By J. Einar. City University of Los Angeles. 2018.

In eight patients reported to the Investigational Drug Branch of the National Cancer Institute between January 1982 and May 1983 buy generic artane on-line, these reactions included flushing cheap generic artane canada, respiratory problems 2 mg artane with amex, changes in blood pressure and abdominal pain, often occurring soon after the start of drug administration and generally resolving rapidly when the infusion was stopped. These reactions are less common with etoposide than with the related drug teniposide and have not been reported after oral administration, suggesting that other agents in the formulation may be at least partly responsible. The very low incidence of reported cases may reflect only serious hyper- sensitivity reactions (Weiss, 1992), as mild reactions were found in 51% of patients receiving etoposide as part of combination chemotherapy for Hodgkin disease (Hudson et al. Most patients can be successfully re-treated with etoposide after a premedication comprising antihistamine and/or corticosteroids (Hudson et al. Cardiotoxicity was reported in three of eight patients with pre-existing cardiac disease who received etoposide by infusion (Aisner et al. Four-week studies of toxicity were conducted in rats treated intraperitoneally at 0. At the highest doses, the main toxic effect was myelosuppression, with anaemia, leukopenia and thrombocytopenia, and some hepatotoxicity. Pathological changes were noted in the lung in rats, and mild enteritis was seen in dogs. After oral and intravenous administration at the same doses as in the previous studies, no additional toxicity was observed up to nine weeks (review of unpublished studies by Achterrath et al. No other effects were seen in the rats, while those in dogs included renal and hepatic impairment, electrocardiographic changes, decreased testis weight and disorders of spermatogenesis (review of unpublished studies by Achterrath et al. After intraperitoneal administration of a clinical formulation or intrapleural adminis- tration of etoposide dissolved in dimethyl sulfoxide and Tween 80 diluted in Hank’s buffer to rats and mice, delayed chronic pleuritis and peritonitis, with liver and spleen inflammation were reported. After intravenous infusion of a single dose of 461 mg/m2 etoposide phosphate to dogs over 5 min, all animals vomited, and leukopenia and thrombocytopenia were seen at this and lower doses (Igwemezie et al. Etoposide- and etoposide phosphate-induced sensory neuropathy has been reported in mice after single doses of 88 mg/kg bw and 100–150 mg/kg bw, respectively (Bregman et al. Six days later, she developed neutropenia and septicaemia and had a spontaneous vaginal delivery. The female infant developed profound leukopenia with neutropenia three days later (10 days after in-utero exposure), which had resolved by day 13. At 10 days of age, the infant started to lose her hair, which was growing again when she was discharged at 12 weeks. A woman was treated for acute leukaemia at 25 and 30 weeks of gestation with cytarabine, daunorubicin and etoposide (400 mg/m2 per day for three days). Her infant, delivered by caesarean section at 32 weeks because of fetal distress, had leukopenia with profound neutropenia, which was confirmed to be due to bone-marrow suppression by measurement of circulating haemopoietic progenitor cells. This condi- tion responded to transfusion of packed cells and subcutaneous injections of granulocyte colony-stimulating factor, and the infant was well at follow-up at one year (Murray et al. Three women treated for acute leukaemia, ovarian cancer and non-Hodgkin lymphoma with multiple drug cycles including etoposide (100–125 mg/m2 per day) in the third trimester had normal, healthy infants (Buller et al. In one case, a woman with a cervical ectopic pregnancy of six weeks was given oral doses of etoposide of 200 mg/m2 for five days. The pregnancy was termi- nated, but there was evidence of bone-marrow suppression in the mother and almost complete loss of hair (Segna et al. The second case, a tubal pregnancy of five weeks, was successfully terminated by two injections of 50 mg etoposide locally into the gestational sac, with no side-effects (Kusaka et al. In a study of 20 young and two older (> 50 years) women with gestational trophoblastic disease treated orally with etoposide and who had serial hormone assays, transient ovarian failure lasting two to four months was observed in five of the young women, and the two older women both had permanent ovarian failure. In the younger women, fertility was unaffected and six became pregnant within one year of therapy (Choo et al. In a similar study on 47 women treated with etoposide, ovulation ceased in about half of the patients but returned within four months after treatment in all of the patients under 40 years of age. In nine patients over 40 years of age, ovulation did not return within the follow-up period of 12 months. The effects on the ovary were not related to the dose of etoposide but were related to the age of the patient (Matsui et al. Etoposide was not found to have any long-term effect on fertility in 77 women treated for gestational trophoblastic tumours (Adewole et al. Excretion of etoposide in breast milk was demonstrated in a woman with acute promyelocytic leukaemia receiving daily doses of 80 mg/m2 [route not stated]. Reproductive capacity was assessed in 30 men with germ-cell tumours after treatment with cisplatin, etoposide and bleomycin. The results are difficult to interpret, since most men with testis tumours are oligospermic before chemotherapy. Oligo- spermia (< 40 × 106 total sperm) was diagnosed in 13 of the men, including six with azoospermia. Morphological abnormalities were common, and only one man had more than 50% normal sperm. Eight of the men subsequently fathered children, none of whom had birth defects (Stephenson et al. Etoposide did not cause permanent damage to the germinal epithelium in 47 young men receiving it for Hodgkin disease (Gerres et al.

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Clinically important drug interactions • Drugs that increase effects/toxicity of ondansetron: cimetidine cheap artane on line, allopurinol purchase artane 2mg visa, disulfiram purchase artane 2mg on line. Alternatively, administration of diphenhydramine and ben- ztropine may be indicated. Editorial comments • Ondansetron is useful as an alternative to metoclopramide in patients likely to develop extrapyramidal reactions from meto- clopramide. Advice to patient: Take fat-soluble vitamin supplements (vitamins A, D, E, and K) at least 2 hours before or after taking orlistat. Clinically important drug interactions: Orlistat reduces absorp- tion of fat-soluble vitamins. Parameters to monitor: Weight of patient to determine whether drug is losing effectiveness. Editorial comments • The benign side effect profile of this drug makes it a safe antiobesity agent. There are no data concerning the safety or efficacy of combining this drug with other anti-obesity drugs such as phentermine. Editorial comments • This drug is not listed in the Physicians’Desk Reference, 54th edition, 2000. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. American Academy of Pediatrics expresses concern about breast- feeding while taking benzodiazepines. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Blocks acetylcholine effects at muscarinic receptors throughout the body. Mechanism of action: Binds to opiate receptors and blocks asce- nding pain pathways. Contraindications: Hypersensitivity to oxycodone or other nar- cotics of the same chemical class, respiratory depression, severe bronchial asthma, paralytic ileus. Warnings/precautions • Use with caution in patients with: head injury with increased intracranial pressure, serious alcoholism, prostatic hypertro- phy, chronic pulmonary disease, severe liver or kidney disease, disorders of biliary tract, supraventricular tachycardia, history of convulsion disorder, postoperative patients with pulmonary disease. If nausea and vomiting persist, it may be necessary to administer an antiemetic, eg, droperidol or prochlorperazine. Mechanism of action: Binds to opiate receptors and blocks ascending pain pathways. Contraindications: Hypersensitivity to narcotics of the same chemical class, paralytic ileus, acute asthmatic attack, severe respiratory depression, upper urinary tract obstruc- tion, pulmonary edema secondary to chemical respiratory irritant. If nausea and vomiting persist, it may be necessary to administer an antiemetic, eg, droperidol or prochlorperazine. Mechanism of action: Oxytocic action: stimulates contractions of uterine smooth muscle. Contraindications: Hypersensitivity to oxytocin, fetal distress, severe toxemia, total placenta previa, anticipated nonvaginal delivery (invasive cervical cancer), prolapse, active herpes genitalis, unfavorable fetal position, hyperactive uterus, contraindicated vagi- nal delivery, women with four or more previous deliveries. Clinically important drug interactions: Drugs that increase effects/ toxicity of oxytocin: sympathomimetics, vasoconstrictors, cyclo- propane, thiopental. Parameters to monitor • Fetal maturity, presentation, adequacy of pelvis before admin- istration of oxytocin for labor induction. Mechanism of action: Inhibits normal reorganization of micro- tubules required for mitosis, thus inhibiting tumor cell division. Note: This course of treatment should not be repeated unless the neutrophil count is at least 1500 mm3 or platelet count is 100,000/mm3. Contraindications: Contraindicated in patients with hypersensi- tivity to paclitaxel or polyoxyethylated castor oil (excipient), neutrophil count <1500 mm3, pregnancy. Advice to patient: Use two forms of birth control including hor- monal and barrier methods. Adverse reactions • Common: nausea, vomiting, diarrhea, alopecia, myalgia, phlebitis, erythema at site of injection. Clinically important drug interactions • Cisplatin increases the effects/toxicity of paclitaxel. Parameters to monitor • Monitor vital signs frequently, particularly during the 24 hours of infusion. It is recommended that all patients should receive one of the following prior to administration of paclitaxel: diphenhydramine, an H2 blocker, dexamethasone. Infusion should be stopped if patient mani- fests dyspnea, chest pain, hypotension. Paclitaxel is active in breast cancer, ovarian cancer, non-small cell lung cancer, and head and neck cancers.

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The illustrations below show the action of direct- order artane 2 mg otc, indirect- order artane 2mg fast delivery, and dual-acting adrenergics purchase 2mg artane fast delivery. Direct-acting adrenergic action Adrenergic Direct-acting adrenergics directly stimulate adrener- drugs can be gic receptors. N N P T O N R D Indirect-acting adrenergic action Indirect-acting adrenergics stimulate the release of norepinephrine from nerve endings into the synapse. Common catecholamines include: Catecholamines • dobutamine are ineffective when taken orally because • dopamine they’re destroyed by • epinephrine, epinephrine bitartrate, and epinephrine hydrochlo- digestive enzymes. Pharmacokinetics Catecholamines can’t be taken orally because they’re destroyed by digestive enzymes. In contrast, when these drugs are given sublin- gually (under the tongue), they’re absorbed rapidly through the mucous membranes. Any sublingual drug not completely ab- sorbed is rapidly metabolized by swallowed saliva. Subcutaneously slow SubQ absorption is slowed because catecholamines cause the blood vessels around the injection site to constrict. Memory jogger Excretion To help you Catecholamines are excreted primarily in urine; however, a small remember amount of isoproterenol is excreted in feces and some epineph- the effects of cate- rine is excreted in breast milk. When catecholamines (and activation, sug- combine with alpha receptors or beta receptors, they cause either gesting an excitatory an excitatory or an inhibitory effect. Typically, activation of alpha response), and B stands for beta (or receptors generates an excitatory response, except for intestinal banished, suggest- relaxation. Activation of beta receptors typically produces an in- ing an inhibitory ef- hibitory response, except in heart cells, where norepinephrine fect). As a result, the ventricles empty more completely with each heartbeat, increasing the heart’s workload and the amount of oxygen it needs to do this harder work. Rapid rates Catecholamines also produce a positive chronotropic effect, which means that they cause the heart to beat faster. As catecholamines cause blood vessels to con- strict and blood pressure to rise, the heart rate can fall as the body tries to compensate for an excessive rise in blood pressure. Fascinating rhythm Catecholamines can cause the Purkinje fibers (an intricate web of fibers that carry electrical impulses into the ventricles) to fire spontaneously, possibly producing abnormal heart rhythms, such as premature ventricular contractions and fibrillation. Epineph- rine is more likely than norepinephrine to produce this sponta- neous firing. Pharmacotherapeutics The therapeutic uses of catecholamines depend on the particular receptor that’s activated. Boosting blood pressure Catecholamines that stimulate alpha receptors are used to treat low blood pressure (hypotension). They generally work best when used to treat hypotension caused by: • relaxation of the blood vessel (also called a loss of vasomotor tone) • blood loss (such as from hemorrhage). It’s electric Almost all body systems can feel the Because they’re believed to make the heart more responsive to de- impact! Better breathing Catecholamines that exert beta2 activity are used to treat: • acute or chronic bronchial asthma • emphysema • bronchitis • acute hypersensitivity (allergic) reac- tions to drugs. Kind to the kidneys Dopamine, which stimulates the dopamine receptors, is used in low doses to improve blood flow to the kidneys by dilating the re- nal blood vessels. Manufactured catecholamines have a short duration of action, which can limit their therapeutic usefulness. Drug interactions Drug interactions involving catecholamines can be serious, result- ing in hypotension, hypertension, arrhythmias, seizures, and high blood glucose levels in diabetic patients. These patients may require an increased dose of insulin or oral antidiabetic agents. Adverse reactions to catecholamines Adverse reactions to catecholamines can include: • restlessness • asthmatic episode • dizziness • headache • palpitations • cardiac arrhythmias • hypotension • hypertension and hypertensive crisis • stroke • angina • increased blood glucose levels • tissue necrosis and sloughing (if a catecholamine given I. Increased risk of adverse effects, such as hypertension, may occur when adrenergic drugs are given with other drugs that can cause hypertension. Absorption and distribution Absorption of the noncatecholamines depends on the administra- tion route: • Inhaled drugs, such as albuterol, are absorbed gradually from the bronchi and result in lower drug levels in the body. Excretion Noncatecholamines and their metabolites are excreted primarily in urine. Some, such as inhaled albuterol, are excreted within 24 hours; others, such as oral albuterol, within 3 days. Acidic urine increases excretion of many noncatecholamines; alkaline urine slows excretion. Pharmacodynamics Noncatecholamines can be direct-acting, indirect-acting, or dual- acting (unlike catecholamines, which are primarily direct-acting). Those that selectively stimulate beta2 re- ceptors include albuterol, isoetharine, metaproterenol, and terbu- taline.

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Calculation of New ττττ Before calculating a new maintenance dose discount 2mg artane free shipping, we can first check to see if we need to use a new dosing interval order artane canada, as follows: (See Equation 13-4 order 2mg artane otc. This every-18-hour dosing interval is a nonstandard interval and can result in administration time errors. Only use intervals such as every 18 or 16 hours when a more standard interval of every 12 or 24 hours does not yield acceptable plasma drug concentrations. Calculation of New K0 Now with the calculated elimination rate constant, volume of distribution, and dosing interval, a revised dosing regimen can be reapplied to solve for the dose. For the concentration at 2 hours after the infusion, we would use the desired concentration of 20 mg/L: Rearranging gives: (See Equation 13-3. In this instance, a peak of more than 20 mg/L is more desirable than a peak less than 20 mg/L, so we would use the dose of 900 mg. The resulting concentration at the end of the dosing interval (trough) can be estimated: (-0. Her recovery is complicated by the onset of acute renal failure 1 week after admission. During the second week, she experiences a spiking fever; gram-positive bacilli, resistant to methicillin but susceptible to vancomycin, are subsequently cultured from her blood. Two hours after the end of a 1000-mg loading dose administered over 1 hour, the vancomycin plasma concentration was 29 mg/L; it is 17. Calculate the vancomycin elimination rate constant, half-life, and volume of distribution in this patient. Note that there are two opportunities to calculate patient-specific pharmacokinetic valuesafter the first dose or after steady state has been achieved. In this case, because the patient has such a long half-life, it is decided to calculate these parameters after the first dose, which allows for subsequent dose adjustments without waiting the many days necessary for steady state to be reached. First, we calculate the elimination rate constant (K) and half-life (T1/2): (See Equation 3-1. Therefore, we must account for the 2 hours that lapsed between the end of the infusion and first plasma level. When calculating the elimination rate constant from two different plasma concentrations, the concentrations should be at least one half-life apart to determine a reasonably accurate slope of the line. Drug concentrations less than one half-life apart can incur great errors in the estimate of the elimination rate constant (K). With the information just determined, calculate when the next vancomycin dose should be given and what it should be. Assume that the plasma vancomycin concentration should decline to 10 mg/L before another dose is given and that the plasma concentration desired 2 hours after the infusion is complete is 20 mg/L. First, we must know the time needed for the plasma concentration to decline to 10 mg/L. It can easily be calculated from the known plasma concentrations, the elimination rate constant, and the desired trough plasma concentration: -Kt Ctrough = Cpeak(steady state)e where: Cpeak(steady state) = observed concentration of 29 mg/L, -1 K = elimination rate constant (0. Next, we determine dosing interval and maintenance dose as follows: (See Equation 13-4. Rearranging to solve for K0: Because 350 mg is used instead of 366 mg, the peak will be 19. Finally, we must check to see what our trough concentration will be after rounding both dose and dosing interval. Plasma concentrations after loading dose of vancomycin in patient with renal impairment (29 mg/L at 2 hours and 17. She was given a 1000-mg vancomycin loading dose and is now receiving 500 mg (infused over 1 hour) every 12 hours. Predict the steady-state Cpeak and Ctrough from this dose, using population average values for K and V. How do they compare to the recommended Cpeak of 18-26 mg/L and Ctrough of 5-10 mg/L? The equation for a one-compartment, intermittent-infusion drug can be used to solve for Cpeak(steady state) and Ctrough(steady state): (See Equation 13-3. By application of the general equation for a one-compartment, first-order, intermittently infused drug, we get: (See Equation 13-3. Therefore: This value is within the desired Cpeak range of 18-26 mg/L for this patient. Then: Using this new dosing interval of 48 hours, we can solve for the maintenance dose that gives our desired Cpeak and Ctrough of 25 and 5-10 mg/L, respectively: (See Equation 13-3. Then: Note that this answer can range from 1245 to 1345 mg, depending on the amount of rounding used in this complex calculation. Try to develop a step-by-step model to walk you through the calculations, such as: 1.