By Z. Cyrus. Life Pacific College. 2018.

Drugs such as the tetracyclines cheap 20 mg tadora with amex, which are FACTORS AFFECTING RATE OF highly ionized buy generic tadora 20 mg, can complex with Ca ions in mem- GASTROINTESTINAL ABSORPTION branes, food, or milk, leading to a reduction in their In addition to the lipid–water partition coefficient of rate of absorption. For drugs that are ionized in the drugs, local blood flow, and intestinal surface area, other stomach and un-ionized in the intestine, overall ab- factors may affect absorption from the gastrointestinal sorption will be delayed by any factor that delays gas- tract. Finally, increased splanchnic blood flow, as occurs during eating, will increase the rate of drug Gastric Emptying Time absorption. The rate of gastric emptying markedly influences Formulation Factors the rate at which drugs are absorbed, whether they are acids, bases, or neutral substances. In general, fac- The ability of solid drug forms to dissolve and the sol- tors that accelerate gastric emptying time, thus permit- ubility of the individual drug in the highly acidic gas- ting drugs to reach the large absorptive surface of the tric juice must be considered. For example, although small intestine sooner, will increase drug absorption the anticoagulant dicumarol has a very high lipid– unless the drug is slow to dissolve. A list of physiolog- water partition coefficient, it precipitates at the low ical, pathological, and pharmacological factors that in- pH of gastric juice, and the rate of its absorption is TABLE 3. Taken together, the absorbed faster and more completely than tablet or Pgp transporter and the cytochrome P450 enzymes suspension forms. Suspensions of fine particles (mi- form a mechanism to reduce the amount of drug reach- crocrystalline) are better absorbed than are those of ing the systemic circulation. Metabolism and Efflux Transporters ABSORPTION OF DRUGS FROM THE LUNG Drugs may be inactivated in the gastrointestinal tract before they are absorbed. Until recently, only gut mi- The lungs serve as a major site of administration for a croflora were implicated in the metabolism of drugs in number of agents given for both local and systemic ef- the gastrointestinal system, affecting drug absorption. Absorption of agents from the lung is zymes, play a major role in determining the extent of facilitated by the large surface area of the pulmonary drug absorption of some drugs. Significant expression of alveolar membranes (50–100 m2), the limited thickness cytochrome P450 3A4 and 3A5 occurs in the entero- of these membranes (approximately 0. For example, less than 20% of a dose of the im- for diffusion is a combination of the blood–air partition munosuppressant cyclosporine reaches the systemic cir- coefficient (which is a measure of the capacity of blood culation intact. In fact, most of the metabolism of cy- to dissolve drug) and the difference in partial pressure closporine prior to reaching the systemic circulation between the alveoli and the arterial and venous blood. Thus, gut me- quire more drug to be dissolved in the blood for equi- tabolism is the major factor responsible for the low per- librium to be reached. Cytochrome P450 2C9 and 2C19 are also expressed in measurable quantities in the human ABSORPTION OF DRUGS THROUGH intestine. With any of these four cytochrome P450 en- THE SKIN zymes, the variation in expression between individuals is substantial, and so their relative contribution to Most drugs that have been incorporated into creams or presystemic metabolism of drugs will vary from person ointments are applied to the skin for their local effect. However, the stratum corneum, or outer out of a cell) are also present in human intestinal ente- layer of the epidermis, forms a barrier against the rapid rocytes on the apical side nearest the lumen of the in- penetration of most drugs. The predominant transporter protein identified the relatively close-packed cellular arrangement and to date is P glycoprotein (Pgp), which is a product of the decreased amount of lipid in these cells.

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Bacitracin preparations are ef- trough concentration between 5 and 15 g/mL buy tadora 20 mg line, and the fective in the treatment of impetigo and other peak should stay below 60 g/mL to avoid side effects buy tadora 20 mg. Bacitracin has been used with limited success for avoid toxicity or ineffective treatment, especially in pa- eradication of S. Pediatric oncology pa- of serious nephrotoxicity, the parenteral use of baci- tients with normal renal function may require van- tracin is not justified. Similar studies in adult patients with hematological malignancies have suggested a larger GLYCOPEPTIDES: VANCOMYCIN dosage requirement as well, owing to an increased vol- AND TEICOPLANIN ume of distribution. After IV administration, vancomycin diffuses into serous cavities and across inflamed but not normal Structure and Mechanism of Action meninges. It can be used in the treatment of meningitis Vancomycin (Vancocin) is a complex tricyclic glycopep- with susceptible organisms. It is also given via ventricu- tide antibiotic produced by Streptomyces orientalis, loatrial or ventriculoperitoneal shunts when these be- while teicoplanin (Targocid) is derived from Actino- come infected. Teicoplanin has Renal excretion is predominant, with 80 to 90% of two major components: a phosphoglycolipid (A1) and an administered dose eliminated in 24 hours. Teicoplanin, like vancomycin, is not absorbed from They bind to the terminal carboxyl group on the D- the intestinal tract. Peak plasma levels are achieved alanyl-D-alanine terminus of the N-acetylglucosamine- about 2 hours after intramuscular administration. The N-acetylmuramic acid peptide and prevent polymeriza- drug distributes widely in tissues; plasma protein binding tion of the linear peptidoglycan by peptidoglycan is about 90%. Antimicrobial Spectrum The glycopeptides are narrow-spectrum agents that are Clinical Uses active against gram-positive organisms. Like van- comycin, teicoplanin is bacteriostatic against staphylo- Vancomycin and teicoplanin display excellent activity cocci, streptococci, and enterococci. Gram-positive against staphylococci and streptococci, but because of rods, such as Bacillus anthracis, Corynebacterium diph- the wide availability of equally effective and less toxic theriae, Clostridium tetani, and Clostridium perfringens, drugs, they are second-line drugs in the treatment of most are also sensitive to the glycopeptides. As antistaphylococcal agents they are less tides are not effective against gram-negative rods, my- effective than -lactam cephalosporin antibiotics, such cobacteria, or fungi. They have attained much wider use in recent years as a consequence of the emer- gence of methicillin-resistant S. In use of intravascular catheters and in patients with peri- neutropenic patients and others with altered gastroin- tonitis who are on continuous ambulatory peritoneal testinal mucosa with denudation, significant oral ab- dialysis. The combination of vancomycin and either Except for the treatment of staphylococcal enterocolitis streptomycin or gentamicin acts synergistically against and pseudomembranous colitis, it is administered intra- enterococci and is used effectively for the treatment or 554 VI CHEMOTHERAPY prevention of enterococcal endocarditis. Vancomycin in oral form can also be the effects of bacterial lipopolysaccharide (LPS) of used in patients in whom C. These antibi- not as effective as the -lactams, but its actions are similar otics also are toxic to mammalian cells. An increased prevalence of MRSA has resulted in a Antimicrobial Spectrum greater use of vancomycin for this disorder.

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While several studies have demonstrated hepatic protection against earlier studies did indicate lowered PSA levels cheap 20mg tadora visa, more re- alcohol effective tadora 20 mg, acetaminophen, and mushroom toxins and pro- cent research has not supported these findings. Indication Numerous (but not all) trials have indicated improve- Adverse Reactions, Contraindications, ment in BPH symptom scores compared to placebo and Interactions with 1 to 3 months of therapy. Saw palmetto extract ap- Milk thistle appears to be remarkably safe, with loose pears to be equally effective as finasteride (see Chapter stools due to increased bile solubility and occasional al- 63) but is less effective than 1-adrenoceptor antago- lergic reactions being the common side effects. Adverse Reactions, Contraindications, Dosage and Interactions Dry extract capsules standardized to 70% silymarin Headache and GI symptoms are the most frequently re- (calculated as silibinin) are administered at 200 to 400 ported side effects. Teas are not fects, such as nausea, abdominal discomfort, and diar- recommended, since silymarin is not water soluble. It is important to rule tion parameters in various hepatotoxic situations, such out prostate cancer in those taking saw palmetto for as alcoholic cirrhosis and mushroom poisoning. The effect of saw unclear whether it will offer protection against viral palmetto on prostatic cancer would likely be beneficial hepatitis and various nephrotoxic agents. Saw Palmetto Saw palmetto (Serenoa repens) is a dwarf American Dose palm native to the extreme southeastern United States. For BPH, 320 mg of the lipidosterolic extract by mouth A lipidosterolic extract of its berries contains fatty acids daily in two divided doses with food is usually recom- (especially lauric acid), phytosterols, monocylglycerides, mended. The dried berries and tea are 80% of the extract and are thought to be the most clin- not recommended, since the fatty acids responsible for ically effective component. The berries them- selves are less well absorbed than the extract and are Conclusion therefore believed to be less effective. Saw palmetto extract is a fairly well tolerated, safe al- Mechanism of Action ternative to finasteride for long-term treatment of BPH, although 1-adrenoceptor blocking agents undoubtedly Saw palmetto extract can inhibit the enzyme 5- -reductase afford more rapid symptom relief. Its name is 794 VII DRUGS AFFECTING THE ENDOCRINE SYSTEM derived from the Old English word for plant, wort, and ropathy has also been described, and it is possible that from the fact that it often starts blooming around June hypericin may also increase the risk of cataracts with 24, St. While a prior allergy to the herb is the tionally been used for wound healing, insomnia, main contraindication, St. Although this the numerous clinically significant herb–drug interac- herb is now commonly standardized for its hypericin tions that have been reported. This first came to light following acute heart transplant rejection in a per- Mechanism of Action son taking cyclosporin and St. The of digoxin, warfarin, theophylline, and oral contracep- hypaphorine constituent may possess serotonin reup- tives. Breakthrough bleeding has been observed in take inhibitor activity, and it also inhibits synaptic up- young women taking this herb, and patients starting take of amino butyric acid (GABA) and L-glutamate.

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They are often small for their sis of PMD order 20 mg tadora with visa, but if changes are seen on MRI generic 20 mg tadora otc, it does not age and have trouble gaining weight. Changes in the white floppy muscles called hypotonia, but later develop spas- matter may only be seen after one to two years of age ticity, which is stiffness or tightness in the muscles and when the brain has matured. If no one else in the family is known to be affected, Those patients who have classical PMD, which is testing may be performed to rule out conditions other less severe than the connatal type, usually have nystag- than PMD. Nystagmus develops within the first few months of when no one else is affected in the family. Other symptoms typically develop within the first uncommon for people to be misdiagnosed initially. These children also have hypotonia that turns Sometimes the diagnosis of PMD is made only after a into spasticity. Sometimes these patients will learn to second affected child is born into a family. Although these children often have The only way to be absolutely sure that someone has moderate mental retardation, they often learn to talk and PMD is by genetic testing, usually done by a blood test. First, the genetic material is evaluated to see if a PLP A less severe type of PMD is called the PLP null gene duplication is present. Those affected do not usually have nystagmus tional testing can be done to look for other mutations in 900 GALE ENCYCLOPEDIA OF GENETIC DISORDERS the gene. In 80% of people who have clear symptoms of PMD, a mutation can be found in the PLP gene. If a KEY TERMS mutation in the PLP gene has been identified in a family member, testing on another child suspected of having Central nervous system (CNS)—In humans, the PMD is possible to look at the mutation known to cause central nervous system is composed of the brain, PMD in the family. Treatment and management Leukodystrophy—A disease that affects the white There is no treatment or cure for PMD. For example they may suggest installing bars Proteolipid protein gene (PLP)—A gene that to use in the bathroom or shower or special utensils for makes a protein that is part of the myelin in the eating. There are also med- Spasticity—Increased muscle tone, or stiffness, ications that can assist in treating spasticity and which leads to uncontrolled, awkward move- seizures. Prenatal testing Testing during pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a specific PLP mutation. This can be done at 10–12 weeks gestation by a procedure called PLP null syndrome usually reach adulthood, and some chorionic villus sampling (CVS), which involves remov- have survived into their 70s. Some people may tation by removing a small amount of the amniotic fluid seem to get worse over time but it is likely to be due to surrounding the baby and analyzing the cells in the fluid. Couples interested in these options Most patients with PMD die from pulmonary or breath- should have genetic counseling to carefully explore all ing difficulties. Another procedure, called preimplantation diagno- Resources sis, allows a couple to have a child that is unaffected with PERIODICALS the genetic condition in their family. Boespflug-Tanguy, interested in learning more about this procedure should and the Clinical European Network on Brain check with their doctor or genetic counselor.

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