O. Fraser. Virginia Military Institute.

This may result in increased borns generic 300 mg quetiapine amex symptoms 9 days after embryo transfer, and every 24 hours in extremely premature in- plasma levels of free drug and the potential for toxicity quetiapine 100mg low cost symptoms 13dpo. The glomerular filtration rate of the term newborn the past, concerns were raised that certain drugs, such as is approximately 50% less than the adult level but sulfonamides, could displace endogenous substances, like reaches adult values by 1 year of age. Tubular secretory functions mature at a slower rate than Although this belief has been challenged recently, reluc- does glomerular filtration. Renal elimination of drugs appears to play a greater role than As with adults, the primary organ responsible for drug does metabolism in newborns. Phase I oxidation reactions and demethylation enzyme systems are signif- Drug Action icantly reduced at birth. However, the reductive enzyme Most drugs are administered to infants and children for systems approach adult levels and the methylation the same therapeutic indications as for adults. Among to the production of different metabolites in newborns these are theophylline and caffeine, which are used to from those in adults. For example, newborns metabolize treat apnea of prematurity; indomethacin, which closes a approximately 30% of theophylline to caffeine rather patent ductus arteriosus; and prostaglandin E1, which than to uric acid derivatives, as occurs in adults. Para- most phase I enzymes have reached adult levels by 6 doxically, drugs such as phenobarbital, which have a months of age, alcohol dehydrogenase activity appears sedating action on adults, may produce hyperactivity in around 2 months of age and approaches adult levels children, and some adult stimulant drugs, such as methyl- only by age 5 years. Phase II synthetic enzyme reactions are responsible for the elimination of endogenous compounds, such as bilirubin, and many exogenous substances. The immatu- Adverse Reactions rity of the glucuronidation pathway was responsible for Children may display adverse reactions different from the development of gray baby syndrome (see Chapter those noted in adult patients. The plasma half-life was found to be 26 hours in Several problems unique to pediatric drug therapy de- these patients compared with 4 hours in older children. For example, most medications Infants and children have a greater capacity to carry are commercially available only in adult dose forms. For example, Preparing pediatric doses from adult tablets or capsules acetaminophen is excreted predominantly as a sulfate can be very difficult and may require special skill on the conjugate in children as opposed to a glucuronide con- part of the pharmacist. This enhanced sulfation of acetamino- administer the intravenous (IV) preparation orally than phen, along with decreased metabolism via cytochrome to develop a preparation from the oral medication. P450 pathways and increased glutathione turnover, are IV drug administration is most effective in children thought to explain the decreased hepatotoxicity caused when given via a pump infusion system close to the site by this analgesic in children under 6 years of age. Because of the small size of many pedi- II enzyme systems reach adult levels between 3 and 6 atric doses and the fact that some drugs adhere to IV months of age. Drug Reactions Drug Reaction DRUG DISPOSITION IN GERIATRIC PATIENTS Furosemide (Lasix) Nephrocalcinosis Indomethacin (Indocin) Renal Failure, bowel perforation The elderly (individuals over 65 years of age) constitute Adrenocorticoids Delayed development, growth more than 13% of the population. This figure is increas- suppression Tetracyclines Discolored teeth ing steadily and is expected to reach 50 million by the Phenobarbital Hyperactivity, impaired intellec- year 2020. This segment of our society is the most highly tual development drug-treated and accounts for about 25% of prescrip- Phenytoin (Dilantin) Thickened skull, coarse features tion drugs dispensed. A clear relationship between the appearance of untoward it is given using techniques usually reserved for adults. For some 90 other drugs in common ministration is also critical and therefore much more clinical use, age alone was not a major determinant of easily managed by IV infusion pumps. It is apparent that an increase in life Most adult drugs must be diluted to achieve appro- span is accompanied by an increase in chronic illnesses priate pediatric dosages. Some drugs such as NPH (Neutral these conditions, especially when the same person has Protamine Hagedorn) insulin may lose their effective- several diseases, becomes increasingly complex. Age-related alterations in pharmacokinetics (ab- Children with chronic illnesses require special con- sorption, distribution, metabolism, and excretion) have sideration. Thus, physiological have increased hepatic metabolism and therefore in- changes in elderly patients, when taken together, may creased drug clearance. This may necessitate the admin- contribute to impairments in drug clearance in this seg- istration of increased drug dosages. Repeated increases in drug dosage are re- more slowly because of decreased splanchnic blood flow quired to accommodate for growth in children receiving or delayed gastric emptying. In summary, children, especially those in the first year of life, present significant pharmacological chal- Distribution lenges. Drug administration must be tailored to meet the unique needs of children at their varied stages of de- Drug distribution in elderly patients may be altered by velopment. Special attention must be given to unex- hypoalbuminemia, qualitative changes in drug-binding pected drug actions and adverse reactions in these pa- sites, reductions in relative muscle mass, increases in the tients, who are maturing at variable rates. When proportion of body fat, and decreases in total body planning drug therapy for children, it is important to water.

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In a flexible talipes pla- novalgus deformity discount quetiapine 50 mg with amex treatment gout, the tiptoe stance will bring about a varus shift in the heel to compensate for the valgus deformity purchase 50mg quetiapine with mastercard medicine keri hilson lyrics, and the medial longi- tudinal arch will reappear. The examiner grasps the foot of the affected leg with one hand and attempts to correct the pes adductus deformity by pressing on the medial aspect of the forefoot with thumb of the other hand. Assessment: Where this maneuver readily moves the forefoot across the midline and eliminates the pes adductus, the deformity is usually flexible and will be spontaneously corrected. Congenital pes adductus deformities that resist manual correction will require rigorous timely treatment in corrective plaster casts. Test of Lateral and Medial Ankle Stability Assesses a lateral ligament injury in the ankle. The examiner grasps the posterior lower leg adjacent to the malleoli with one hand. With the other hand, the examiner grasps the lateral metatarsus and attempts to open the ankle by means of passive supination. To test the medial ligaments, the examiner grasps the medial metatarsus and attempts to open the ankle medially by means of pronation. The tibiotalocalcaneal joint complex is comprised of the ankle and subtalar joint. These are complex articulations that combine to form a functional unit; the subtalar joint also acts in concert with the trans- Buckup, Clinical Tests for the Musculoskeletal System © 2004 Thieme All rights reserved. Some of the medial and lateral collateral ligaments span both joints; others span only the ankle. The lateral (fib- ular) structures include the anterior talofibular, calcaneofibular, and posterior talofibular ligaments; the medial (tibial) structures include the deltoid ligament. Upward motion of the forefoot is referred to as dorsiflexion, down- ward motion as plantar flexion. Lifting of the medial margin of the foot is referred to as supination; lifting of the lateral margin, pronation. Assessment: Injury to one of these ligaments leads to instability and increased opening of the lateral or medial joint cavity. Increased supi- nation suggests an injury to the anterior talofibular and calcaneofibular ligaments. Rotational trauma in supination is the most common mech- anism of ankle injury and almost invariably involves the anterior talo- fibular ligament. Children normally have greater mobility in the ankle, which must not be misinterpreted as a ligament injury. This means that a comparative examination of both feet should be performed as matter of course. Stress radiographs are necessary to document capsular liga- ment injuries particularly in the ankle. Depending on specific require- ments, they may be obtained with a supination or pronation stress applied, with the foot in a middle position, and in an anterior or posterior drawer position. Buckup, Clinical Tests for the Musculoskeletal System © 2004 Thieme All rights reserved. The examiner immobilizes the pos- terior tibia with one hand and grasps the metatarsus with the other. The examiner then pushes the foot posteriorly in the ankle against the hand immobilizing the tibia. In a second step, the examiner grasps the ante- rior tibia and grasps the heel posteriorly. A torn lateral collateral ligament in the ankle will result in increased mobility of the foot in the ankle; there will be increased anterior mobility where the anterior ligaments are involved and increased pos- terior mobility with involvement of the posterior ligaments. Assessment: Where an interdigital neuroma is present, pushing the metatarsal heads against one another will cause pain with occasional paresthesia radiating into the adjacent toes. Small fibroma-like hard- ened areas between the toes will also be palpable and will displace, sometimes with a clicking sound, as the forefoot is compressed. Painful interdigital neuromas usually develop in the second or third interdigital fold; neuromas in the first or fourth interdigital fold are rare. Assessment: In a stress fracture of the calcaneus, the patient will feel intense pain in the heel.

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Ifosfamide also has (B) Cyclophosphamide a broad spectrum of antitumor activity although it is (C) Mechlorethamine not as broad as that of cyclophosphamide purchase quetiapine 50mg fast delivery medications not to be crushed. The effectiveness of chemotherapy in human cancer was the use of melphalan is limited because a substituted phenyl which agent in trophoblastic choriocarcinoma in ring in the molecule reduces its reactivity quetiapine 300 mg without prescription internal medicine. The long-term complete remissions of tro- (A) Chlorambucil phoblastic choriocarcinoma in women was the first (B) Thiotepa demonstration of the curative potential of (C) Methotrexate chemotherapy in human cancer. Which class of drugs bind avidly to tubulin and mission in patients with primary brain tumor, the cause arrest of cells in metaphase? The mechanism of action of nitrogen mustards (C) Alkylating agents is to form covalent bonds with adjacent guanine (D) Antiestrogens residues and inhibit DNA replication and transcrip- (E) Antimetabolites tion. The patient man breast cancer cells that contain estrogen recep- inquires about her chances for remission. Interferon alfa-2b has been somewhat of a disap- known as interferons were capable of containing vi- pointment as an anticancer drug. However, it has ral infections led to the hope that they would have proved useful in the treatment of which of the fol- many beneficial results, including anticancer activity. Pharmacogenetic determinants of anti- tion, differences in the toxicity profile, duration of cancer drug activity and toxicity. Receptor tyrosine kinases as rational tar- Vinorelbine for treatment of advanced non-small cell gets for prostate cancer treatment: Platelet-derived lung cancer. Case Study Treatment of Leukemic Meningitis 15-year-old girl moves into your neighborhood ANSWER: Immediately arrange for an evaluation of Aand makes an appointment to see you. She consider administering methotrexate 12 mg in- tells you that she has been doing well, but recently trathecally every day for 4 days. With such a regi- she has had frequent severe headaches, and her men, subsequent evaluations of the CSF often indi- mother said she has stumbled a couple of times dur- cate no leukemic cells present. Sauers DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Azathioprine 660 Levamisole 662 Bacillus Calmette-Guérin 662 Methotrexate 661 Chlorambucil 661 Muromonab-CD3 661 Cyclophosphamide 661 Mycophenolate mofetil 661 Cyclosporine 659 Myeloid Colony-Stimulating Factors 663 Immune Globulin 662 Sirolimus 660 Interferon- 663 Tacrolimus 660 Interleukin 2 662 Thymic Factors 662 Immunopharmacology is the study of the use of circumstances, normal control is lost and the aberrant pharmacological agents as modulators of immune re- immune reaction will result in disease. The principal applications are in the use of im- Myasthenia gravis is an example of an autoimmune munosuppressive agents (i. Phagocytic cells are in turn attracted to these react against normal endogenous proteins and thereby sites, where they release enzymes that destroy sur- effect a reaction against certain body tissues. Approximately 70 PIDs have been Idiopathic thrombocytopenic purpura described, including those specific for humoral immu- Membranous glomerulonephritis Polymyalgia rheumatica nity (e. Systemic lupus erythematosus The treatment of a PID is based on the aspect of the Ulcerative colitis Uveitis immune system that is lacking. For those with deficiencies in cell-mediated immunity, there is no effective pharmacological treatment. The clinical manifestations of PIDs vary with the as- A list of autoimmune diseases for which immuno- pect of the immune system affected. In general, because suppressive therapy is commonly used can be found in of the role of antibodies in protection against bacterial Table 57. These ORGAN TRANSPLANTATION individuals are also prone to infections of the respira- tory, gastrointestinal, and urinary tracts because of the Suppression of the immune system is a requirement dur- protective role of IgA in secretions. Since transplantation is usually per- Candida albicans, cytomegalovirus, and Pneumocystis formed in patients with a poor prognosis for survival, carinii, since cell-mediated immune responses are the the use of immunosuppressive agents has potentially primary defenses against these types of infection. In the past, immunosuppression could be achieved only through the use of nonspecific cytotoxic drugs (e. Consequently, serious side effects, including bone consider three principles of immunosuppressive therapy. Therefore, components of concurrent use of corticosteroids with the immunosup- the primary phase of the immune response, such as pro- pressants increased the risk of additional toxicity. With cessing, proliferation, and differentiation, will be the the development of the immunosuppressants cy- most sensitive to drug action. Drugs that are effective in closporine and tacrolimus it is now possible to avoid suppressing an immune response in an unsensitized per- much of this toxicity. Because of their relatively low tox- son generally will show much less effect, if any, in a sen- icity, these drugs have revolutionized the field of trans- sitized individual. It is now possible to successfully transplant has been established, immunosuppressive drugs show tissues to patients not previously considered as candi- little effectiveness.

Yellow or brownish extrinsic stain of teeth is a fre- bacteria discount 300mg quetiapine with visa treatment refractory, but Streptococcus mutans and Actinomyces quently observed side effect of viscosus discount quetiapine 50mg fast delivery treatment anal fissure, two bacteria particularly associated with (A) Fluoride dental lesions, are especially susceptible to its ac- (B) Triclosan tion. Stannous fluoride (D) is widely used in caries (C) Essential oils prevention, and many studies have proven its effec- (D) Chlorhexidine tiveness. The LEAST effective chemical agent for reduction shown to decrease supragingival plaque in combina- of dental plaque is tion with the polymer in a commercial preparation. Proceedings of the 2nd involved in drug elimination, while absorption (B) European Workshop on Periodontology. Rinsing, irrigation and sustained local scribes the ability of a drug to enter a variety of body delivery. In most instances, dental plaque can cause ery- Administration was evaluating the results of a new thema and gingival bleeding, but the gingival re- drug for the treatment of periodontal disease. Her sponse can also be exacerbated by a variety of review of the phase III clinical data caused her to systemic conditions, including diabetes mellitus, visit her dentist, since she was concerned that her leukemia, malnutrition, puberty and pregnancy. For exam- revealed swollen and tender gingiva that were ple, the age of the patient, her appearance, and accompanied by erythema and bleeding upon mild questions about her diet should be enough to provocation. Her dental radiographs revealed no rule in or out issues concerning puberty and mal- abnormalities, and her physician found her to be nutrition. She reports be ruled out, an additional physical examination taking no medications and denies allergies to any by a physician may be necessary. She is concerned about her health to be requested could include oral glucose toler- because her gingiva will bleed when she eats fibrous ance test for diabetes mellitus, human chorionic foods (e. What do you think is the most likely cause of her tative and quantitative evaluation of bone mar- periodontal disease? Should an oral chemotherapeutic agent be pre- using over-the-counter toothpastes with triclosan scribed for her periodontal disease? If the patient one would you prescribe and what would be the is pregnant, a thorough review of oral hygiene benefit and disadvantage of using this agent for combined with over-the-counter toothpaste with this patient? If persistent in- flammation and gingival enlargement continue, the use of a prescription antiplaque rinse, such as chlorhexidine, would be warranted. Therapy of Human Immunodeficiency Sulfonamides, Trimethoprim, Nitrofurans, Virus 584 Quinolones, Methenamine 515 Knox Van Dyke and Karen Woodfork Marcia A. Lazo and Jennifer Rubin Grandis Introduction to Chemotherapy 4343 Steven M. Belknap Paul Ehrlich introduced the term chemotherapy toxic substances that kill or suppress the growth of com- in 1907 to describe his important early studies of peting microorganisms or facilitate infection of a host. Trypanosoma brucei, the tsetse fly–borne parasite that Plants make a vast array of toxins for their self-defense. The Exploitation of the selective toxicity of chemicals is an term chemotherapy, initially referring to antiparasitic ancient and widely employed technique. Ehrlich had previously developed selective bacterial effect of a substance secreted by Penicillium chemical stains for the microscopic examination of notatum mold. Howard Florey subsequently had the Mycobacterium tuberculosis and other microorganisms, insight that this substance could be purified and in- using the coal-tar derivative dyes. He tested many of jected into patients so as to provide systemic treat- these organic compounds for their selective toxicity ment of infection. Once scientists had learned of peni- against trypanosomes but failed to find an effective non- cillin, they found many other naturally synthesized toxic antischistosomal agent. Turning to the chemother- antibiotics, including tetracycline, streptomycin, and apy of syphilis, Ehrlich eventually discovered the arseni- the cephalosporins. When the structures of these natu- cal compound salvarsan, which was both remarkably ral antibiotics were elucidated, chemists began to ex- nontoxic to humans and remarkably toxic against a periment with semisynthetic derivatives of the natural number of treponemal diseases, including syphilis and products and invented entire classes of related drugs yaws. The new semisynthetic or wholly drugs is hindered by the common evolutionary legacy synthetic drugs had improved pharmacokinetic prop- humans share with all living organisms; success requires erties, greater stability, and extended spectrums of exploitation of metabolic or structural differences be- action. The emergence of microbial antibiotic drug resist- The more closely related the undesirable cells are to ance was speeded by the indiscriminate use of antibi- normal human cells, the more difficult the task of find- otics in humans and livestock. For example, it is easier to cure concentrations of antibiotic in meat or milk may have malaria than cancer. Since viruses commandeer human provided a path whereby human pathogens could cells to provide the necessary structural and metabolic eventually evolve high-level antibiotic drug resistance. Inappropriate use of antibiotics is very common, Humans were not the first to exploit the selective and it accelerates the development of resistance in toxicity of chemicals. Aluminum, calcium, man disease is complex, as it depends on a complex and magnesium ions in antacids or dairy products form patient–drug–pathogen interaction.

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