By B. Thorus. Chaminade University of Honolulu, Hawaii. 2018.

Contraindications Contraindications to argatroban are hypersensitivity to argatroban or major bleeding buy cheap serophene 25 mg menstruation problems blood. Precautions/Warning Caution should be taken in administering argatroban to patients with increased risk of hemorrhage (e cheap serophene 25 mg with visa breast cancer options. Poisoning Information A minimum toxic dose of argatroban in humans has not been established. Treatment of possible overdose is symptomatic and supportive, with no specific antidotes available. Monitor for signs of bleeding, vital signs, electrocardio- gram, and renal and hepatic function in symptomatic patients. Discontinue or decrease infusion to control excessive anticoagulation with or without bleeding. Reversal of anticoagulant effects may be longer than 4 hours in patients with hepatic impairment. Hemodialysis may remove up to 20% of the drug; however, this is considered clinically insignificant. Off-label use of aspirin includes the treat- ment of Kawasaki Disease and to prevent thrombosis in patients after single ventricle palliation with a shunt, bidirectional Glenn, or Fontan procedure. Mechanism of Action Aspirin is a salicylic derivative that inhibits both prostaglandin synthesis and platelet aggregation. Dosing Children: Analgesic and antipyretic (oral, rectal): 10 to 15mg/kg/dose every 4 to 6 hours; maximum dose, 4 grams/day Anti-inflammatory (oral): initial, 80 to 100 mg/kg/day in divided doses Kawasaki Disease (oral): 80 to 100 mg/kg/day divided every 6 hours for 2 weeks, then 3 to 5 mg/kg/day once daily for 7 weeks or longer Antiplatelet effects: adequate pediatric studies have not been per- formed, therefore, the dose is not well established. Doses ranging from 3 to 10mg/kg/day administered as a single daily dose have been used; doses are rounded to a convenient amount; maximum, 325 mg/dose Mechanical heart valves: 6 to 20 mg/kg/day either alone or in combina- tion with dipyridamole Blalock-Taussig shunt and endovascular stents:2,11 1 to 5 mg/kg/day Fontan procedure: 5 mg/kg/day Arterial ischemic stroke: 2 to 5 mg/kg/day after discontinuation of anti- coagulants Adults: Analgesic and antipyretic (oral, rectal): 325 to 1000 mg every 4 to 6 hours (up to 4 grams/day) Anti-inflammatory (oral): 2. The immediate-release formulation is completely absorbed, whereas the enteric-coated form is erratically absorbed. The half-life of the active drug is 6 hours with a time-to-peak serum concentration being 1 to 2 hours (this may be delayed with controlled- or timed-release preparations). Patients with asthma, rhinitis, or nasal polyps may be more sensitive to the effects of salicylates. Combination therapy of salicylates and carbonic anhydrase inhibitors, such as acetazolamide, brinzolamide, dichlorphenamide, dorzolamide, and meth- azolamide, has resulted in significant metabolic acidosis in pediatric and adult patients. Nondihydropyridine calcium channel blockers (diltiazem and verapamil) may enhance the anticoagulant effect of salicylates. Salicylates may enhance the adverse/toxic effect of varicella virus-containing vaccines causing Reye’s syndrome, and they may increase serum concentration of methotrexate. Adverse Effects Adverse effects of aspirin use include rash, urticaria, nausea, vomiting, dys- pepsia, epigastric discomfort, occult bleeding, prolongation of bleeding time, leukopenia, thrombocytopenia, hepatotoxicity, bronchospasm, tinnitus, head- ache, dizziness, confusion, metabolic acidosis, and hyperpyrexia. Poisoning Information Salicylate serum concentrations correlate with the pharmacological actions, and adverse effects are observed with serum salicylate levels of approximately 100mg/dL. Patients with mild-to-moderate intoxication may develop fever, tachypnea, tinnitus, respiratory alkalosis, metabolic acidosis, lethargy, mild dehydration, nausea, and vomiting. Severe intoxication may result in encepha- lopathy, coma, hypotension, pulmonary edema, seizures, acidemia, coagulopa- thy, cerebral edema, and dysrhythmias. Treatment of accidental or chronic ingestion is supportive and can include the use of activated charcoal and gastric lavage. Hemodialysis can be considered for patients with high blood salicylate levels (>80 to 100mg/dL after acute overdose, >50 to 60mg/dL after chronic over- dose). Do not crush or chew controlled-release, timed-release, or enteric- coated tablets; these are designed to be swallowed whole. Mechanism of Action Clopidogrel blocks adenosine diphosphate receptors, preventing fibrinogen binding and platelet adhesion and aggregation. Dosing Children: Safety and efficacy in pediatric patients are not established; how- ever, clopidogrel has been used in pediatric patients, with data published in infants as young as 6 weeks of age. Anticoagulants, Antithrombotics, and Antiplatelets 261 patients with increased risk factors for intracranial hemorrhage and those with intracranial vasculopathies. Clopidogrel has been used in addition to aspirin therapy in patients with Kawasaki’s Disease and giant coronary artery aneurysms. Although there are no published studies in children, doses of 1mg/kg/day by mouth to a maximum adult dose (75mg/day) have been used.

Drug interactions H2-receptor antagonists may interact with antacids and other drugs serophene 50mg online menstruation every 3 weeks. How H -receptor antagonists work 2 These illustrations show how histamine-2 (H2) receptor antagonists reduce the release of gastric acid purchase serophene 50mg overnight delivery menstruation 3 weeks apart. To stimulate gastric acid secretion, certain endogenous sub- stances—primarily histamine, but also acetylcholine and gas- trin—attach to receptors on the surface of parietal cells. The pump catalyzes the exchange of extracellular potas- sium (K) ions for intracellular hydrogen (H) ions. H2-receptor • Cimetidine taken with carmustine increases the risk of bone antagonists marrow toxicity. They include: dine may produce • esomeprazole headache, dizziness, • lansoprazole malaise, muscle pain, • omeprazole nausea, diarrhea or con- • pantoprazole stipation, rash, itching, • rabeprazole. Pharmacokinetics • Famotidine and nizati- Proton pump inhibitors are given orally in enteric-coated formulas dine produce few ad- to bypass the stomach because they’re highly unstable in acid. These medications are highly protein-bound and are extensively metabolized by the liver to inactive compounds and then eliminat- ed in urine. Pharmacodynamics Proton pump inhibitors block the last step in the secretion of gas- tric acid by combining with hydrogen, potassium, and adenosine triphosphate in the parietal cells of the stomach. Two other drugs currently in use are: • misoprostol (a synthetic form of prostaglandin E1) • sucralfate. Absorption, metabolism, and excretion After an oral dose, misoprostol is absorbed extensively and rapid- ly. It’s metabolized to misoprostol acid, which is clinically active, meaning that it can produce a pharmacologic effect. Safe and sound Dangers of misoprostol use during pregnancy Adverse reactions to Use of misoprostol during pregnancy can lead can cause uterine rupture as well. Misopros- to premature birth, birth defects, or fetal abor- tol-induced abortions may be incomplete. When used after the 8th week of preg- these reasons, the drug is contraindicated for ulcer drugs nancy to induce labor or abortion, misoprostol gastric ulcer prevention during pregnancy. Misoprostol • Diarrhea (common and usually dose-related) Protective paste • Abdominal pain Sucralfate works locally in the stomach, rapidly reacting with hy- • Gas drochloric acid to form a thick, pastelike substance that adheres • Indigestion to the gastric mucosa and, especially, to ulcers. By binding to the • Nausea and vomiting ulcer site, sucralfate actually protects the ulcer from the damaging effects of acid and pepsin to promote healing. Adsorbent drugs Natural and synthetic adsorbents are prescribed as antidotes for the ingestion of toxins, substances that can lead to poisoning or overdose. Charcoal sketch The most commonly used clinical adsorbent is activated charcoal, a black powder residue obtained from the distillation of various organic materials. Pharmacokinetics Activated charcoal must be administered soon after toxic inges- Don’t worry. After initial absorption, some poisons move back into the in- testines, where they’re reabsorbed. Absorption, metabolism, and excretion Activated charcoal, which isn’t absorbed or metabolized by the body, is excreted unchanged in stool. However, this binding doesn’t change toxic effects caused by earlier absorp- tion of the poison. Pharmacotherapeutics Activated charcoal is a general-purpose antidote used for many types of acute oral poisoning. Adverse reactions to Drug interactions activated Activated charcoal can decrease absorption of oral medications; charcoal therefore, medications (other than those used to treat the ingested toxin) shouldn’t be taken orally within 2 hours of taking the acti- Activated charcoal turns vated charcoal. The effectiveness of activated charcoal may be de- stools black and may creased by vomiting induced by ipecac syrup. They’re distrib- uted only in the intestinal lumen and are eliminated intact in stool. By produc- intestines that ing a film in the intestines, simethicone disperses mucus-enclosed collapses and disperses gas gas pockets and helps prevent their formation. Pharmacotherapeutics Antiflatulents are prescribed to treat conditions in which excess gas is a problem, such as: • functional gastric bloating • postoperative gaseous bloating • diverticular disease • spastic or irritable colon • air swallowing. Drug interactions Simethicone doesn’t interact significantly with other drugs and doesn’t cause known adverse reactions.

Altering the structure of the drug carries the concomitant risks of: • compromising the activity of the drug; • increasing the toxicity of the drug; • increasing the molecular weight to such an extent that the molecule will be too large to cross the membrane barrier (see Section 1 cheap serophene 25 mg otc the women's health big book of exercises pdf free. An alternative strategy cheap serophene 50mg free shipping ehealthforum.com › womens health › birth control forum, which overcomes these limitations, is to use the prodrug approach (Figure 1. This involves the chemical transformation of the active drug substance to an inactive derivative (prodrug), which is subsequently converted to the parent compound in vivo by an enzymatic or non-enzymatic process. Thus a prodrug of a drug, because of its increased lipid solubility, may demonstrate enhanced membrane permeability in comparison to the parent drug. Enzymatic or chemical transformation converts the inactive prodrug to the pharmacologically active drug, after absorption has taken place. A further important point, discussed in detail in the next section, is that lipid solubility must be considered in the context of the degree of ionization of the drug. Therefore the pH of the solution will affect the overall partition coefficient of an ionizable substance. For ionizable drugs log P is pH dependent and hence log D, the log distribution coefficient of the drug at different pHs, is usually employed instead of log P, as an estimation and/or prediction of absorptive potential. The pH at which the log D is measured should be reported but values normally correspond to determinations carried out at a physiological pH of 7. Log D is effectively the log partition coefficient of the unionized form of the drug at a given pH. The relationship between the observed overall partition coefficient and the distribution coefficient is given by the equation: where α is the degree of ionization of drug. The interrelationship between the dissociation constant and lipid solubility of a drug, as well as the pH at the absorption site, is known as the pH-partition theory of drug absorption. Accordingly, rapid transcellular passive diffusion of a drug molecule may be due to: • a high proportion of unionized molecules; • a high log P (high lipophilicity); • or a combination of both. The extent of ionization of a drug molecule is given by the Henderson-Hasselbalch Equation (Box 1. In contrast, a very low percentage is unionized in the small intestine, which suggests unfavorable absorption. Strong acids, such as cromoglycate, are ionized throughout the gastrointestinal tract and are poorly absorbed. The reverse is true 22 for weak bases (with pK ′s in the range 5 to 11), which are poorly absorbed, if at all, in the stomach sincea they are largely ionized at low pH, but are well absorbed in the small intestine, where they are unionized. Strong bases, such as mecamylamine, are ionized throughout the gastrointestinal tract and are therefore poorly absorbed. Although the pH-partition hypothesis is useful, it must be viewed as an approximation because it does not adequately account for certain experimental observations. For example, most weak acids are well absorbed from the small intestine, which is contrary to the predictions of the pH-partition hypothesis. These discrepancies arise because the pH-partition hypothesis does not take into account the following: • the large mucosal surface area of the small intestine, which compensates for ionization effects; • the relatively long residence time in the small intestine, which also compensates for ionization effects; • even the ionized form of a drug displays limited absorption; • charged drugs, such as quaternary ammonium compounds, may interact with organic ions of opposite charge, resulting in a neutral species, which is absorbable; • bulk transport of water from the gut lumen to the blood, or vice versa, can drag water-soluble molecules with it, resulting in an increase or decrease in the absorption of water-soluble drugs respectively. A more complex relationship pertains for more complex and organized structures such as lipid bilayers, but again, drug diffusivity is inversely proportional (probably by an exponential relationship) to the molecular volume. This means that drug diffusivity across membranes is sensitive to molecular weight, since molecular volume is determined by a number of factors, including the molecular weight of the molecule. Therefore, in general, large molecules will diffuse at a slower rate than small molecules. However, molecular volume is also determined by: • the overall conformation of the molecule; • the heteroatom content that may be involved in inter- and intramolecular hydrogen bonding. Thus molecules which assume a compact conformation will have a lower molecular volume and thus a higher diffusivity. An important consequence of this property is that even if such molecules have a high molecular weight (i. Molecular size and volume also have important implications for the paracellular route of drug absorption. It would appear that tight junctions bind cells together very efficiently and can block the passage of even relatively small molecules.

A steeper slope (Figure 3-4 generic 50mg serophene with amex women's health of westerly, top graph) indicates a faster rate of elimination than does a flatter slope (Figure 3-4 effective serophene 50 mg breast cancer 5k in washington dc, bottom graph). For first-order processes, the rate of elimination (expressed as the fraction of drug in the body removed over a unit of time) is the same at high or low concentrations and is therefore called an elimination rate constant. Because we know that a plot of the natural log of drug concentration over time is a straight line for a drug following first-order elimination, we can predict drug concentrations for any time after the dose if we know the equation for this line. Remember that all straight lines can be defined by: Y = mX + b As shown in Figure 3-3: Y axis = natural log of drug concentration in plasma X axis = time after dose m = slope of line, "or negative elimination rate constant" b = intercept on natural log of plasma drug concentration axis (y-intercept) Now, when we convert to our new terms: ln drug concentration = (-elimination rate constant × time) + ln concentration at y-intercept If we know the slope of the line and the intercept of the y-axis, we can predict the natural log of drug concentration at any time after a dose. Drug concentrations can be predicted using these mathematical methods instead of the previously described graphical methods. With mathematical methods, our predictions of drug concentrations over time are more accurate. So, if the negative slope of the natural log of drug concentration versus time plot equals the elimination rate constant, our equation for the line: Y = mX + b becomes: ln (drug concentration) = (-elimination rate constant × time) + ln y-intercept To simplify our terminology here, let: ln C = natural log of drug concentration, K = elimination rate constant, and t = time after dose. Also, we shall call the y-intercept "ln C0," the drug concentration immediately after a dose is administered (at time zero, or t0). Therefore, our equation becomes: ln C = (-K × t) + ln C0 or This last equation is valuable in therapeutic drug monitoring. If two plasma drug concentrations and the time between them are known, then the elimination rate can be calculated. If one plasma drug concentration and the elimination rate are known, then the plasma concentration at any later time can be calculated. Clinical Correlate The concepts presented in this lesson can be used to predict plasma concentrations in some situations. For example, if a patient with renal dysfunction received a dose of vancomycin and plasma concentrations were determined 24 and 48 hours after the dose, then two plasma concentrations could be plotted on semilog paper to determine when the concentration would reach 10 mg/L (Figure 3-5). The slope of the natural log of plasma concentration versus time curve can be determined if two plasma concentrations and their corresponding times are known. For example, in Figure 3-6, C0 is the first plasma drug concentration, measured just after the dose is given, and C1 is the second plasma drug concentration, measured at a later time (t1). From our previous discussion, we know that the equation for this line (y = mX + b) is: ln C1 = -Kt + ln C0 Furthermore, we know that the slope of the line equals -K, and we can calculate this slope: 3-1 It is a property of logarithms that: Then, using numbers from Figure 3-6: -1 -1 So, -K = -0. This means that 15% of the drug remaining in the body is removed each hour, so an initial plasma concentration of 10 mg/L will decrease 15% (0. The equation ln C = -Kt + ln C0 is important because it allows the estimation of the concentration at any given time. Remembering p the rule of logarithms, that ln X = P ln X, if we take the antilog of each part of this equation, we get: 3-2 where: C = plasma drug concentration at time = t, C0 = plasma drug concentration at time = 0, K = elimination rate constant, t = time after dose, and e = base of the natural log (approximately 2. The preceding equation can also be used to predict the concentration at any time, given an initial concentration of C0 and an elimination rate of K. Through these mathematical manipulations, simple equations have been derived to aid in predicting -Kt drug plasma concentration after a given dose. It is essentially the same as the equation for the straight line (ln C1 = -Kt + ln C0), and either equation can be used to predict drug concentrations. The half- life is the time necessary for the concentration of drug in the plasma to decrease by half. One way to estimate the half-life is to visually examine the natural log of plasma drug concentration versus time plot and note the time required for the plasma concentration to decrease by half. Because the half-life is the time for a concentration to decrease by half, T1/2 can be estimated by halving the initial concentration, then taking half of that concentration to get a second concentration, and so on until the final concentration is reached. The number of halves required to reach the final concentration, divided into the time between the two concentrations, is the estimated half-life. For example, the following two concentrations were determined at the times stated after a dose was administered: C (mg/L) 8. To get from 12 to 3 requires a halving of 12 to 6 and a halving of 6 to 3, representing two half-lives in 4 hours, or one half-life of 2 hours. They indicate how quickly a drug is removed from the plasma and, therefore, how often a dose has to be administered.