Nimotop
By H. Basir. Western International University.
Selective antibodies can also be used to quantitate the amount of a particular P450 or P450 family in liver tissue generic nimotop 30mg free shipping muscle relaxant xylazine. A common feature of liver tissue preparations is that there is usually large inter- individual variation between preparations. This arises in part from true individual dif- ferences and from differences in tissue preparation. The metabolic pathway in question is measured in the different preparations and plotted as a scatter gram against the marker activities or contents. High and low correlation coefficients provide supportive evi- dence of the enzymes’ positive or negative involvement, respectively. As with any cor- relation experiments the distribution of activities should be carefully examined to assure no heterogenous scatter is creating a biased result (24). By themselves, they can only determine the ability of the enzyme to perform the reaction. Involvement of Specific P450s in the Metabolism of Benzodiazepines The metabolism of a number of benzodiazepines has been studied using the meth- ods described above. P450 3A4 is the most abundant P450 in most livers, while 3A5 is detected in only approximately 20% of livers (51). In a few of the studies cited above, 3A4 and 3A5 mediated activities have been compared. Equivalent activities were found for diazepam 3-hydroxylation and N-demethylation (27,29), and for midazolam 4-hydroxylation (33,35). Drug Interactions with Benzodiazepines 23 was more active than 3A5 for nordiazepam 3-hydroxylation and temazepam N-dealkyla- tion (27,28). As some differences have been observed in the response of 3A4 and 3A5 to inhibitors (22), the differential metabolism of benzodiazepines by these two members of the 3A family may play a factor in suscep- tibility to certain drug interactions. P450 2C19 appears to play a role in the N-demethylation of diazepam, temazepam, adinazolam, N-desmethyladinazolam, and flurazepam. For diazepam, this involvement has been confirmed from studies comparing extensive and poor 2C19 metabolisors (52). For 3 poor metabolizers, compared to 13 extensive metabolizers, the clearance of diaz- epam was reduced by 50%, and the elimination half-life was increased twofold (52). With nordiazepam also, the clearance was reduced by 50%, and the elimination half-life was increased twofold (52). This suggests that 2C19 can also be involved in some 3-hydroxylation reactions, which was not readily apparent from the results of the in vitro studies (27). Whether this role of 2B6 will have clinical significance has yet to be determined. If high 2B6 content is coupled with low 3A4 and 3A5 content, then the likelihood of 2B6’s contribution to the metabolism of some ben- zodiazepines may be increased. In summary, P450 3A4 (and 3A5) are extensively involved in many pathways of oxidative metabolism of benzodiazepines. P450 2C19 is involved in many of the N- demethylation reactions, and may play a role in some other oxidative pathways. Though a number of metabolic pathways of benzodiazepines have been studied, many have not. Little is known of the role of specific uridine diphosphate glucuronosyl transferases or sulfotransferases in conjugation of benzodiazepines or of the enzymes involved in reduction and subsequent acetylation of the nitroso-benzodiazepines. General Considerations Both pharmacodynamic and pharmacokinetic mechanisms have been observed for drug interactions concerning benzodiazepines. Most pharmacokinetic drug interac- tions involve either the inhibition or induction of specific P450s involved in the metab- 24 Moody olism of benzodiazepines. They are the most common and the better documented of drug interactions with benzodiazepines. Most, however, result in either an increased (inhib- itors) or decreased (inducers) activity of the benzodiazepine.
Research shows that women who have the highest endogenous levels of estradiol (meaning the estradiol their body creates) have the greatest risk of breast cancer discount nimotop 30mg overnight delivery muscle relaxer kick in. It stands to reason that low progesterone, the first step toward menopause, is also genetically determined. It’s good to find out if you have a genetic predisposition to that problem, because then you can look into boosting your progesterone using The Gottfried Protocol. Start the inquiry by asking your mother about her age at menopause, and when her menstrual cycles started to change. Of course, exposure to environmental factors, such as endocrine disruptors and birth control pills, can affect when you have your final period. Stop, Thief: Stress and Pregnenolone Steal Although progesterone is mostly made in the ovaries, a small amount is produced in the adrenal glands, where it can be converted into other hormones, such as cortisol. Your adrenal glands have a crucial job: to respond to stress by producing cortisol and the neurotransmitters epinephrine and norepinephrine, which help you focus, and tend and befriend as needed in a dangerous situation. Progesterone is made from pregnenolone, the main “prehormone,” or biochemical precursor, from which all sex hormones are derived. It may not surprise you to learn that there’s a link between progesterone and cortisol: just as pregnenolone is the prehormone of progesterone, progesterone is the prehormone of cortisol. Still, when you are chronically stressed, your body uses cortisol faster than it can be produced, so you need to get more. You take it from cortisol’s prehormones: pregnenolone and progesterone, fittingly called Pregnenolone Steal. If you have a lifestyle that keeps you in high demand for cortisol (see chapter 4 for assessment), your body will steal from your supply of progesterone by shunting pregnenolone so that it can make more cortisol. As if that weren’t bad enough, when chronic stress causes cortisol levels to rise, the cortisol also will block your progesterone receptors. If progesterone can’t bind with a receptor because cortisol is having molecular sex with it, you will feel low in progesterone even if your serum level is normal, because progesterone cannot get inside of your cell’s nucleus. Since progesterone is a diuretic, you’ll notice fluid retention, and perhaps breast tenderness as well. Clearly, stress relief is essential for more than regulating high or low cortisol. Other Hormones That Take Down Progesterone From chapter 2, “A Hormonal Primer,” you are well aware of the cross talk between the ovaries, adrenals, and thyroid, which I liken to Charlie’s Angels. When it comes to low progesterone, a slow thyroid can lower progesterone too, and vice versa. Finally, one other minor hormone worth mentioning is prolactin, the hormone that originates in the pituitary of the brain and controls breast milk production (or lactation); women with high prolactin usually have a milky discharge from both breasts. Prolactin has many other jobs, related to water and salt balance, growth and development, ovulation, behavior, and immune regulation. Making too much prolactin can lower your progesterone level and stress raises prolactin. Low progesterone is one of the top three hormone imbalances, and it’s also one of the easiest to mend. Rather than jumping to the solution for your low-progesterone symptoms, I encourage you to perform root-cause analysis. When you understand why your progesterone is low, you’ll get better results because you can customize your solution. When I say a patient needs to balance her estrogen and progesterone, I have something quite specific in mind, a clear solution based on solid numbers. Here it is: You want your serum progesterone on Day 21 or 22 of your menstrual cycle to be 10 to 25 ng/mL. Additionally, you want the ratio of your salivary progesterone to your estradiol to be 1 to 300. To put it another way, during the luteal phase, the amount of progesterone in a normal woman who is fertile and ovulating is three hundred times the concentration of estradiol, ideally measured five to six days before your period starts. You may need to have a pelvic ultrasound or a biopsy to make sure you don’t have an excessively thick uterine lining. Four other, more serious conditions related to low progesterone include the following: 1. The most common cause of pelvic pain, endometriosis affects up to 10 percent of the women in the United States. It occurs when cells of the endometrium, or uterine lining, migrate and implant outside the uterus, usually on the ovaries or other pelvic organs, causing inflammation and sometimes extreme pain.
These demonstrate that ketoconazole can inhibit many P450s discount 30 mg nimotop free shipping spasms when i pee, 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.
The mixed inductive and inhibitory nature of the protease inhibitors and the nonnucleoside reverse transcriptase inhibitors may make it more difficult to predict when drug interactions will occur generic 30 mg nimotop visa spasms lower back pain. Interactions with Grapefruit Juice In a seminal study reported in 1991, Baily et al. P450 3A4 is also the major P450 in the gastrointestinal system (327,328), and the drugs affected by grapefruit juice are 3A4 substrates (329,330). Efforts to determine the components of grapefruit juice responsible for its inhibitory effects therefore cen- tered on P450 3A4 inhibitors. It can make up to 10% of the dry weight of the juice and is responsible for the bitter taste. Additional studies confirmed the ability of these flavonoids to inhibit 3A4 specific activities, including nifedipine oxidation (334), midazolam a-hydroxy- lation (37,335), quinidine 3-hydroxylation (335), 17b-estradiol metabolism (336), and saquinavir metabolism (337). Two clinical studies examined the relative inhibitory action of quercetin vs grapefruit juice on nifedipine pharmacokinetics (338) and narin- gen vs grapefruit juice on felodipine pharmacokinetics (339). Neither flavoniod when administered at doses comparable to those in the grapefruit juice caused any effect on the bioavailability of the drug (338,339). Their inhibitory capacity for 3A4-related substrates was one to two orders of magnitude greater than the flavonoids (Fig. The relative potency of components of grapefruit juice to inhibit P450 3A4 activities. The data for the flavonoids are for nifedipine oxidation and are from Guengerich and Kim (333). With only limited amounts of the furanocoumarins available, there has not yet been a clinical study to indicate they can substitute for grapefruit juice in causing drug inter- actions. Their role in grapefruit juice drug interactions therefore has not yet been established. Grapefruit juice also effects P-glycoprotein-mediated transport, increas- ing the basolateral to apical flux (337,346,347). The relative role the transporter and P450 3A4 have on the bioavailability of a drug may also be important in determining the active component in the effect of grapefruit juice. For benzodiazepines undergoing oxidative metabolism, P450 3A4 appears to be more important. In normal subjects, the effect was modest, and accompanied with no or only minor effects on the pharmacodynamics of the benzodiazepines (348,350–352). This suggests that cirrhotics are more dependent upon intestinal metabolism of midazolam. In a study on other juices, tangerine juice was found to delay the absoprtion of midazolam and slightly delay its pharmacodynamic effects (353; Table 29). Interactions with Miscellaneous Agents Clinical studies concerning potential drug interactions with benzodiazepines have been performed with a number of drugs for which either only a single drug in its class was studied, or there was no explicit connection with an aspect of drug metabolism. It did produce a significant decrease in the pharmacodynamic measures of diazepam (354; Table 30). The effect of chronic theophylline on alprazolam was compared in subjects with chronic obstructive pul- monary disease that were or were not taking theophylline. Caffeine was found to have no effect on the pharmacokinetics of diazepam (356) or alprazolam (203); but caffeine did slightly diminsh the pharmaco- dynamic measures for diazepam (356; Table 30). Chronic disulfiram treatment was found to diminsh the elimination of chlordiazepoxide and diazepam, but not that of oxazepam in normal subjects (Table 30). The clearance and t1/2 of the three benzodiazepines in chronic alcoholics who had received chronic disul- firam treatment were similar to those in the disulfirma-treated normal subjects (358). In a study with 11 chronic alcoholics, alprazolam was given prior to initiation of disul- firam treatment and again after 2 wk of disulfiram; no change in the pharmacokinetics of alprazolam was noted (359). Like oxaze- pam it is primarily elimated after glucuronidation, and both are highly protein bound. When oxazepam was given before and after 7 d of 2/d treatment with diflunisal, the Cmax of oxazepam was decreased and its oral clearance increased. The authors conclude that the interaction resulted from the displacement of oxazepam from its protein-binding sites and by inhibition of the tubu- lar secretion of the oxazepam glucuronide. The authors concluded that these find- ings were consistent with the induction of P450 and/or glucuronidation (360).
