decompensated chronic heart failure. In the latter condi- tion, the stroke volume of the dilated ventricle is not preload-dependent, and therefore relatively normal left ventricular filling pressures can be targeted. In acute heart failure, particularly when myocardial ischemia is present, attention to Starling mechanisms with respect to preload and augmentation of stroke volume remains important. While titrat- ing nitroprusside to achieve hemodynamic goals, doses are rarely greater than 4 µg/ kg/min to maintain adequate vasodilation in the acute heart failure setting, and dosing this high should generally be avoided for prolonged periods (more than 72 h) due to the risk of thiocyanate and cyanide toxicity. The most common serious adverse effect of nitroprusside administration in acute heart failure is systemic hypotension. One should be particularly cautious when initiating nitroprusside in a patient with ischemia or infarction and a systolic arterial pressure of less than 100 mmHg. An increase in heart rate during the infusion is an ominous finding and usually presages hypotension. This 240 Auer typically occurs when stroke volume has not increased appropriately, often because of ongoing or worsening ischemia, valvular regurgitation, and inadequate cardiac reserve. Alterna- tively, the addition of a positive inotropic agent such as dobutamine is often advantage- ous and may allow for the continuation of nitroprusside. Such a combination is commonly used while stabilizing particularly severe, low-output heart failure until more definitive therapy can be instituted. When systemic hypotension and poor peripheral perfusion is present at the outset, nitroprusside should generally be avoided as initial treatment. As noted above, thiocyanate toxicity is a potentially serious side effect of pro- longed nitroprusside infusion and is manifest clinically by nausea, disorientation, psy- chosis, muscle spasm, and hyperreflexia when plasma thiocyanate concentrations exceed 6 mg/dL. This is uncommon in the management of acute heart failure where nitroprus- side therapy is usually a temporary means of support while awaiting definitive therapy. Cyanide toxicity is extremely rare in heart failure management and only occurs during prolonged, high-dose infusions, usually in the setting of significant hepatic dysfunction. The concept of intravenous vasodilator therapy in acute heart failure is based on correc- tion of hemodynamic derangement and stabilization of the patient while a therapeutic plan is devised. The necessity for prolonged treatment (>72 h) often portends a poor prognosis, particularly in the absence of a reversible underlying disorder. Hydralazine Hydralazine, like diazoxide, is a direct arteriolar vasodilator with little or no effect on the venous circulation. Thus, the same precautions apply in patients with underlying coronary disease or a dissecting aortic aneurysm, and a beta-blocker should be given concurrently to minimize reflex sympathetic stimulation. The hypotensive response to hydralazine is less predictable than that seen with other parenteral agents and its current use is primarily limited to pregnant women. Minoxidil In the case of refractory hypertension, powerful additional hypertension agents such as minoxidil may be necessary. The glucuronide metabolite appears to have some activity either alone or possibly as a reser- voir for endogenous cleavage back to the parent compound. Cardiovascular Drugs 241 of glucuronide and parent drug occurs, and pharmacologic effect may be enhanced in patients with decreased renal function. In general, lowering the blood pressure with antihypertensive agents, weight loss, or dietary sodium restriction decreases cardiac mass in patients with left ventricular hypertrophy. Regression is largely absent with direct vasodilators (such as hydralazine or minoxidil) despite adequate blood pressure control. Diazoxide Diazoxide, in comparison to nitroprusside and nitroglycerin, is an arteriolar vaso- dilator that has little effect on the venous circulation. Diazoxide is also longer acting and, in the currently recommended doses, requires less monitoring than nitroprusside, since the peak effect is seen within 15 min and lasts for 4–24 h. A beta-blocker such as propranolol or labetalol is usually given concurrently to block reflex activation of the sympathetic nervous system.