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Forxiga

Forxiga

By E. Jose. Dillard University.

A disappearing act Methotrexate exhibits a three-part disappearance from plasma; the rapid distributive phase is followed by a second phase buy discount forxiga 10mg line, which reflects kidney clearance discount forxiga 10mg mastercard. The last phase purchase 10 mg forxiga with amex, the terminal half-life, is 3 to 10 hours for a low dose and 8 to 15 hours for a high dose. Methotrexate is especially useful in treating the most Pharmacodynamics common childhood Methotrexate reversibly inhibits the action of the enzyme dihydro- leukemia. Folinic acid is used in high-dose methotrexate therapy to help prevent cell death. Kidney concerns • Salicylates and nonsteroidal anti-inflammatory drugs, especially With high doses, kidney diclofenac, ketoprofen, indomethacin, and naproxen, also in- toxicity can also occur crease methotrexate toxicity. It consists of a sugar, a nitrogen-containing Climbing the ladder to understanding base, and a phosphate group. Cytosine and thymine are pyrimidines; After pyrimidine analogues are converted into adenine and guanine are purines. Pharmacokinetics Because pyrimidine analogues are poorly absorbed when they’re given orally, they’re usually administered by other routes. Pharmacodynamics Pyrimidine analogues kill cancer cells by interfering with the nat- ural function of pyrimidine nucleotides. Adverse reactions to pyrimidine analogues Like most antineoplastic drugs, pyrimidine ana- • Diarrhea logues can cause: • Fever • fatigue and lack of energy • Hand-foot syndrome • inflammation of the mouth, esophagus, and • Crab erythema (when high-dose cytarabine throat is combined with continuous infusions of fluo- • bone marrow suppression rouracil) • nausea and anorexia. Fluorouracil With Cytarabine • Diarrhea pyrimidine • Severe cerebellar neurotoxicity • Hair loss analogues, we • Chemical conjunctivitis • Mucositis (when combined with folinic acid) may all win! Drug interactions No significant drug interactions occur with most of the pyrimidine analogues; however, several drug interactions are possible with capecitabine. They include: • fludarabine phosphate • cladribine • mercaptopurine • pentostatin • thioguanine. Pharmacodynamics As with the other antimetabolites, fludarabine, mercaptopurine, and thioguanine first must be converted via phosphorylation (in- troduction to a phosphate) to the nucleotide level to be active. Analogous to pyrimide analogues This conversion to nucleotides is the same process that pyrimi- dine analogues go through but, in this case, it’s purine nucleotides that are affected. Purine analogues are cell cycle–specific as well, exerting their effect during that same S phase. Fludarabine, when used at high doses, may Down to the bone cause severe neurologic • Concomitant administration of mercaptopurine and allopurinol effects, including blind- may increase bone marrow suppression by decreasing mercapto- ness, coma, and death. They include: • anthracyclines (daunorubicin, doxorubicin, idarubicin) • bleomycin • dactinomycin • mitomycin • mitoxantrone. Direct deliveries Some drugs are also administered directly into the body cavity be- ing treated. Bleomycin, doxorubicin, and mitomycin are some- times given as topical bladder instillations, resulting in minimal systemic absorption. When bleomycin is injected into the pleural space for malignant effusions, up to one-half of the dose is ab- sorbed systemically. Distribution, metabolism, and excretion Distribution of antibiotic antineoplastic drugs throughout the body varies; their metabolism and elimination also vary. Clean break Mitomycin is activated inside the cell to a bifunctional or even tri- functional alkylating drug. Ir- • melanoma • osteogenic sarcoma and rhabdomyosarcoma (malignant neo- reversible cardiomyopa- plasm composed of striated muscle cells) thy and acute electro- • squamous cell carcinoma of the head, neck, and cervix cardiogram changes • testicular cancer can also occur as well • Wilms’ tumor (a malignant neoplasm of the kidney, occurring in as nausea and vomiting. Extra steps An antihistamine and an Drug interactions antipyretic should be Antibiotic antineoplastic drugs interact with many other drugs. Hormonal antineoplastic drugs and hormone modulators Hormonal antineoplastic drugs and hormone modulators are prescribed to alter the growth of malignant neoplasms or to man- age and treat their physiologic effects. Aromatase inhibitors In postmenopausal women, estrogen is produced through aromatase, an enzyme that converts hormone precursors into estrogen. Aromatase inhibitors prevent androgen from being converted into estrogen in postmenopausal women, thereby blocking estrogen’s ability to activate can- cer cells; limiting the amount of estrogen means that less estrogen is available to reach cancer cells and make them grow. Type 1, or steroidal, inhibitors include exemestane; type 2, or nonsteroidal, inhibitors include anastrozole and letrozole. Pharmacokinetics Aromatase inhibitors are taken orally (in pill form) and are usually well tolerated. Pharmacodynamics Aromatase inhibitors work by lowering the body’s production of estrogen. In about one-half of all patients with breast cancer, the tumors depend on estrogen to grow. Aromatase inhibitors are used only in postmenopausal women because they lower the Memory amount of estrogen that’s produced outside the ovaries, such as in jogger muscle and fat tissue. Because these drugs induce estrogen depri- Remember: vation, bone thinning and osteoporosis may develop over time. Hormonal- dependent (gender To reverse or not to reverse: That is the question specific) tumors are Type 1 inhibitors, such as exemestane, irreversibly inhibit the aro- treated with hormon- matase enzyme, whereas type 2 inhibitors, such as anastrozole, re- al therapies; tumors versibly inhibit it. Type 1 aromatase inhibitors may still be effec- common to both gen- ders are treated with tive after a type 2 aromatase inhibitor has failed. Adverse reactions to Pharmacotherapeutics aromatase Aromatase inhibitors are primarily used to treat postmenopausal inhibitors women with metastatic breast cancer. They may include Drug interactions dizziness, mild nausea, Certain drugs may decrease the effectiveness of anastrozole, in- mild muscle and joint cluding tamoxifen and estrogen-containing drugs. The antiestrogens include tamoxifen citrate, toremifene cit- density and low-density rate, and fulvestrant. Aromatase Pharmacokinetics inhibitors help treat metastatic breast After oral administration, tamoxifen is well absorbed and under- cancer that occurs goes extensive metabolism in the liver before being excreted in after menopause. Estrogen re- ceptors, found in the cancer cells of one-half of premenopausal and three-fourths of postmenopausal women with breast cancer, respond to estrogen to induce tumor growth. It’s bound to inhibit growth The antiestrogens fulvestrant, tamoxifen, and toremifene bind to the estrogen receptors and inhibit estrogen-mediated tumor growth in breast tissue. However, tamoxifen has serious adverse A report from the 2000 annual meeting of the American Society effects that include potentially fatal blood clots and uterine of Clinical Oncology, presented an analysis of data gathered cancer. The question is whether these risks are worth the ben- from the National Surgical Adjuvant Breast and Bowel Project’s efits in healthy women. The National Cancer Institute’s report The data analysis indicates that tamoxifen is as effective in To help answer this question, the National Cancer Institute Black women as in White women in reducing the occurrence published a report in November of 1999. They concluded that of contralateral breast cancer (breast cancer that develops in most women older than age 60 would receive more harm than the healthy breast after treatment in the opposite breast). Breaking it down further The results showed that the raloxifem-treated group had a low- The report also concluded that the risks of tamoxifen were er incidence of uterine cancer and clotting events than the ta- greater than the benefits for black women older than age 60 moxifen group. I predict hormonal therapies will duces the number of free receptors in the cytoplasm. Pharmacotherapeutics Tamoxifen is used alone and as adjuvant treatment with radi- ation therapy and surgery in women with negative axillary lymph nodes and in postmenopausal women with positive axillary nodes.

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With high doses and high plasma concentrations (and resulting lower clearance) buy forxiga 10 mg with visa, the time to reach steady state is much longer than with low doses and low plasma concentrations (Figure 10-7) buy discount forxiga 10mg line. Theoretically cheap forxiga 10 mg line, if the dose is greater than Vmax, steady state will never be reached. The Michaelis-Menten equation can be rearranged to provide an equation that estimates the time required (in days) for 90% of the steady-state concentration to be reached (t90%), as shown below (where the dose equals the daily dose): 10-4 From the previous example, when dose = 300 mg/day, Vmax = 700 mg/day, Km = 12 mg/L, and the volume of distribution (V) is estimated to be 50 L: When the dose is increased to 400 mg/day: We can see that as the dose is increased, it takes a longer time to reach steady state, drug continues to accumulate, and the plasma drug concentration continues to rise. Clinical Correlate The t90% equation will only provide a rough estimate of when 90% of steady state has been reached, and its accuracy is dependent on the Km value used. Other ways to check to see if a patient is at steady state are to examine two levels drawn approximately a week apart. Additionally, it is safe to wait at least 2 weeks (and preferably 4 weeks) after beginning or changing a dose before obtaining new steady-state levels. Linear pharmacokinetics means that the plot of plasma drug concentration versus time after a dose is a straight line. When hepatic metabolism becomes saturated, any increase in drug dose will lead to a proportionate increase in the plasma concentration achieved. When the rate of drug elimination proceeds at half the maximum rate, the drug concentration is known as: A. Which of the equations below describes the form of the Michaelis-Menten equation that relates daily drug dose to Vmax, Km, and the steady-state plasma drug concentration? The phenytoin dose is then changed to 400 mg/ day, and 2 months after the dose change the plasma concentration determined just before a dose is 18 mg/L. After the dose of 400 mg/day is begun, how long will it take to reach 90% of the steady-state plasma concentration? Drugs with linear pharmacokinetics may exhibit plasma concentrations versus time plots that are not straight lines, as with multiple-compartment drugs. There will be a disproportionate increase in the plasma concentration achieved because the amount of drug that can be eliminated over time cannot increase. At very low concentrations, drugs are more likely to exhibit first-order kinetics because hepatic enzymes are usually not yet saturated, whereas at higher concentrations, enzymes saturate, making zero-order kinetics more likely. Use dose pairs of 300 and 400 and concentration pairs of 10 and 18 to calculate Km. The steady-state plasma concentration resulting from a daily dose of 500 mg would be estimated from the line equation as follows: Rearranging gives: C, D. When using the t90% equation, examine what happens to t90% when dose greatly exceeds Vmax. Discuss several practical methods to determine when a nonlinear drug has reached steady state. Examine the "time to 90% equation" and note the value of Km that is used in this equation. Substitute several different phenytoin Km values based on a range of population values (i. Based on this observation, what value of Km would you use when trying to approximate the t90% for a newly begun dose of phenytoin? Discuss the patient variables that can affect the pharmacokinetic calculation of a nonlinear drug when using two plasma drug concentrations obtained from two different doses. Write a pharmacy protocol describing an appropriate phenytoin dosing and monitoring service. Explain how the various sources of pharmacokinetic variation affect pharmacokinetic parameters. Describe ways to avoid or minimize errors in the collection and assay of drug samples. These differences in drug effect are sometimes related to differences in pharmacokinetics. However, irrespective of pharmacokinetics, drug effects may vary among individuals because of differences in drug sensitivity. Age At extremes of age, major organ functions may be considerably reduced compared with those of healthy young adults. In neonates (particularly if premature) and the elderly, renal function and the capacity for renal drug excretion may be greatly reduced. Renal function declines at a rate of approximately 1 mL/minute/year after the age of 40 years. In the neonate, renal function rapidly progresses in infancy to equal or exceed that of adults. When dosing a drug for a child, the drug may need to be administered more frequently. Compared with adults, the neonate has a higher proportion of body mass made up of water and a lower proportion of body fat. The elderly are likely to have a lower proportion of body water and lean tissue (Figure 11-1) Both of these changes, organ function and body makeup, affect the disposition of drugs and how they are used. Reduced function of the organs of drug elimination generally requires that doses of drugs eliminated by the affected organ be given less frequently. With alterations in body water or fat content, the dose of drugs that distribute into those tissues must be altered. For drugs that distribute into body water, the neonatal dose may be larger per kilogram of body weight than in an adult. Disease States Drug disposition is altered in many disease states, but the most common examples involve the kidneys and liver, as they are the major organs of drug elimination. In patients with major organ dysfunction, drug clearance decreases and, subsequently, drug half-life lengthens. Some diseases, such as renal failure or cirrhosis, may even result in fluid retention and an increased volume of drug distribution. Alterations in drug clearance and volume of distribution require adjustments in the dose administered and/or the dosing interval. For most drugs, when clearance is decreased but the volume of distribution is relatively unchanged, the dose administered may be similar to that in a healthy person but the dosing interval may need to be increased. Alternatively, smaller doses could be administered over a shorter dosing interval. When the volume of distribution is altered, the dosing interval can often remain the same but the dose administered should change in proportion to the change in volume of distribution. Effect of Volume of Distribution and Impaired Renal/Hepatic Function on Drug Dose Clinical Correlate When adjusting a dose of a drug that follows first-order elimination, if you do not change the dosing interval, then the new dose can be calculated using various simple ratio and proportion techniques. For example, if gentamicin peak and trough serum drug concentrations, in a patient receiving 120 mg Q 12 hours), were 9 and 2. Likewise, one can check to see if this trough would be acceptable with this new dose: "if 120 mg gives a trough of 2. A 23-year-old male experienced a major traumatic injury from a motor vehicle accident. On the third day after injury, his renal function is determined to be good (creatinine clearance = 120 mL/minute), and his weight has increased from 63 kg on admission to 83 kg. Note that fluid accumulation (as evidenced by weight gain) is an expected result of traumatic injury.

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Proceedings of the 16th International Conference on Alcohol, Drugs and Traffic Safety, 4-9 August, Montreal. Singleton N, Murray R & Tinsley L (2006) Measuring different aspects of problem drug use: methodological developments. The Health and Social Care Information Centre (2011) Statistics on drug misuse: England, 2011. Scottish Government (2008) The road to recovery: a new approach to tackling Scotland’s drug problem. World Health Organization (2004) Neuroscience of psychoactive substance use and dependence. Yokoyama A, Muramatsu T, Ohmori T et al (1998) Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics. Kuepper R, Van Os J, Lieb R et al (2011) Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. Advisory Council on the Misuse of Drugs (2008) Cannabis: classification and public health. 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