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That type of information is spread within a large body of literature that is relatively recent but expanding at a fast pace order cheap clomipramine line anxiety 24 hour helpline. A description of the database generic 75 mg clomipramine fast delivery anxiety herbs, examples of queries purchase clomipramine now anxiety 7 minute test, and sample outputs are presented in this chapter purchase cheap clomipramine on-line bipolar depression quiz online. Detailed records are generated from each research article, highlighting study results as well as experimental conditions; the data extracted from each article are structured in the database according to a defined hierarchy. For example, relevant information collected from in vitro studies pertain to the role of particular metabolic enzymes in the various metabolic pathways of substrates and the inhibition and induction spectra of drugs toward metabolic enzymes. In vivo studies include pharmacokinetic studies with blood level measurements, pharmacokinetic-pharmacodynamic studies, as well as case reports. Queries are structured along intuitive themes such as drug, enzyme, therapeutic class, transporter, and thus allow the user to quickly select the appropriate queries without the need for extensive training. The eight sets of queries can be categorized into qualitative or quantitative queries as shown below: Qualitative: Drug Search by drug name, using generic names Enzyme Search by enzyme name Therapeutic class Search by therapeutic class Transporters Search by transporter name Other Search for articles using journal or author name. A precipitant can be an inhibitor, inducer, or activator, but may not have any effect. In human liver microsomes, efavirenz undergoes hydroxylation to 8-hydroxyefavirenz (major in vivo) and 7-hydroxyefavirenz (minor) and secondary metabolism to 8,14-dihydroxyefavirenz. The query used is labeled ‘‘multiple objects’’ and is available under the section ‘‘Drug Queries’’ (Fig. Metabolism and Transport Drug Interaction Database 571 Figure 2 List of precipitants evaluated with the substrates bupropion and efavirenz and which have shown more than 20% effect in in vivo inhibition. Result Output The display shown on Figure 2 has an alphabetical list of four precipitants (clopidogrel, erythromycin, ticlopidine, and levofloxacin) that have been eval- uated with the substrates bupropion and efavirenz and which have shown more than 20% effect in in vivo inhibition. There are several options of displaying the results in a table and performing filter operations as well as exporting capabilities into Microsoft Excel or Microsoft Word. The product label indicates that the compounds examined for their inhibitory effects on efavirenz are: indinavir, lopinavir/rit, nelfinavir, ritonavir, saquinavir, azithromycin, clarithromycin, fluconazole, paroxetine, sertraline, ethinyl estradiol, famotidine, voriconazole, and cetirizine (20). Dis- play from the Metabolism and Transport Drug Interaction Database (http://www. Interpretation Inhibitors obtained from in vitro data include a number of compounds with different selectivities and specificity toward this enzyme. Most of them have not been tested for their in vivo effects and some may also inhibit other enzymes (ticlopidine, fluvoxamine, miconazole, nefazodone, paroxetine, etc. Result Output In the case of simvastatin and midazolam, nine shared inhibitors, tested at a com- parable dose regimen, are available. Exceptions pertained to buspirone and simvastatin that seemed to be systematically more sensitive than midazolam and saquinavir that appeared less sensitive (22). Furthermore, results of this analysis allow an extrapolation of the inhibitory effect of a compound from one probe to another avoiding a duplication of studies (i. In Vitro Data Related to Transporters Transporter-based interactions have been increasingly documented. Guidance for Industry: Drug Metabolism/Drug Interaction Studies in the Drug Development Process, Studies In Vitro. Guidance for Industry: In Vivo Drug Metabolism/ Drug Interaction Studies—Study Design, Data Analysis, and Recommendations for Dosing and Labeling U. Guidance for Industry: Drug Interaction Studies— Study Design, Data Analysis, and Implications for Dosing and Labeling. Development of a metabolic drug interaction database at the University of Washington. Pharmacogenetic determinants of inter- individual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. However, even before this critical event, it was apparent that the oxidative metabolism of drugs often exhibits large interindividual variability; moreover, drug-metabolizing activity may be modulated by environmental, pathophysiological, and genetic factors (1). Research during the subsequent four decades has largely focused on determining the mechanisms involved in such variability and, in the case of drug metabolism in humans, its clinical signifi- cance and importance. In certain situations, genotyping with respect to the presence of allelic variants can be of some value in accounting for this inter- individual variability, especially, if a strong genetic determinant is involved (2,3). However, even when genetic polymorphism is present, considerable variability is often present within a phenotypic group (2); moreover, genotyping cannot take into account the modulation of catalytic activity by environmental and disease-state factors. However, the application of such invasive pro- cedures to the clinical situation is obviously limited, especially when studying healthy subjects. Accordingly, so-called ‘‘noninvasive’’ procedures, utilizing readily available fluids, such as plasma and saliva, or excretions, such as urine and expired air, form the basis for measuring in vivo metabolizing ability. These measures are generally applied to two related types of experimental questions: What is the basal level of catalytic activity in an individual subject, i. What are the determinants of interindividual variability within or between populations, e. The use of ‘‘model’’ compounds or, as currently termed, in vivo probes, has been extensively applied for these purposes since its conception some 30 years ago (4). The plasma levels of g-glutamyltransferase and bilirubin as markers of hepatic dysfunction and the urinary excretion of endogenous 6b-hydroxycortisol and D-glucaric acid have been sporadically investigated for this purpose over the years (5,6). With the exception of 6b-hydroxycortisol, these approaches have proven fruitless, but even the measurement of the hydroxysteroid’s excretion has limi- tations. Collectively, these data raise serious questions regarding the nature and inter- pretation of any measured increase in urinary 6b-hydroxycortisol excretion over its basal level. Regardless, the current status of this endogenous probe would appear to be limited to its use as a relatively nonspecific indicator of enhanced oxidative metabolism following pretreatment with a putative inducing agent (14–16). Desirable Phenotypic Trait Characteristics Beginning with the use of antipyrine (4), administration of a model drug to quantitatively assess oxidative drug-metabolizing activity has been an important experimental tool. However, available in vivo probes provide a collective estimate of the measured catalytic function within the body. That is, assessment of activity by an individual organ is usually not possible, despite the fact that this may be critical to inter- preting the phenotyping result. Following administration of an in vivo probe, an experimental measure characterizing the enzyme’s functional activity is obtained. Ideally, this phe- notypic trait should exclusively reflect the catalytic activity of a single pathway of metabolism mediated by the isoform of interest. In practice, evidence of such absolute specificity is difficult, if not impossible, to obtain in vivo, so the trait measure should be considered a primary, rather than an exclusive, reflection of the isoform’s activity. It is also desirable that the trait measure be sensitive to changes/differences in the enzyme’s catalytic activity produced, for example, by a drug interaction or a genetic factor. Unless this characteristic is present, small changes/differences in activity will not be recognized. Additionally, differences in enzyme activity should ideally result in a linear change in the phenotypic 584 Wilkinson value so that discrimination between values is readily interpretable. It also makes common sense and is esthetically more satisfying if the value of the trait measure increases with an increase in catalytic activity.

Use dependence issimply a result of binding kinetics order clomipramine with a mastercard anxiety 30000, which reflects that at faster heart rates buy cheap clomipramine 50 mg on-line depression rates, there is less time for the drug to unbind from the sodium channel before the next actionpotential begins; thus purchase clomipramine us anxiety from weed, at faster heart rates buy cheap clomipramine 75mg on line symptoms depression versus bipolar, the drugs have a more profound effectonconduction velocity than they have at slower heart rates. In addition, ischemia, hyperkalemia, and acidosis can slow the binding kinetics of Class I drugsand thus increase the effectofthedrugson the sodium channel. The Vaughan-Williams classification system accounts for the bind- ing kinetics of the sodium-blocking drugs. Although no classification systemislikely to neatly charac- terize the nuances of sodium binding for every drug, the Vaughan- Williams system offers reasonably accurate generalizations about sodium-binding properties of antiarrhythmic drugs. The Vaughan-Williamsscheme is more challengedwhen one be- ginstoconsider the effectofantiarrhythmic drugson the potassium channel. As a result, application of the Vaughan-Williams system becomes very difficult in some cases. Ultimately, the classification of some drugsappears to be a matter of consensus rather than a matter of science. Although the Vaughan-Williamsschemethusappears incapable of offering definitive classification for all possible mixtures of sodium- and potassium-channel blockade, it nonetheless suggests a frame- work for characterizing evendifficult-to-classify drugs. The frame- work becomes apparent when onethinks of the general interplay of sodium-blocking and potassium-blocking properties as represent- ing a continuum of possible effects instead of a categorical series of discrete effects (Figure 2. The advantageofthinking about drug effects along a continuum is that hard-to-classify drugs, suchasmori- cizineand amiodarone, can be positioned at appropriate points along the continuum instead of being arbitrarily assigned to a specificclass. The Vaughan-Williams classification system, thoughad- mittedly imperfect, helpstolocate drugs along the continuum,and therefore helpstoelucidate the electrophysiologic properties even of drugs that are difficult to formally classify. As ithappens, the Vaughan-Williamsscheme also allowsoneto make other clinically relevant generalizations aboutantiarrhythmic drugs. What emergedwas a new approach to the classification of antiarrhythmic drugs; the inventors imaginatively named the approach the Sicilian Gambit. The Vaughan-Williamsscheme is based onwhether drugs pro- duce block in oneormore of a few sites on the cell membrane, but the Sicilian Gambit takes into account a host of additional actions 50 Chapter 2 of antiarrhythmic drugs—the typeand degree of blockadeofchan- nels, antagonistic and agonistic effects on receptors, effects on the sodium–potassium pump, the time constants of binding to cellular sites, effects on second messengers, and the affinity for binding on the basisofwhether the cell is in an active or inactive state. Digoxin Relative potency of block: Low Moderate High A=Activated state blocker =Agonist =Agonist/Antagonist I = Inactivated state blocker Figure 2. Effects of each drug onchannels, receptors, and pumps are shown, as are someoftheclinical effects. Introduction to antiarrhythmic drugs 51 Two major differences exist between the Vaughan-Williams schemeand the Sicilian Gambitapproach. First, the Sicilian Gambit is far more thorough than the Vaughan-Williams systemindescrib- ing the precise actionsofantiarrhythmic drugs. Second, inasmuch as each drug is essentially in its own class (since notwo drugs are exactly alike in all the ways listed), the Sicilian Gambit is notatrue classification system. It is, in fact, useful to have a complete tabulation of all known effects of antiarrhythmic drugs. Such a table allowsonetoeasily compare the recognized similarities and differences among drugs. Further, when the mechanisms of arrhythmias have become more precisely delin- eated, precise knowledgeofindividual drugs may helpinformu- lating more accurate guesses as to effective pharmacologic therapy (which was a specificgoal in devising the Sicilian Gambit), although it islikely to be always true that nearly identical patients with nearly identical arrhythmias often respond differently to the same drug. However, because the Sicilian Gambit is not a true classification system, it does not offer much help to the average clinicianinlearn- ing aboutorcommunicating aboutantiarrhythmic drugs. Es- pecially for the nonexpert, the Vaughan-Williams system, with all its limitations, remains the most useful meansofcategorizing an- tiarrhythmic drugs;it is the system that will be used throughoutthis book. Yet, because of their varied effects on the sodium channel and the potassium channel, drugs assigned to Class I can behave very differently from oneanother. The major clinical features, electrophysiologic properties, and adverse effects of Class I antiarrhythmic drugs are summarizedinthe accompanying tables. Unfortunately, they are also moderately effective in causing both major varieties of side effects—end-organ toxicity and proarrhythmias. Quinidine Quinidine is the D-isomer of the antimalarial quinine, a drug that was noted to be effective in the treatmentofpalpitationsaslong 55 56 Chapter 3 Figure 3. Quinidine itself was recognized as an effective antiarrhythmic agent in the early twentieth century. Clinical pharmacology Quinidine isadministered orally as one of three salts (quinidinesul- fate, quinidine gluconate, or quinidine polygalacturonate). All three forms of the drug have beenmade available because some patients tolerate one salt better than another. Approximately 80–90% of the sulfate preparationis absorbed after oral administration,and peak plasma concentrations are reachedwithin 2 hours. The gluconate and polygalacturonate preparations are absorbedmore slowly and less completely than the sulfate formulation. Quinidine is 80–90% protein bound in the circulation and has a large volumeofdistribu- tion. The concentration of the drug is 4–10 times higher in the heart, liver, and kidneys thanit is in the circulation. Its elimination half-life is 5–8 hours but may be prolongedinpatients with congestive heart failure or in the elderly. Electrophysiologic effects Quinidine blocks the sodium channel and slows the rate of depo- larization of the actionpotential. Its effects on the potassium channels result in prolongation of the actionpotential and, therefore, of the refractory period. Like all drugs that prolong refractoriness, quinidine cancause early afterdepolar- izations(and thus torsades de pointes) in susceptible individuals. Hemodynamic effects Quinidine blocks the α-adrenergic receptors, which can lead to pe- ripheral vasodilation and reflex sinustachycardia. The effects tend to be minimal when the drug is given orally but can be profound with intravenousadministration. Therapeutic uses Quinidine is moderately effective in treating both atrial and ven- tricular tachyarrhythmias. Approximately 50% of patients treated with quinidine for atrial fibrillation remain in sinus rhythm af- ter 1 year. Thus, quinidine has Class I antiarrhythmic drugs 59 beenused to treat virtually all varieties of reentrantsupraventricular tachyarrhythmias. Quinidine is effective in suppressing premature ventricular com- plexes and nonsustained ventricular tachycardias, butbecause of the proarrhythmic potential of quinidine(and most other antiarrhyth- mic agents), these arrhythmias shouldnot be treated excepttosup- press significantsymptoms. For the same reason,quinidine should not be used to treat sustained ventricular tachycardia without the protection of an implantable defibrillator. Adverse effects and interactions Symptomatic side effects occur in 30–50% of patients taking quini- dine, and the drug must be discontinuedin20–30% of patients be- cause of toxicity. Ingeneral, if diarrhea occurs, the drug should be discontinued,because the diarrhea is usually not adequately con- trolledwith medication and the resultant electrolyte imbalances may exacerbate the very arrhythmias that are being treated. Quinidine can also cause dizziness, headache, or cinchonism (tinnitus, visual blurring,and hearing disturbances). Rashes are fairly common,and significanthypersensitivity reactionssuchashemolytic anemiaand thrombocytopenia can also occur.

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If the drug follows first-order elimination kinetics purchase generic clomipramine canada anxiety 4 weeks after quitting smoking, how much of the drug will remain 6 hours after its administration? A subject in whom the renal clearance of inulin is 120 mLimin is given a drug buy clomipramine 50 mg mood disorder questionnaire history, the clear- ance of which is found to be 18 mLimin cheap clomipramine uk mood disorder 29699. If the drug is 40% plasma protein bound buy clomipramine amex mood disorder unspecified icd 9, what percentage of filtered drug must be reabsorbed in the renal tubules? If a drug is known to be distributed into total body water, what dose (mg) is needed to obtain an initial plasma level of 10 mg/L in a patient weighing 70 kg? A drug achieves a plasma level of 16 mg/L shortly after the administration of the first oral dose. If the half-life and the dosing interval are both 6 hours, what is the approximate plasma level shortly before the administration of the 5th dose? What is the dose needed to achieve a plasma level equivalent to a steady-state level of 20 ~g/L? At 12 h after N administration of a bolus dose, the plasma level of a drug is 3 mglL. If the Vd = 10 L and the elimination half-life = 6 h, what was the dose administered? The inhalational mode is the most rapid because of the great area of the absorptive surface and the close proximity to the blood. Albumin is the major plasma protein to which drugs bind, and the constant positive charge on quaternary amines prevents their binding to plasma proteins. Competition between drugs for plasma protein binding sites can lead to drug interactions (e. The permeation of most drugs through cellular membranes is by the process of passive diffusion, a nonsaturable process that follows first-order kinetics. Concentration gradient and lipid solubility of the drug are important determinants of the rate of diffusion. One half of the drug dose is eliminated in 120 min, so its elimination half-life = 2 hours. With the passage of each half-life, the amount in the body (or in the blood) will decrease to 50% of a former level. Thus, at 6 hours after drug administration, the amount of drug remaining is 160 divided by (2 x 2 x 2) or 160/8 = 20 mg. In this case, Vd = 42 L, which approximates total body water in a patient weighing 70 kg. The reductive biotransformation of certain drug molecules containing alde- hyde, ketone, or nitro groups can be catalyzed by cytochrome P450, and such reactions represent phase I drug metabolism. All of the other drugs listed are known to be inducers of cytochrome P450 with chronic use. The typical log dose-response figure with the parallel nature of the curves suggests that the three drugs are interacting with the same receptor system. Drug C is a partial agonist with less efficacy than either of the other two drugs. The fact that the drug has therapeutic efficacy for 6 h has no direct relationship to its half-life-it simply means that the drug is above its minimal effective concentration for 6 h. Doubling the dose (to 1 g) means that the drug level will be above the minimum for a longer period. Because the elimination half-life is 8 h, 500 mg of the drug will remain in the body 8 h after a dose of 1 g. Immediately "after" the 5th dose, the plasma level should be approximately 30 rng/L, but just before it would be close to half of that level. In first-order kinetics, the elimination rate of a drug is directly proportional to its plasma concentration, which in turn is proportional to the dose. Likewise, clearance and vol- ume of distribution are pharmacokinetic characteristics of a drug that do not routinely change with dose, although they may vary in terms of disease or dysfunction. The curves in the figure suggest that drugs A and B have similar receptor binding: Drug A is a partial agonist, and drug B is a full agonist, having greater efficacy. Drug A appears more potent than drug B below the 50% response but has no effectiveness at all above the 50% response. At 12 h after N injection (which corresponds to two half-lives of the drug), the plasma level is 3 mglL. Epinephrine (E, from adrenal medulla) activates most adrenoceptors and is transported in the blood. The resulting decreases in cardiac output and total peripheral resistance contribute to resto- ration of mean blood pressure toward its normal level. The system is affected only by decreases in mean blood pressure (hypotension), which result in decreased renal blood flow. Decreased renal pressure causes the release of renin, which promotes formation of the angiotensins. Such compensatory mechanisms may result in tachycardia and both salt and Figure 11-1-3. Accommodation to far vision leading to Cyclopegia (paralysis of accommodation) a1-Agonists 1. No Cycloplegia Accommodation Adrenergic Stimulation radial muscle (aj) phincter muscle (M) contraction of radial muscle adrenergic aj agonists stimulation Normal Mydriasis Figure 11-1-5. Cholinergic Neuroeffector Junction • Choline is accumulated in cholinergic presynaptic nerve endings via an active trans- port mechanism linked to a Na+ pump. Properties ofIndirect-Acting Cholinomimetics Late-onset dementia with progressive memory loss Drug Characteristics Clinical Uses and cognitive decline. Nicotine acts as a cholinomimetic on nicotinic receptors, whereas bethanechol and pilocarpine are cholinomimetic drugs that act on muscarinic receptors. Those acting on the end-plate nicotinic receptors (N ) are tubocurarine, atracurium, and succinylcholine. Those acting on muscarinic (M) receptors M include atropine, benztropine, and scopolamine. All M-receptor activators are nonspecific (they act on Ml-3), and, in general, M-receptor activation decreases cardiovascular function and increase secretions and smooth muscle contraction. Table 11- 2-1 summarizes the type of M receptor involved and the specific end-organ responses to M-receptor activators. Table 11-2-2summarizes the effects of nicotinic receptor activation on the adrenal medulla, the autonomic ganglia, and the neuromuscular junction. The effect of autonomic ganglia stimulation depends upon the transmission system used to connect the ganglia to the end organ. Table 11-2-3summarizes the receptor mechanisms used by the various receptor types. Table 11-2-4summarizes the activity, properties, and clinical uses for the direct-acting cholinomimetics, and Table 11-2-5 does the same for the indirect-acting ones. Although these are less toxic for humans, they still provide a hazard, causing poisoning with both acute and chronic symptoms caused by both muscarinic and nicotinic hyperactivity ("dumbbelss"). In simple terms, increasing doses of atropine progressively decreases secretions and causes mydriasis, blurred vision, tachycardia, constipation, and urinary retention. Overdoses of over-the-counter medications containing M blockers are common causes of toxicity.