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By L. Thorek. Yeshiva University.

Tocolytic therapy invariably occurs outside embryogenesis purchase generic viagra sublingual canada, so congenital anomalies are not an issue buy 100mg viagra sublingual mastercard. The primary concern is for adverse maternal cheap generic viagra sublingual uk, fetal cheap viagra sublingual 100 mg line, and neonatal effects (Sanchez-Ramos et al. The three principal indications that guide the use of tocolysis in the treatment of preterm labor are: (1) prophylaxis, (2) acute therapy, and (3) maintenance. Instances do exist when exposure to tocolytic agents occurs during organogenesis, and is used for other indications: terbutaline (asthma), indomethacin (pain), and nifedipine (hypertension). Use for these indications is discussed in the chapters on antiasthma (Chapter 5), analgesic (Chapter 8), and cardiovascular drugs (Chapter 3), respectively. Pharmacokinetics of tocolytic drugs Pharmacokinetic data on tocolytic drugs in pregnancy are limited to five studies of four drugs (Table 15. Half-life and steady-state concentrations are generally not different between pregnant and nonpregnant states. Beta-adrenergic receptor agonists Ritodrine and terbutaline are beta-agonist drugs, structurally related to epinephrine, and are used as tocolytics. This type of tocolytic binds to beta-adrenergic receptors on the outer myometrial cell membrane and acti- vates adenylate cyclase. Another pathway is the phosphorylation of myosin light chain kinase which inactivates the enzyme, thus inhibiting subsequent phosphorylation of the myosin light chain. Maternal metabolic abnormalities (gluconeogenesis, hypokalemia, and hyper- glycemia), as well as cardiopulmonary complications (tachycardia, hypotension, arrhyth- mias, myocardial ischemia, pulmonary edema) are associated with beta-agonist tocolyt- ics (Box 15. Every beta-agonist is associated with pulmonary edema and occurs among as many as 5 percent of gravidas who took any of these drugs (Boyle, 1995; McCombs, 1995). Maternal tocolytic therapy has been associated with neonatal hypoglycemia and tachycardia. Several fetal and neonatal cardiovascular adverse effects are associated with beta-sympathomimetic therapy (Katz and Seeds, 1989) (Box 15. Decreases in the systolic/diastolic ratios of the umbilical artery have been reported in patients using either terbutaline or ritodrine (Brar et al. By 1979, ritodrine was available as a tocolytic agent in 23 foreign countries (Barden, et al. Ritodrine hydrochloride is a beta-adrenergic agonist with beta2-receptor effects that relax smooth muscle in the arterioles, bronchi, and uterus. Although ritodrine use is in widespread use for the inhibition of preterm labor (Leveno et al. No long-term benefi- cial effect of tocolytic therapy (decreased perinatal mortality or severe neonatal respira- tory disorders) was found in meta-analysis of 890 pregnancies in which ritodrine or another beta-mimetic tocolytic agent was used to prevent premature delivery (King et al. Downregulation of beta2-adrenergic receptors following the use of these drugs may explain their poor efficacy because uterine-relaxant effects are short lived (Berg et al. For this indication, a dose of 1–3 mg is usually given over a 2-min period (Smith, 1991). It is possible that a weak effect was pres- ent and the signal could not be separated from background noise. Maternal effects Acute maternal pulmonary edema, in addition to hypokalemia and hyperglycemia, has been reported among women given ritodrine. Steroids administered concomitantly to accelerate fetal lung maturity seem to increase the risk for this maternal complication Tocolytics 283 (see Box 15. Severe maternal cardiovascular complications occurred among nearly 5 percent of women treated with terbutaline (Katz et al. Beta-mimetics also alter glucose tolerance and have been associated with ketoacidosis among women with poorly controlled insulin-dependent diabetes. Fetal effects Fetal tachycardia and arrhythmias are associated with beta-mimetic therapy, including ritodrine (Barden et al. Protracted ritodrine therapy has been associated with increased septal thickness in exposed neonates (Nuchpuckdee et al. However, these do not appear to be frequent complications of ritodrine, or beta-mimetic, therapy in general. Beta-sympathomimetic tocolytic therapy, including ritodrine, was associated with a 2. In another investiga- tion, no association of ritodrine with intraventricular–periventricular hemorrhage was found (Box 15. Beta-mimetics are generally not used during the period of organogenesis, with the exception of terbutaline for asthma. An increased frequency of cardiovascular anomalies in chick embryos exposed to ritodrine and terbutaline was found in one study, and it was concluded that teratogenic effects were secondary to stimulation of beta-2-adrenergic receptors (Lenselink et al. Interestingly, according to its manufacturer, it should not be used for tocolysis. Terbutaline has also been utilized in the management of symptomatic placenta previa in pregnancies remote from term (Besinger et al. Neonatal myocardial dysfunction and necrosis have been associated with terbutaline tocolytic therapy (Fletcher et al. Neonatal hypoglycemia and fetal tachycardia were associated with terbutaline tocolytic therapy late in pregnancy (Peterson et al. Neonatal behavior was transiently altered among the infants of pregnant women who received terbutaline tocolysis (Thayer and Hupp, 1997). One review of car- diopulmonary effects of low-dose continuous terbutaline infusion in 8709 women found 47 women (0. In another review of 1000 women given a combination of intravenous terbutaline and mag- nesium sulfate, the side effects of protracted therapy were negligible (Kosasa et al. Magnesium sulfate has no proven efficacy in delaying delivery beyond 24–48 h (Cotton et al. Maternal effects Hypermagnesemia (cutaneous flushing, nausea, vomiting, respiratory depression, intracar- diac conduction delays) is the major maternal adverse effect of magnesium sulfate therapy. Protracted ther- apy (many days) with magnesium sulfate for preterm labor increases calcium loss and may decrease bone mineralization (Smith et al. Bleeding time during pregnancy may be prolonged with magnesium sulfate therapy, but this is not clinically significant (Fuentes et al. Unlike ritodrine, magnesium sulfate is not associated with a ‘peripheral vascular steal’ syndrome and does not decrease placental perfusion (Dowell and Forsberg, 1995). Fetal effects Magnesium sulfate crosses the placenta and, in extremely large doses, may cause neona- tal cardiorespiratory depression and transient loss of beat-to-beat variability (Hallak et al. Osseous lesions (metaphyses, costochondral junctions, skull) have been reported among infants born to women treated with magnesium sulfate for more than a week prior to delivery (Malaeb et al. Indomethacin is effi- Tocolytics 285 cacious as a tocolytic for short periods of time (Niebyl et al. Maternal effects Indomethacin resulted in few maternal side effects when used as a tocolytic. Potential adverse effects include: interstitial nephritis, acute renal failure, peptic ulcer disease, decrease in platelets, prolonged bleeding time (Clive and Stoff, 1984; Lunt et al. Among 83 women who received indomethacin during pregnancy, no adverse mater- nal or fetal effects were noted, except for oligohydramnios, which resolved sponta- neously (Sibony et al. Fetal effects In a review of 28 studies including 1621 infants exposed to indomethacin for tocolysis, the risk for adverse neonatal outcomes was not increased (Loe et al. However, there were only three randomized clinical trials included and one of them did find an increased risk for adverse neonatal outcomes associated with indomethacin tocolysis. Sulindac was as effective as indomethacin, but with fewer adverse fetal effects in a randomized prospective study of 36 women in preterm labor (Carlan et al. No epidemiological studies of sulindac during pregnancy have been published, but it is probably associated with potential adverse effects similar to indomethacin. Owing to smooth muscle relaxation, there may be maternal hypotension and subsequent decreased uteroplacental perfusion, although in human studies there has been no evidence that nifedipine compromises the fetus (Ray and Dyson, 1995). In a preliminary study of nifedipine versus ritodrine, it was suggested that nifedipine was associated with fewer maternal and fetal side effects (van Dijk et al. A recent case report of severe hypotension and fetal death associated with nifedipine, tocolysis- ascribed causality (van Veen et al. No epidemiologic studies on the safety of this agent during pregnancy have been published. Maternal hypotension and resultant decreased uterine blood flow are the major risks from the use of this agent. Consistent reduction in uterine activity during the infusion of atosiban has been observed (Goodwin et al. No studies regarding the safety of this agent have been published, but a review is available (Shubert, 1995).

He determined to try them in other cases of throat disease order viagra sublingual 100mg on line, and had a tincture prepared from the berries best 100 mg viagra sublingual. Shortly after discount 100 mg viagra sublingual with amex, in a severe epidemic of malignant diphtheria generic viagra sublingual 100mg fast delivery, he treated eighteen cases without the loss of one, using the ceanothus in all cases. He has used it since in diphtheria, pharyngitis, tonsilitis, and nasal catarrh, with good results. He gives it in diseases of the mucous surface where the discharge is profuse, thick and tenacious. He has further employed the remedy in the treatment of subinvolution, and evaporating it on a water bath, has made an ointment which is Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 105 applied to ulcers of the os uteri. It gives good results as a wash in the treatment of gonorrhea, gleet, leucorrhea, and ulcers and old sores. He believes the berries should be gathered just before they are ripe, to obtain the best action. Ipecac et Opii, Powder of Ipecac and Opium, composed of Ipecac and opium of each ten parts, Sugar of Milk, eighty parts; dose, from three to ten grains. Specific Medicine Ipecac; dose, for gastric, intestinal or bronchial irritation, five drops in four ounces of water; a tablespoonful every hour. It represents the medicinal properties of the ipecac, but will not produce nausea or emesis. It may be given in doses of one, two or three tablets three times per day, before meals, Physiological Action of Ipecac, (J. The peculiar effect that the dust of ipecacuanha powder exerts upon the respiratory organs of some persons has been noted by early observers. Lewis, in 1761, makes the following statement: “Geoffroy observed that in pulverizing considerable quantities, the finer powder that flies off, unless great care be taken to avoid it, is apt to afflict the operator with difficulty of breathing, spitting of blood and bleeding at the nose, or swelling and Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 106 inflammation of the eyes and face, and sometimes of the throat, adding that these symptoms disappear in a few days, usually spontaneously. Poisoning in this manner may be treated by blood-letting and the taking of a decoction of uva ursi and extract of rhatany; in another more recent instance, relief was afforded by a dose of extract of quebracho. The powdered ipecac in one-sixth of a grain doses is a stomachic tonic, stimulating the salivary and gastric secretions. In doses of ten grains it will act as a nauseating, emetic, but the emesis occurs slowly and is not extreme, persistent nor prostrating like that of lobelia or tartar emetic. In some cases continued repetition of the emetic dose produces a toleration, when the emetic effect ceases, but there is diarrhea—an active cathartic influence, with stools characteristic of this agent. In some children the persistent use of the syrup of ipecac will invariably produce diarrhea often persistent and difficult to cure. This important discovery has placed this alkaloid (like the hypodermic use of lobelia has placed that important remedy) in a most conspicuous position, making it at once a specific for the conditions named. Barlow, Chief Surgeon to the Hospital at Cuyamel, Honduras, now using these preparations, says: “My impressions are that while Alcresta ipecac cannot replace emetine in cases which can be seen daily, or in severe cases, it has certain uses in which it is superior to emetine. Cases living at such a distance or too poor to make daily visits to a physician; 3. In the after treatment of cases which have been relieved by the treatment of emetine; 4. In the treatment of carriers; and Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 107 5. In the treatment of cases of Craigiasis, which indeed cannot be treated so well with emetine alone as with emetine combined with some preparation of ipecac which can be administered orally. Bass and Johns found that the germ would disappear from all lesions in from one to three days in ninety per cent of the cases, and in six days from ninety-nine per cent of the cases. The peculiar combination involved in this substance prevents the alkaloids from being dissolved in acid or neutral solutions. The local influence of this agent upon the endameba in the mouth is very prompt and satisfactory. In extreme inactive conditions of the stomach and bowels, with or without pain—the inactivity shown by a broad, pallid tongue, covered very thickly with a dirty white coat, which finally becomes sleek on the top, increasing from tip to base in dirtiness, to a brown color-full emetic doses of the common forms of ipecac persisted in for a short time will quickly correct almost the entire train of symptoms. Specific Symptomatology—Persistent irritation in mucous membranes, with deficient secretion, demand ipecac in small closes. Persistent nausea and vomiting, with pale, relaxed membranes, whitecoated, broad tongue, will often yield most readily to minute doses (1/ of a drop) frequently repeated. It is indicated also in croup, with sudden dypsnea and threatening suffocation, extreme secretion, without ability to dislodge. Therapy—For its emetic influence ipecac is one of the most satisfactory of the emetics. When there is undigested food in the stomach, causing irritation, when mild poisons are taken, when emesis is demanded to relieve sick headache, this agent is used in preference to others. If promptness of action be demanded the full dose should be given in a bowl of warm water—not hot—or a single full dose of lobelia may be given Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 108 with it. If powerful poisons are taken, and active emesis is demanded, the sulphate of zinc or lobelia in persistent doses, or some other emetic more immediate in its influence, is usually used, although the writer has always been able to adjust ipecac with such adjuvants as warm water, mustard, or tickling of the throat, to every case. In cases where foreign bodies are lodged in the esophagus, and in the threatened suffocation of mucous croup, or in membranous croup, ipecac is the remedy, especially in childhood. In the developing stage of malarial fevers it was once the practice to produce active diaphoresis by a hot pediluvium and hot drinks, the patient being wrapped in warm blankets, and to produce profound emesis with ipecac. Often the most desirable results were obtained, and in some cases where an acute cold had been contracted or where there was a severe chill, in strong, previously healthy patients, the disease, was suddenly terminated by this course. In the bronchitis of childhood occurring often suddenly, with a dry, hoarse, stridulous or croupal cough, without secretion, ten drops of the syrup of ipecac given every half hour, hour, or two hours until nausea in induced, will sometimes abort the condition in a few hours, the influence of the agent dissipating the conditions essential to the progress of the disease. This form of bronchitis is common in furnace-heated houses, and in close, hot, unventilated apartments, in the beginning of the winter when the furnace fire is first started, and in the spring. Ipecac in small doses given in conjunction or in alternation with aconite or bryonia or belladonna, is of great service in pneumonia, especially that of childhood. Five drops in a half glass of water, a teaspoonful every hour, may be given with the best of results. In the stage of active inflammation it is useful as stated, but is not given in the same. It is an excellent remedy to assist in clearing up hepatization and in restoring normal conditions in the lung cells. The author, when the temperature has subsided, gives one-fourth to one- half a grain of powdered ipecac to an adult, every two or three hours in a capsule, with two grains of the bisulphate of quinine. Ipecac is of value in coughs when there is a deficient secretion, whatever the cause. Emetic doses are not desirable if the agent is to be continued Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 109 for a length of time. It has been beneficial in spasmodic asthma, whooping cough and in laryngismus stridulus. This agent is advised in irritation of the bowels resulting in acute inflammation. In small doses it is given with good results in cholera infantum and in diarrheas, but is of no benefit beyond the acute stage. While ipecac has been known as a cure for certain forms of dysentery for more than a century, the use of its active principle emetine as a cure for amebic dysentery is just now coming into prominence. Our writers have always advised ipecac for this disease, but not all have given it in sufficiently large doses. Administered now in the form of alcresta ipecac or emetine hypodermically, the cures are prompt and highly satisfactory. In fact, the remedy is already being classed with quinine for malaria, and antitoxin for diphtheria, as one of the great specifies. If the dysenteric tenesmus is relieved with prompt doses of gelsemium— and we have a no more efficient remedy in the materia medica for this condition than that agent—the beneficial effects of the ipecac upon the local inflammatory processes will be more plainly marked. Recent observers in the general hospital in Calcutta, India, have found that large doses of ipecac have most beneficial effects in amebic hepatitis and hepatic abscess. If the diagnosis be made before the formation of pus, this is prevented by the agent. It should be given when the patient suffers with a general feeling of lassitude, foul tongue, pain in the right shoulder and in the right hypochondrium. Ipecac is given in these cases in single large doses, usually from twenty to thirty grains, given at least two hours after eating and best taken at bedtime. Frazier claims that ipecac in large doses is an excellent addition to the treatment of typhoid fever.

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The kinetic constants (Km and Vm) can then be determined for the enzymes that are likely to be important generic viagra sublingual 100mg amex. Most P450 oxidations and drug interactions can be predicted from inhi- bition studies purchase 100 mg viagra sublingual free shipping, since most P450 inhibitors show competitive Michaelis-Menten kinetics order 100mg viagra sublingual otc. In this chapter generic 100 mg viagra sublingual with mastercard, both Michaelis-Menten kinetics and more complex kinetics will be discussed. General experimental protocols that can be used to obtain and analyze kinetic data will be presented, and the implications of the results when predicting drug interactions will be discussed. Likewise, when a drug binds In Vitro Enzyme Kinetics Applied to Drug-Metabolizing Enzymes 33 Figure 1 Simple schemes for (A) protein binding and (B) enzyme catalysis. Under steady-state conditions, the velocity of the simple reaction shown in Figure 1B can be described by the Michaelis-Menten equation: v Vm½SŠ ¼ ð2Þ Et Km þ½SŠ In this equation, a hyperbolic saturation curve is described by two constants, Vm and Km. In the simple example in Figure 1B, v is velocity, Vm is simply k23[E ]t and Km is (k21þ k23)/k12. Vmax (or Vm) is the reaction velocity at saturating con- centrations of substrate, and Km is the concentration of the substrate that achieves half the maximum velocity. Although the constant Km is the most useful descriptor of the affinity of the substrate for the enzyme, it is important to note the difference between Km and Kb. More complex enzymatic reactions usually display Michaelis-Menten kinetics and can be described by Eq. However, the forms of constants Km and Vm can be very complicated, consisting of many individual rate constants. King and Altman (7) have provided a method to readily derive the steady-state equations for enzymatic reactions, including the forms that describe Km and Vm. The advent of symbolic mathematics programs makes the implementation of these methods routine, even for very complex reaction schemes. However, most P450-mediated reactions display standard hyperbolic saturation kinetics. Therefore, although the rate constants that determine Km and Vm are 34 Korzekwa Figure 2 P450 catalytic cycle. Another constant that has important implications in drug metabolism is the ratio of Vm to Km,orV/K. This ratio is the slope of the hyperbolic saturation curve at low substrate concentrations. Since most P450-mediated reactions have relatively high Km values, most drug metabolism occurs in the linear or V/K region of the saturation curve. P450 Enzyme Preparations The P450 enzymes are found primarily in the outer membrane of the endo- plasmic reticulum. Enzyme activity requires that the enzyme be integrated into a membrane that contains P450 reductase and, for some reactions, cytochrome b5. Characterization of the saturation kinetics for the P450 enzymes can be deter- mined using a variety of enzyme preparations, including tissue slices, whole cells, microsomes, and reconstituted, purified enzymes. The more intact the in vitro preparation, the more it is likely that the environment of the enzyme will represent the in vivo environment. However, intact cell preparations do not In Vitro Enzyme Kinetics Applied to Drug-Metabolizing Enzymes 35 generally give kinetic parameters that are observed with microsomal preparations. This could be due to factors such as limiting diffusion into the cells, binding to intracellular proteins, or differences in membrane partitioning. Therefore, when whole-cell preparations are used, observed kinetic characteristics may not provide the true kinetic constants for the enzyme being studied. Microsomal preparations generally provide reproducible kinetic analyses when only one enzyme is involved in the reaction. However, microsomal prep- arations (and other intact preparations) contain many different P450 enzymes. Although this characteristic is useful when trying to mimic the metabolic char- acteristics of an organ, it is a drawback when trying to characterize the kinetic constants of an individual P450 enzyme or when trying to determine which enzyme is involved in the metabolism of a particular drug. Because of the generally broad substrate selectivities of the P450 enzymes, most observed metabolic reactions can be catalyzed by more than one enzyme. Interindividual variability in the content of the different P450s makes it even more difficult to determine the different kinetic parameters when more than one enzyme is involved in a given reaction. Preparations containing a single P450 isozyme are available as either expression systems or purified, reconstituted enzymes. The P450s have been expressed in bacterial, yeast, insect, and mammalian cells (8). However, in order to obtain adequate enzyme activity for most expression systems, it is necessary to supplement the membranes with reductase and in some cases cytochrome b5. This is accomplished by either supplementing the membranes with purified coenzymes or by coexpression of the coenzymes. Alternatively, the P450 enzymes can be purified and reconstituted with coenzymes into artificial membranes. Micro- somes may more closely represent the in vivo activity of a particular organ, but kinetic analyses are complicated by the presence of multiple enzymes. It is not possible to spectrally quantitate the content of any individual enzyme when a mixture of enzymes is present. Expression systems provide isozymically pure preparations, but they also have their disadvantages. The P450 enzymes are membrane bound, and for the nonmammalian expression systems the membranes may have different interactions with the P450 proteins. Although expression levels in most of the systems are adequate for spectral quantitation, coexpression of the coenzymes adds variability to different batches. However, the membranes are artificial and can have an influence on enzyme activity. Finally, these differences are further complicated by unpredictable influences of ionic strength, pH, etc. Incubation Conditions Enzyme kinetics are normally determined under steady-state, initial-rate con- ditions, which place several constraints on the incubation conditions. First, the amount of substrate should greatly exceed the enzyme concentration, and the consumption of substrate should be held to a minimum. This constraint ensures that accurate substrate concentration data are available for the kinetic analyses and minimizes the probability that product inhibition of the reaction will occur. This constraint can be problematic when the Km of the reaction is low, since the amount of product (10% of a low substrate concentration) may be below that needed for accurate product quantitation. One method to increase the substrate amount available is to use larger incubation volumes. For example, a 10-mL incubation has 10 times more substrate available than a 1-mL incubation. When more than 10% of the substrate is con- sumed, the substrate concentration can be corrected via the integrated form of the rate equation (Dr. James Gillette, personal communication): v Vm½SŠ ¼ ð3Þ Et Km þ½SŠ 0 ½SŠ0 À½SŠf S ¼ ð4Þ ln½SŠ0/½SŠf In Eq. S0 0 f approaches [S] when substrate consumption is minimal, and S0 is substituted for [S] to correct for excess substrate consumption. In these analyses, however, substrate inhibition can be a problem if the product has a similar affinity to the substrate. Fortunately, most P450 oxidations produce products that are less hydrophobic than the substrates, resulting in lower affinities to the enzymes. There are exceptions, including desaturation reactions that produce alkenes from alkanes (10) and carbonyl compounds from alcohols. These products have hydrophobicities that are similar or increased relative to their substrates. In the presence of reducing equivalents, the P450 enzymes will generally lose activity over time. Provided that the loss of enzyme is not dependent on substrate con- centration, the Vm of the enzyme will change, but not the Km. For P450 reactions, the presence of substrate in the active site can either protect the enzyme or increase its rate of deactivation.

Another func- tion of tyrosine hydroxylase is in production of additional tyrosine through the hydroxyla- tion of phenylalanine buy cheap viagra sublingual 100mg on line. However cheap viagra sublingual 100mg overnight delivery, phenylalanine hydroxylase is the enzyme primary enzyme responsible for the hydroxylation of phenylalanine order viagra sublingual online from canada. L-dopa is converted into dopamine through the action of the enzyme dopa decarboxylase 100mg viagra sublingual fast delivery, a pyridoxine-depen- dent enzyme, which removes the carboxyl group from dopa. Dopa decarboxylase, also referred to as aromatic amino acid decarboxylase, can also act on 5-hydroxytryptophan to form serotonin. Dopa decarboxylase is found in both catecholaminergic and sero- tonergic neurons and nonneuronal tissues (e. Dopamine is then acted on by the enzyme dopamine -hydroxylase that hydroxylates the -car- bon on the ethylamine side chain forming norepinephrine. Both dopamine -hydroxy- lase and tyrosine hydroxylase are mixed function hydroxylase that use molecular oxygen. Also, the highest concentration of dopamine -hydroxylase is found in vesicles that store catecholamines. Further conversion of nor- epinephrine to epinephrine takes place in a few neurons of the brain stem that utilize epinephrine as a neural transmitter and in adrenal medullary cells that secrete epineph- rine as the primary neurohormone. The Following Classes of Drugs May Interact with -Adrenoceptor Agonists 2 and Other Sympathomimetics When Administered Concurrently (25,63) 14. Less frequent effects are asthenia, back pain, bone pain, pelvic pain, arthralgia, dyspnea, hypertension, increased cough, pharyngi- tis, rash (unspecified), vasodilation, and edema. The most frequent adverse reactions are bone pain, back pain, hot flashes, nausea, arthralgia, and dyspnea. The most common adverse effects include hot flashes, fatigue, pain (unspecified), depression, insomnia, anxiety, dyspnea, dizziness, headache, and weight gain. Less frequent adverse effects include arthralgia, alopecia, confusion, dyspep- sia, respiratory infections, and urinary tract infections. Adverse reactions include drowsiness, morbilliform skin rash, nausea/vomiting, anorexia, adrenal insufficiency, hypothyroidism, masculinization, hirsutism, headache, dizziness, hypotension, pruritus, myalgia, and fever. The following classes of drug may interact with aromatase inhibitors when admin- istered concurrently : These products will interfere with the pharmacological actions of aromatase inhibitors. N (111) (49) 596 von Deutsch, Abukhalaf, and Socci is not intended to explain peculiarities of state law in these areas. Rather, it reports the law as stated in the drug interaction cases within the scope of this chapter. The reader is advised to seek local counsel in the jurisdiction in which an action is filed for a review of the law applicable to the action. The plaintiff’s physician had prescribed Isocet to the patient to treat his complaints of tension headaches in 1994 and 1995. In 1997, the patient was referred to an epilepsy specialist who prescribed Dilantin to control the patient’s sei- zures. The first physician was involved in administering and monitoring the levels of Dilantin. While taking the Dilantin, the patient experienced a tension headache and took two Isocet tablets from his earlier prescription, and shortly thereafter was diag- nosed with acute liver failure. The epilepsy specialist testified that she was aware of the medical risk of the interaction of Isocet and Dilantin, but still would have prescribed Dilantin because of the greater risk posed by the patient’s seizures. The court held that the plaintiffs failed to controvert this testimony, that the defendant manufacturers were shielded from liability under the “learned intermediary doctrine,” and that any failure to warn on the part of the defendants was therefore not the proximate cause of Mr. The plaintiffs had alleged that the defendant manufacturers had failed to label their products with adequate warnings of Dilantin’s propensity to interact with acetamin- ophen, placed defective and unreasonably dangerous products in the marketplace that caused Mr. Eck’s liver failure, and were negligent in the designing, testing, warning, and marketing of their products through their failure to provide adequate instructions or warnings, and by misrepresenting the safety of their products when used in conjunc- tion with one another. Applying Oklahoma law, the court reasoned that, in order to recover in a failure to warn case against a drug manufacturer, a plaintiff must establish both cause-in-fact (that the product in question caused the injury) and proximate cause (that the manufac- turer of the product breached a duty to warn of possible detrimental reactions, and this breach was a substantial contributing factor in causing the harm). Under Restatement (Second) Torts § 402A comment K, certain products, including prescription drugs, are “unavoidably unsafe products” that cannot be made completely safe, but serve a public benefit, so drug manufacturers cannot be held strictly liable merely because of the dan- gerous propensities of their products. Although the manufacturer has a duty to warn ultimate consumers of known dangers of prescription drugs and their interactions, there is an exception to this duty—the “learned intermediary doctrine”—under which the manufacturer is shielded from liability where the product is properly prepared and mar- keted and proper warning is given to prescribing physicians. The prescribing physician acts as a learned intermediary between the patient and the prescription drug manufac- turer by assessing the medical risks in light of the patient’s needs. No part of this book may be reproduced in any form, by photostat, microfilm, xerography or any other means, or incorporated into any information retrieval system, electronic or mechanical, without the written permission of Kaplan, Inc. Drugs for Inflammatory and Related Disorders Chapter 1: Histamine and Antihistamines 227 Chapter 2: Drugs Used in Gastrointestinal Dysfunction. Chapter 1: Anticancer Drugs 307 Chapter 2: Anticancer Drug Practice Questions 311 Sedion X: Immunopharmacology Chapter 1: Immunopharmacology 315 Chapter 2: Immunopharmacology Practice Questions. The Notes were designed to be accompanied by faculty lectures-live, on video, or on the web. To maximize the effectiveness of these Notes, annotate them as you listen to lectures. While these margins are occasionally punctuated by faculty high-yield "margin notes," they are, for the most part, left blank for your notations. Many students find that previewing the Notes prior to the lecture is a very effective way to prepare for class. It also affords you the opportunity to map out how the information is going to be presented and what sorts of study aids (charts, diagrams, etc. Pharmacokinetics Pharmacokinetic characteristics of drug molecules concern the processes of absorption, distri- bution, metabolism, and excretion. The biodisposition of a drug involves its permeation across cellular membrane barriers. Absorption into Plasma Drug"Excretion Drug Metabolism (Renal, Biliary, (Liver, Lung, Blood, etc. Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs; however, water solubility Can influence permeation through aqueous phases. Diffusion down a concentration gradient--only free, unionized drug forms contribute to the concentration gradient. The larger the surface area and the greater the vascularity, In A Nutshell the better is the absorption of the drug. Clinical Correlate ~ • Only nonionized forms undergo active secretion and active or passive reabsorption. Renal Clearance of Drug Modes of Drug Transport Across a Membrane Bridge to Physiology Table 1-1-1. Mechanism Direction I mechanisms are discussed No No No I in greater detail in Section Passive diffusion Down gradient! Facilitated diffusion Down gradient No Yes Yes Active transport Against gradient Yes Yes Yes (concentration! For some drugs, their rapid hepatic metabolism decreases bioavailability-the "first- pass" effect. Effect of Rate of Absorption on Plasma Concentration Cmax and tmax are rate dependent. The faster the rate of absorption, the smaller the tmax and the larger the Cmax and vice versa. Drug + Protein ~ Drug-Protein Complex (Active, free) (Inactive, bound) - Competition between drugs for plasma protein-binding sites may increase the "free fraction," possibly enhancing the effects of the drug displaced. Example: levodopa versus dopamine Apparent Volume of Distribution 01d) A kinetic parameter of a drug that correlates dose with plasma level at zero time. This raises the possibility of displacement by other agents; examples: verapamil and quinidine can • blood volume (5 L) displace digoxin from tissue-binding sites. With a second dose, the blood/fat is less; therefore, the rate of redistribution is less and the second dose has a longer duration of action. A few compounds (prodrugs) have no activity until they undergo metabolic activation. Inactive metabolite(s) Active Metabolites Drug -----+ Active metabolite(s) Biotransformation of the Prodrug ---+~ Drug benzodiazepines diazepam results in formation of nordiazepam, a metabolite Figure 1-1-9.

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