By K. Chris. New England Conservatory of Music.

When these drugs are administered concomitantly 800 mg neurontin free shipping, the tissue binding of digoxin is reduced discount neurontin 300mg mastercard. This is also an example of displacement but buy generic neurontin 100mg on-line, in this case, quinidine has a higher affinity for the tissue protein binding site and displaces digoxin, resulting in a high unbound fraction in the tissue. What are the consequences of digoxin having a higher unbound fraction in the tissue due to quinidine displacement? We next consider the effect of a disease state (chronic renal failure) on the volume of distribution of phenytoin and digoxin. The equation below predicts that an increase in the unbound fraction in the plasma would result in an increase in the volume of distribution of phenytoin, which would increase the concentration of the active unbound phenytoin able to cross the blood-brain barrier. Because digoxin is negligibly bound to plasma proteins, changes in its concentration should not be of clinical significance. However, renal failure does reduce the cardiac muscle-to-plasma digoxin concentration ratio to 30:1. The mechanism by which renal failure alters the tissue protein binding of digoxin is presently not fully understood. The equation below predicts that an increase in the unbound fraction in the tissue would result in a decrease in the volume of distribution of digoxin and may cause an increased plasma digoxin drug concentration: In all these examples, the volume of distribution of the drug in question was altered as a consequence of a drug-drug or drug-disease state interaction. Drugs are generally less well distributed to highly perfused tissues (compared with poorly perfused tissues). Estimate the volume of distribution for a drug when the volume of plasma and tissue are 5 and 20 L, respectively, and the fraction of drug unbound in plasma and tissue are both 0. The portion of drug that is not bound to plasma protein is pharmacologically active. Penetration of drug into tissues is directly related to the extent bound to plasma proteins. Predict how the volume of distribution (V) would change if the phenytoin unbound fraction in plasma decreased from 90% to 85%. Assume that unbound fraction in tissues (Ft) and volumes of plasma (Vp) and tissues (Vt) are unchanged. A new drug has a tissue volume (Vt) of 15 L, an unbound fraction in plasma (Fp) of 5%, and an unbound fraction in tissues (Ft) of 5%. What will be the resulting volume of distribution if the plasma volume (Vp) is reduced from 5 to 4 L? How is the volume of distribution (V) of digoxin likely to change if a patient has been taking both digoxin and quinidine and the quinidine is discontinued? Assume that plasma volume (Vp), tissue volume (Vt), and unbound fraction of drug in plasma (Fp) are unchanged. Solve the equation using Vp = 5 L, then re-solve using 4 L and compare: If Vp is decreased to 4 L, 8-11. Remember, when quinidine is administered concomitantly with digoxin, quinidine competes with digoxin for tissue binding sites and increases the unbound fraction of digoxin in the tissues (Ft). Therefore, assuming Vp and Vt remain unchanged, the effect of quinidine is shown below: When quinidine is discontinued, the unbound fraction of digoxin in the tissues (Ft) decreases as the tissue binding sites formerly occupied by quinidine become available. Draw representative concentration versus time curves for: (a) a drug that diffuses into highly vascularized tissue before equilibrating in all body compartments, and (b) a drug that distributes equally well into all body compartments. Clinically, what type of loading dose adjustments can be made to account for these factors? A patient has a total plasma phenytoin concentration of 19 mcg/mL with a serum albumin concentration of only 2. In the same patient as described in discussion point D-4, calculate a new total phenytoin concentration that would yield a therapeutic unbound phenytoin concentration. Describe the impact of disease and altered physiologic states on the clearance and dosing of drugs. Define the methods of hepatic drug metabolism and the approaches used to quantitate and characterize this metabolism. Define both the physiologic and mathematical relationship of drug clearance to glomerular filtration. Although both organs share metabolic and excretory functions, the liver is principally responsible for metabolism and the kidneys for elimination. The importance of these organs cannot be overestimated in determining the magnitude and frequency of drug dosing. Additionally, an appreciation of the anatomy and physiology of these organs will provide insight into the impact of disease and altered physiologic states, as well as concomitant drug administration, on the clearance and dosing of drugs. The physical and chemical properties of a drug are important in determining drug disposition. For example, lipophilic drugs (compared with hydrophilic drugs) tend to be: • bound to a greater extent to plasma proteins, • distributed to a greater extent throughout the body, and • metabolized to a greater extent in the liver. Hydrophilic drugs, particularly ionized species, tend to have more limited distribution and more rapid elimination (often by renal excretion). Metabolism (also known as biotransformation) involves conversion of the administered drug into another substance. Metabolism can result in the formation of either an active or inactive metabolite, which is then eliminated from the body faster than the parent drug.

However cheap neurontin 300 mg without prescription, as with Qh buy generic neurontin 400mg on line, the extent and magnitude of such an effect would depend on the extraction characteristics of the drug buy neurontin 800mg amex. Examination of the equation for the venous equilibrium model at the extremes of intrinsic clearance values provides insight into the influences of hepatic blood flow and intrinsic clearance on drug dosing. For high intrinsic clearance drugs, Cl is much greater thani Qh; Qh becomes insignificant when compared to Cli. Therefore, when Cl is large, Cli h equals Qh, or hepatic clearance equals hepatic blood flow. Hepatic clearance is essentially a reflection of the delivery rate (Qh) of the drug to the liver; changes in blood flow will produce similar changes in clearance. Consequently, after intravenous administration, the hepatic clearance of highly extracted compounds (e. This particular commonly used model is best applied to intravenously administered drugs, as orally absorbed drugs with high extraction ratios may act more like low-extraction drugs. However, there is no clear- cut division between the classes described; additional factors may need to be considered when predicting drug disposition. However, the magnitude of change in E depends on the initial value of the intrinsic clearance of the drug. Increasing Cl causes ani i almost proportional increase in extraction and hepatic clearance. However, if Cl and E are alreadyi high, a further increase in intrinsic clearance does not greatly affect the extraction ratio or hepatic drug clearance. The result can be that the amount of drug reaching the systemic circulation is considerably less than the dose given. The first-pass effect becomes obvious when we examine comparable intravenous and oral doses of a drug with a high extraction ratio. For propranolol, plasma concentrations achieved after oral doses of 40-80 mg are equivalent to those achieved after intravenous doses of 1-2 mg. The difference in required dosage is not explained by low oral absorption but by liver first-pass metabolism. Therefore, the liver can metabolize or extract a certain portion of the drug before it reaches the systemic circulation. Also, enzymes in the gut wall can metabolize the drug before it reaches the liver. For example, if the drug is 100% absorbed across the gut wall and the liver extracts 70% before it reaches the systemic circulation, 30% of the dose finally reaches the bloodstream. Therefore, we will consider the potential impact that changes in Qh, Fp, and Cli will have on the steady-state concentration of both total and free drug concentration. Remember, we will assume that Cl (totalt body clearance) equals Clh (hepatic clearance) and that steady-state free drug concentration is the major determinant of pharmacologic response. When trying to assess clinical implications, always consider the following: • route of administration (intravenous vs. In the following three examples, we apply the previously described hepatic extraction equation to several cases involving a specific disease state effect or drug interaction. Considerations • Theophylline (in this example) is administered via a constant intravenous infusion (K0). Because theophylline has a low extraction ratio and is not extensively bound to proteins, Clh = Fp × Cl. Impact on Css(free) Because K0 is unchanged and Cl is reduced by 50%,i Css(free) should double. Consequence You should anticipate significant side effects as a consequence of a higher free steady-state concentration of theophylline (Figure 9-8). Figure 9-9 demonstrates changes in plasma theophylline concentrations when enoxacin is begun and then later 1 discontinued. Considerations • Phenytoin is administered by intermittent intravenous administration. Impact on Css(free) BecauseK0 and Cl are unchanged,i Css(free) should remain unchanged. However, the total concentration necessary to achieve this therapeutic unbound concentration will be less than the normal reference range for phenytoin. Myocardial infarctions are known to significantly increase the concentration of alpha-1-acid glycoprotein (a serum globulin) and the protein binding of drugs associated with it. The protein binding of lidocaine is known to be high and primarily dependent on alpha-1-acid glycoprotein. Because lidocaine has a high extraction ratio and binds extensively to alpha-1-acid glycoprotein, Clh = Qh.

Profts of Indian menthol mint Mentha Brussels order neurontin 800mg visa, Belgium: Scientifc Committee on Food 400 mg neurontin with mastercard. Berlin: Springer- botanical and geographical origin of spearmint oils by Verlag; Vol 5 generic 400 mg neurontin overnight delivery, p. Partial characterization of biliary metabolites of pule- Peppermint oil quality diferences and the reason for gone by tandem mass spectrometry. Final report on the safety assessment of menthofuran to the hepatotoxicity of pulegone: of Mentha Piperita (Peppermint) Oil, Mentha assessment based on matched area under the curve Piperita (Peppermint) Leaf Extract, Mentha Piperita and on matched time course. J Pharmacol Exp Ter, (Peppermint) Leaf, and Mentha Piperita (Peppermint) 244(3):825–9. An Encyclopedia of Chemicals, Drugs, limonene-6-hydroxylase, isopiperitenol dehydroge- and Biologicals. Determination of geographical origins of tion, covalent binding to target proteins and toxicity relevance. Due to its hygroscopic nature, commercial methylene blue is typically sold Methylene blue was originally synthesized as the hydrate, but is sometimes incorrectly in 1876 as an aniline-based dye for the textile presented as the trihydrate. Name: Phenothiazin- realize its potential for use in microscopy stains 5-ium, 3,7-bis(dimethylamino)-, chloride (Ehrlich, 1881; Oz et al. Methylene blue Methylthioninium chloride; Phenothiazine- was also the frst synthetic compound ever used 5-ium,3,7-bis, (dimethylamino)-, chloride; as an antiseptic in clinical therapy, and the frst Swiss blue; Tetramethylene blue; Tetramethyl antiseptic dye to be used therapeutically. Instead of sodium dichromate, manga- trimethylthionin (azure B) (PubChem, 2013) nese dioxide, and catalytic amounts of copper sulfate can be used for the oxidation (Berneth, N 2008). In malaria combi- nation therapy, methylene blue is also advanta- (a) Indications geous because the blue colour of the urine can be Methylene blue is used in human and veter- used as an indicator that the drug combination inary medicine for several therapeutic and containing methylene blue has not been counter- diagnostic procedures, including as a stain in feited, which is a serious problem in developing bacteriology, as a redox colorimetric agent, as a countries (Schirmer et al. For inherited methaemo- poisons such as excessive nitrate in well-water, globinaemia, the suggested oral dosage was or cyanide compounds (Sills & Zinkham, 1994; 1 × 50–250 mg/day (for a lifetime), while for acute Christensen et al. In ifosfamid- lytic and antidepressant properties attributed to induced neurotoxicity, oral or intravenous doses its ability to block activation of guanyl cyclase of 4 × 50 mg/day were used. In Alzheimer Drug Administration of the United States issued disease, the dosage was 3 × 60 mg/day, and for a safety warning concerning the risk of serotonin paediatric malaria it was 2 × 12 mg/kg bw orally syndrome when methylene blue is given concur- for 3 days (Schirmer et al. According may have benefcial efects in the treatment of to Medscape (2013), a solution (10 mg/mL) may Alzheimer disease and memory improvement be injected at the following intravenous dosages: (Oz et al. Methylene blue is used as a disinfectant and No systematic data on other exposures, e. As a environmental contamination, were available to disinfectant, methylene blue is sold to end-con- the Working Group. In the few Methylene blue is used to dye paper and ofce available studies, it was found that metabolites supplies, but also to tone up silk colours (Berneth, rather than methylene blue itself were detect- 2008). In the European Union, the use of methylene blue in food-producing animals is not allowed. Specifcations for methylene blue are published in several ofcial pharmacopoeias 1. Cancer in Humans for all routes of administration (151/1507; range, 4–24%) and the incidence in controls in the current study was below the range for historical No data were available to the Working Group. Cancer in Experimental Animals alveolar carcinoma was therefore not related to treatment with methylene blue. Tere was an increase trend: 6/50 (12%), 4/50 (8%), 9/50 (18%), 12/50 in mean body weight in females at the interme- (24%); P = 0. In males, the inci- increase in the trend in the incidence of carci- dences were 2/50 (4%), 2/50 (4%), 2/50 (4%), 5/50 noma (P= 0. While the incidence in the group at the or carcinoma (combined) of the small intestine highest dose was higher than in controls, it was (P = 0. Te incidence of adenoma or carcinoma (combined) in the group receiving the In a study of oral administration, groups of highest dose (12%) exceeded the range for histor- 50 male and 50 female F344/N rats (age, 6 weeks) ical controls (39/1508; range, 0–10%); while the received methylene blue in a 0. Te mean carcinoma of the lung occurred with a signif- body weights of males and females in groups at cant positive trend: 1/50 (2%), 4/50 (8%), 5/50 the intermediate and highest dose were decreased (10%), 7/50 (14%); P = 0. Te incidences of adenoma were: 4/50 and excreted largely in the urine as the reduced (8%), 9/50 (18%), 12/50 (24%), and 8/50 (16%); leucomethylene blue (colourless) form (DiSanto and the incidences of adenoma or carcinoma & Wagner, 1972a; Fig. Te N-demethylated (combined) were: 4/50 (8%), 9/50 (18%), 14/50 metabolites azure A (minor), azure B, and azure (28%), and 8/50 (16%). Te incidences were signif- C (minor), which have the potential to undergo icantly increased only in the group receiving the deprotonation to a neutral quinone imine, have intermediate dose (adenoma, P = 0. Excretion rate–time plots for methylene blue and leucomethylene blue suggested a circadian rhythm (DiSanto & Wagner, 1972a). Mechanistic and Other In another study, the concentration of Relevant Data methylene blue in whole blood was measured in healthy individuals, before and afer oxida- tion, following intravenous (n = 7) or oral (n = 4. Te elim- tion of total methylene blue (methylene blue and ination was slow (t1/2 = 11. In this study, fvefold higher in whole blood than in plasma approximately one third of the methylene blue (Peter et al. It is not intravenously (n = 16) versus 500 mg orally clear whether or not discrepancies in the relative (n = 16).