Timothy A. Sanborn, MD
- Head, Division of Cardiology
- Evanston Northwestern Healthcare
- Professor of Medicine, Northwestern
- Feinberg School of Medicine
- Evanston, Illinois
Enzyme induction is usually maximal after several days of continuing drug administration erectile dysfunction treatment houston order cialis 5 mg overnight delivery. Enzyme induction increases the clearance and reduces the half-life of drugs biotransformed by the enzyme erectile dysfunction injections australia buy cialis 2.5 mg fast delivery. Drug interactions may be caused by changes in the pharmaceutical impotence examination discount 5 mg cialis free shipping, pharmacodynamic latest news erectile dysfunction treatment purchase cialis 20mg with amex, or pharmacokinetic properties of the affected drug (Table 4 impotence over the counter generic cialis 10mg with amex. Pharmaceutical Interactions Pharmaceutical interactions are caused by a chemical reaction between drugs before their administration or absorption. Pharmaceutical interactions occur most frequently when drug solutions are combined before they are given intravenously. For example, if a penicillin solution and an aminoglycoside solution are mixed, they will form an insoluble precipitate, because penicillins are negatively charged and aminoglycosides are positively charged. Many other drugs are incompatible and should not be combined before they are administered. Pharmacodynamic Interactions Pharmacodynamic interactions occur when two drugs have additive, synergistic, or antagonistic effects on a tissue, organ system, microbe, or tumor cells. An additive effect is equal to the sum of the individual drug effects, whereas a synergistic effect is greater than the sum of the individual drug effects. Some pharmacodynamic interactions occur when two drugs act on the same receptor, and others occur when the drugs affect the same physiologic function through actions on different receptors. For example, epinephrine and histamine affect the same function but have antagonistic effects. Instead of giving cimetidine, substitute a histamine blocker that does not inhibit drug metabolism. Make sure the patient understands that disulfiram is used therapeutically to promote abstinence from alcohol (ethanol). Avoid concurrent therapy, if possible; otherwise, give a subnormal dose of the affected drug. Advise the patient that the combination of drugs is intended to increase the plasma concentration of the antibiotic. Estrogen is conjugated with glucuronate and sulfate in the liver, and the conjugates are excreted via the bile into the intestines. Intestinal bacteria hydrolyze the conjugates, and estrogen is reabsorbed into the circulation. The enterohepatic cycling is interrupted if concurrently administered antibiotics destroy the intestinal bacteria. Incomplete blood-brain barrier; higher volumes of distribution for water-soluble drugs. Excretion inducing drug is discontinued, the synthesis of P450 enzymes gradually returns to the pretreatment level. Significant interactions occur when these drugs reduce the clearance and increase the plasma concentration of other drugs. This inhibition increases plasma levels severalfold, sometimes leading to severe muscle inflammation and rhabdomyolysis. Age Factors affecting drug disposition in different age populations are summarized in Table 4. In neonates, and especially in premature infants, the capacity to metabolize and excrete drugs is often greatly reduced because of low levels of drug biotransformation enzymes. Oxidative reactions and glucuronate conjugation occur at a lower rate in neonates than in adults, whereas sulfate conjugation is well developed in neonates. Consequently, some drugs that are metabolized primarily by glucuronate conjugation in adults (drugs such as acetaminophen) are metabolized chiefly by sulfate conjugation in neonates. Nevertheless, the overall rate of biotransformation of most drugs is lower in neonates and infants than it is in adults. In comparison with children and young adults, elderly adults also tend to have a reduced capacity to metabolize drugs. Biotransformation via oxidative reactions usually declines more than biotransformation via drug conjugation. Therefore, it may be safer to use drugs that are conjugated when the choice is available. For example, benzodiazepines that are metabolized by conjugation, such as lorazepam and temazepam, are believed to be safer for treatment of the elderly than are benzodiazepines that undergo oxidative biotransformation. Renal function is lower in neonates and elderly adults than it is in young adults, and this affects the renal excretion of many drugs. For example, the half-lives of aminoglycoside antibiotics are greatly prolonged in neonates. Glomerular filtration declines 35% between the ages of 20 and 90 years with a corresponding reduction in the renal elimination of many drugs. Because the very young and the very old tend to have increased sensitivity to drugs, the dosage per kilogram of body weight should be reduced when most drugs are used in the treatment of these populations. Altered Drug Excretion Drugs can alter the renal or biliary excretion of other drugs by several mechanisms. Probenecid competes with other organic acids, such as penicillin, for the active transport system in renal tubules. Quinidine and verapamil decrease the biliary clearance of digoxin and thereby increase serum digoxin levels. Potentially nephrotoxic drugs, such as the aminoglycoside antibiotics, may impair the renal excretion of other drugs via their effect on renal function. Clinical Significance of Drug Interactions the clinical significance of drug interactions varies widely. In some cases, toxicity is severe and can be prevented only by avoiding the concurrent administration of drugs. In other cases, toxicity can be avoided by proper dosage adjustment and other measures (see Table 4. For example, when quinidine and digoxin are administered concurrently, a subnormal dose of digoxin should be used to prevent adverse effects. Drug interactions are more likely to occur if the affected drug has a low therapeutic index or is being used to treat a critically ill patient. However, polypharmacy, 44 Section I Principles of Pharmacology in Category B may have shown risk in animal studies but not in human studies. For drugs in Category C, adverse effects on the fetus have been demonstrated in animals, but there are insufficient data in pregnant women, so risk to the fetus cannot be ruled out. Drugs in Category D show positive evidence of risk to the fetus, and drugs in Category X are contraindicated during pregnancy. Drugs of choice for pregnant women are listed in clinical references and are selected on the basis of their safety to the fetus as well as their therapeutic efficacy. For example, penicillin, cephalosporin, and macrolide antibiotics (all Category B drugs) are preferred for treating many infections in pregnant women, whereas tetracycline antibiotics (Category D) should be avoided. Acetaminophen (Category B) is usually the analgesic of choice in pregnancy, but ibuprofen and related drugs are also in Category B and may be used when required. Other drugs considered relatively safe for use in pregnancy include insulin and metformin (Glucophage) for treating diabetes mellitus (both Category B drugs), famotidine (Pepcid) and omeprazole (Prilosec) for reducing gastric acidity (Category B drugs), diphenhydramine (Benadryl) for treating allergic reactions (Category B), and tricyclic antidepressants such as desipramine (Norpramin) for treating mood depression (Category B). Most antiepileptic drugs pose some risk to the fetus, and the selection of drugs for treating epilepsy in pregnant women requires careful consideration of the risks and benefits of such medication. Lactating women can take some drugs without posing a risk to their breast-fed infants. Other drugs place the infant Disease Hepatic and renal disease may reduce the capacity of the liver and kidneys to biotransform and excrete drugs, thereby reducing drug clearance and necessitating a dosage reduction to avoid toxicity. Heart failure and other conditions that reduce hepatic blood flow may also reduce drug biotransformation. Oxidative drug metabolism is usually impaired in patients with hepatic disease, whereas conjugation processes may be little affected. Guidelines for dosage adjustment in patients with hepatic or renal disease are available and can be found in clinical references. Dosage adjustments are made by reducing the dose, increasing the interval between doses, or both. Adjustments for individual patients are usually based on laboratory measurements of renal or hepatic function and on plasma drug concentration. Pregnancy and Lactation Drugs taken by a woman during pregnancy or lactation can cause adverse effects in the fetus or infant. The risk of drug-induced developmental abnormalities known as teratogenic effects is the greatest during the period of organogenesis from the 4th to the 10th week of gestation. After the 10th week, the major risk is to the development of the brain and spinal cord. Abnormal facial features; neural tube defects, such as spina bifida; reduced head size; and other anomalies. Fetal warfarin syndrome (characterized by chondrodysplasia punctata, malformation of ears and eyes, mental retardation, nasal hypoplasia, optic atrophy, skeletal deformities, and other anomalies). Effects in female offspring: clear cell vaginal or cervical adenocarcinoma; irregular menses; and reproductive abnormalities, including decreased rate of pregnancy and increased rate of preterm deliveries. Fetal alcohol syndrome (characterized by growth retardation, hyperactivity, mental retardation, microcephaly and facial abnormalities, poor coordination, and other anomalies). Fetal hydantoin syndrome (characterized by cardiac defects; malformation of ears, lips, palate, mouth, and nasal bridge; mental retardation; microcephaly; ptosis; strabismus; and other anomalies). Hydrocephaly; malformation of ears, face, heart, limbs, and liver; microcephaly; and other anomalies. Deafness, heart defects, limb abnormalities (amelia or phocomelia), renal abnormalities, and other anomalies. Cardiac defects, central nervous system defects, lumbosacral spina bifida, and microcephaly. Ethanol Phenytoin Retinoids (systemic) Tetracycline Thalidomide Valproate *Other substances known to be teratogenic include lead, lithium, methyl mercury, penicillamine, polychlorinated biphenyls, and trimethadione. Other drugs that should be avoided during the second and third trimester of pregnancy are angiotensin-converting enzyme inhibitors, chloramphenicol, indomethacin, prostaglandins, sulfonamides, and sulfonylureas. Other drugs that should be used with great caution during pregnancy include antithyroid drugs, aspirin, barbiturates, benzodiazepines, corticosteroids, heparin, opioids, and phenothiazines. Clinical references provide guidelines on the use of specific drugs by lactating women. These subheadings include Pregnancy, Lactation, and a new section entitled Females and Males of Reproductive Potential. This change was to better assist health care providers in benefit-risk decisions and in giving treatment options to pregnant women and nursing mothers who need to take medications. The very young and the very old tend to have an increased sensitivity to therapeutic agents, usually because of a reduced capacity to eliminate drugs. An advertisement in a local newspaper seeks to enroll 20 patients with arthritis in a medical study that would be the first time that a new drug would be tested in persons with this disease. Which one of the following schedules of controlled substances is for drugs with the highest abuse potential that have a legitimate medical use The 4th to the 10th week of gestation is the period of time when there is the greatest concern about drug-induced (A) fetal cardiac arrest. Which of the following drug interaction mechanisms is most likely to lead to sustained elevations of plasma drug concentrations and drug toxicity Elderly persons may have altered drug disposition because of (A) a markedly reduced absorption of many drugs. Amendments have established the prescription class of drugs, stricter requirements for human drug testing, incentives for developing orphan drugs for rare diseases, and abbreviated procedures for marketing generic drug products. Pharmacokinetic effects, particularly inhibition or induction of drug biotransformation, cause most interactions. These substances include pesticides; industrial, household, and agricultural chemicals; environmental pollutants; substances produced by poisonous plants, animals, and fungi; and any other harmful substance to which animals are exposed in toxic amounts, including pharmaceutical and recreational drugs. As with pharmaceutical drugs, the effects of toxic substances often exhibit a dose-response relationship (see Chapter 3) with the magnitude of toxicity increasing proportionally above a threshold dose or concentration to doses that cause maximal toxicity or death. Toxicology is also concerned with the bodily disposition and time-course of harmful substances and with the treatment and prevention of poisoning. This article will describe the basic principles of the treatment of poisoning and discuss some of the most important and commonly encountered household, occupational, and environmental poisons and pollutants. This article will not discuss the adverse reactions to medical or recreational drugs, which are described in other chapters of this book. For example, a person exposed to carbon monoxide from smoke inhalation during a fire should be evacuated to fresh air and given oxygen immediately. Other cardiopulmonary support can then be provided but may not be required if the patient is conscious and breathing. Orally ingested poisons can be removed from the gastrointestinal tract by inducing vomiting or by giving a laxative to evacuate the poison from the intestines. Activated charcoal can be given to adsorb certain poisons and prevent their absorption, followed by a laxative to induce elimination from the intestines. This section will present the basic toxicology of 2,4-dichlorphenoxyacetic acid (2,4-D), glyphosate, and the bipyridyl herbicides, diquat and paraquat. It is used to control broad-leafed weeds in lawns and fields without significantly harming grasses. Decontamination and supportive care is usually all that is required in these cases. Oral ingestion of 2,4-D may cause more serious toxicity, including gastrointestinal distress, hypotension, and neurotoxicity manifested as muscle weakness, ataxia, respiratory failure, and coma.
- Sideroblastic anemia, autosomal
- Pseudohermaphroditism male with gynecomastia
- Cyanide poisoning
- Xeroderma pigmentosum, type 1
- Congenital insensitivity to pain
- Alpha-L-iduronidase deficiency
It usually lowers the diastolic and mean arterial pressure gonorrhea causes erectile dysfunction purchase cialis with american express, but it can increase the systolic pressure by increasing the heart rate and contractility impotence means purchase 10mg cialis amex. Dobutamine selectively increases myocardial contractility and stroke volume while producing a smaller increase in heart rate erectile dysfunction juice cheap cialis express. Dobutamine also reduces vascular resistance by activating 2-adrenoceptors erectile dysfunction 55 years old purchase cialis visa, thereby reducing the impedance to ventricular ejection impotence with blood pressure medication buy cialis 10mg free shipping. In patients with heart failure, this effect contributes to an increased stroke volume and cardiac output (see Chapter 12). When given in low doses, dopamine selectively activates D1-receptors in renal and other vascular beds, thereby causing vasodilation and an increase in renal blood flow. At slightly higher doses, dopamine activates 1-adrenoceptors in the heart, thereby stimulating cardiac contractility and increasing cardiac output and tissue perfusion. At even higher doses, dopamine activates 1-adrenoceptors and causes vasoconstriction. Respiratory Tract Effects Epinephrine and isoproterenol are potent bronchodilators. Although they have been used in the treatment of asthma, more selective 2-adrenoceptor agonists are usually employed for this purpose today. Catecholamines can cause excessive vasoconstriction, leading to tissue ischemia and necrosis. Localized tissue ischemia can result from extravasation of an intravenous drug infusion or from the accidental injection of epinephrine into a finger, such as when a patient is self-injecting epinephrine to stop an acute allergic reaction. He developed edema of the face, lips, eyelids, tongue, and throat and experienced breathing difficulties. Paramedics administered epinephrine intramuscularly and transported thepatienttothehospital,wherehereceivedoxygenand intravenous dexamethasone (a corticosteroid). The child previously had an allergic reaction to a bee sting that did notrequirehospitalization. The administration of excessive doses of catecholamines can reduce blood flow to vital organs, such as the kidneys, or cause excessive cardiac stimulation that leads tachycardia and other cardiac dysrhythmias. The -adrenoceptor agonists can cause hyperglycemia secondary to glycogenolysis, and this is usually undesirable in patients with diabetes. Shock is a condition in which the circulation to vital organs is profoundly reduced as a result of inadequate blood volume (hypovolemic shock), inadequate cardiac function (cardiogenic shock), or inadequate vasomotor tone (neurogenic shock and septic shock). Septic shock is associated with massive vasodilation secondary to the production of toxins by pathogenic microorganisms. Some cases of septic shock, however, may also cause hypoperfusion and cold extremities. Anaphylactic shock, resulting from severe immediate hypersensitivity reactions, is usually manifested by hypotension and difficult breathing caused by bronchoconstriction. These drugs are used in treating shock when organ function is impaired because mean arterial blood pressure is less than 60 mm Hg. Hypovolemia should always be corrected by intravenous fluid administration before the use of vasopressors, because vasopressors will not be effective if hypovolemia is present. Such devices are often used in conjunction with vasopressor drugs in the treatment of this condition. Dopamine is used to treat septic or cardiogenic shock when patients remain hypotensive despite adequate fluid administration. Dopamine is usually started at a dose of 2 mg/ kg body weight per minute, and then the dose is titrated to achieve the desired blood pressure. Although low doses of dopamine can increase urine output by augmenting renal blood flow in normal subjects, ample evidence indicates that low doses of dopamine are usually not effective in preventing and treating acute renal failure. The most effective means of protecting the kidneys in patients with shock appears to be the maintenance of mean arterial pressure of greater than 60 mm Hg with intravenous fluids and adequate doses of a vasopressor agent. Norepinephrine, which is a potent vasoconstrictor, is used to treat septic shock and is often given to persons with cardiogenic shock when the response to dopamine is inadequate or is accompanied by marked tachycardia. Norepinephrine is also used to treat hypotension caused by decreased peripheral resistance such as can occur in persons who have received excessive doses of a vasodilator drug. By producing bronchodilation and increasing blood pressure, epinephrine counteracts the effects of histamine and other mediators that are released from mast cells and basophils during immediate hypersensitivity reactions. Epinephrine is used as a vasoconstrictor to reduce bleeding during surgery and to prolong the action of local anesthetics by retarding their absorption into the general circulation. Epinephrine is also used as a cardiac stimulant in the treatment of cardiac arrest and ventricular fibrillation. Isoproterenol is used to treat refractory bradycardia and atrioventricular block when other measures have not been successful. Although it has been used to treat asthma, a selective 2-adrenoceptor agonist is usually preferred for this indication because it does not increase the heart rate as much as isoproterenol. Dobutamine is a cardiac stimulant (inotropic agent) that also produces vasodilation. It is used as a cardiac stimulant during heart surgery and in the short-term management of acute heart failure and cardiogenic shock. Dobutamine is not routinely used in treating septic shock, however, because its vasodilator effect can further reduce vascular resistance and blood pressure. Its utility in hypotensive patients is limited to situations in which hypotension is caused by bradycardia. For this reason, noncatecholamines are effective after oral administration and have a longer duration of action than do catecholamines. Phenylephrine is adequately absorbed after oral or topical administration and can also be administered parenterally. This produces vasoconstriction and increases vascular resistance and blood pressure. Ocular administration of phenylephrine leads to contraction of the iris dilator muscle and dilation of the pupil (mydriasis). Phenylephrine is used as a nasal decongestant in patients with viral rhinitis, an infection that can be caused by more than a hundred serotypes of rhinovirus, as well as other viruses, and is referred to as the "common cold. In patients with allergic conjunctivitis, an inflammation of the eyes associated with hay fever or other allergies, phenylephrine can be used as a topical ocular decongestant. The ocular preparation of phenylephrine is also used to induce mydriasis and thereby facilitate ophthalmoscopic examination of the retina. Phenylephrine can be administered intravenously to treat forms of hypotension and shock caused by decreased peripheral vascular resistance. These include hypotension caused by excessive doses of vasodilator drugs, drug-induced shock, septic shock, and neurogenic shock such as resulting from spinal cord injury. Midodrine Midodrine forms an active metabolite that selectively activates 1-adrenoceptors in the arteriolar and venous circulation, leading to increased systolic and diastolic blood pressure in the standing, sitting, and supine positions. The drug is rapidly absorbed after oral administration and is used to treat postural (orthostatic) hypotension in persons who are considerably impaired by this condition. It is also used to treat hypotension caused by infections in infants or induced by psychotropic agents, and hypotension in persons undergoing renal dialysis. Albuterol, Salmeterol, Terbutaline, and Related Drugs Chemistry and Pharmacokinetics. Albuterol, salmeterol, and terbutaline are examples of selective 2-adrenoceptor agonists that can be given by inhalation. Albuterol and terbutaline can also be given orally, and terbutaline is available for injection. The oral bioavailability of these drugs is 30% to 50% because of their incomplete absorption and first-pass metabolism. They are partly metabolized to inactive compounds before undergoing renal excretion. These drugs are often administered by inhalation in the treatment of respiratory diseases. Their duration of action is about 4 to 6 hours after inhalation or oral administration. These drugs produce bronchodilation and are beneficial in the treatment of asthma and chronic obstructive lung diseases. Terbutaline is also used off label in the short-term management of preterm (premature) labor, which is defined as labor that begins before the 37th week of gestation. The drug relaxes the uterus and maintains pregnancy for 24 to 48 hours in the majority of cases, which is called tocolysis. Although the tocolytic effect is of limited duration and value, the treatment may delay delivery long enough to enable corticosteroids to be given to prevent neonatal respiratory distress syndrome. The adverse effects of albuterol and other selective 2adrenoceptor agonists include tachycardia, muscle tremor, and nervousness caused by activation of 2-adrenoceptors in the heart, skeletal muscle, and central nervous system. Some imidazolines are administered by topical ocular or nasal administration, whereas others are administered by systemic routes. After systemic administration, these drugs are partly metabolized and then excreted in the urine, and have a duration of action lasting several hours. The first group consists of oxymetazoline and similar drugs that selectively activate 1-adrenoceptors and cause vasoconstriction. Oxymetazoline is available as a nasal spray and ophthalmic solution without prescription. Because it may increase blood pressure, it should not be used by persons with hypertension or heart disease without consulting a health care provider. Topical nasal decongestants should never be used for more than 3 to 5 days to avoid rebound congestion that results from excessive vasoconstriction and tissue ischemia. Oxymetazoline and similar decongestants can also cause central nervous system and cardiovascular depression if they are absorbed into the systemic circulation and distributed to the brain. For this reason, these drugs should be used with caution in children under 6 years of age and in the elderly. Both epinephrine and oxymetazoline are used as vasoconstrictors in local anesthetic formulations. The coadministration of a vasoconstrictor with a local anesthetic limits the systemic absorption of the local anesthetic. This increases the duration of action and decreases adverse effects (see Chapter 21). After topical ocular administration, these agents activate ocular 2-adrenoceptors in the ciliary body and thereby reduce aqueous humor secretion (see Box 6. Apraclonidine and brimonidine are both used to prevent short-term elevations of intraocular pressure after cataract surgery and other types of ocular surgery. The utility of these drugs as single agents in treating chronic open-angle glaucoma is limited by the development of tolerance within several months of starting therapy. However, a fixed combination of brimonidine and the carbonic anhydrase inhibitor brinzolamide (see Chapter 13) has been found to be an effective treatment for open-angle glaucoma and ocular hypertension, and may be particularly useful in patients unable to tolerate -adrenoceptor antagonists such as timolol. The third group of imidazoline agents consists of clonidine and dexmedetomidine, which selectively activate 2adrenoceptors in the central nervous system. In fact, clonidine has a 200-fold greater affinity for 2- than for 1-adrenoceptors. Activation of 2-adrenoceptors leads to a reduction in sympathetic outflow from the vasomotor center in the medulla, and clonidine is used to treat hypertension (see Chapter 10). The activation of 2-adrenoceptors in the central nervous system is also responsible for the sedative and analgesic effects of clonidine and dexmedetomidine. Clonidine has been used to for sedation during pediatric procedures and to reduce anxiety and anesthetic requirements in pediatric surgery. Dexmedetomidine is indicated for sedation of intubated and mechanically ventilated patients during treatment in an intensive care setting. It has also been used as an adjunct to anesthesia during surgical procedures because of its ability to facilitate sedation and analgesia and to prevent delirium during emergence from anesthesia. Dexmedetomidine has the advantage of not causing respiratory depression in these settings. Droxidopa Droxidopa is a recently approved drug for treatment of orthotension with a nonreceptor medicated mechanism of action. Droxidopa is a precursor to norepinephrine in its biosynthetic pathway and effectively increases the amount of norepinephrine produced and released. Norepinephrine then acts as per usual on 1-receptors in the blood vessels to constrict vascular smooth muscle and raise blood pressure. Indirect-Acting Adrenoceptor Agonists Amphetamine and Tyramine Amphetamine and related compounds have high lipid solubility and increase synaptic concentrations of norepinephrine in the central and peripheral nervous systems by mechanisms previously described, causing vasoconstriction, cardiac stimulation, increased blood pressure, and central nervous system stimulation. The central nervous system effects are discussed in greater detail in Chapters 22 and 25. Tyramine is a naturally occurring amine found in a number of foods, including bananas. Cocaine Cocaine, a naturally occurring alkaloid, acts as a local anesthetic and also stimulates the sympathetic nervous system by blocking the neuronal reuptake of norepinephrine at both peripheral and central synapses. Cocaine produces both vasoconstriction and cardiac stimulation and elevates blood pressure. The vasoconstrictive effect can cause ischemia and necrosis of the nasal mucosa in people who abuse cocaine. The sympathomimetic effects of cocaine also appear to be responsible for the severe hypertension and cardiac damage that may occur in people who abuse cocaine. The local anesthetic and central nervous system effects of cocaine are discussed further in Chapter 21. Cocaine also blocks the reuptake of dopamine, leading to its rewarding effects and drug abuse, as discussed in Chapter 25. Mixed-Acting Adrenoceptor Agonists A few drugs activate adrenoceptors by both direct and indirect mechanisms, including dopamine (see earlier), ephedrine, and pseudoephedrine. These agents indirectly increase synaptic concentrations of norepinephrine in a manner similar to that of amphetamine. Mirabegron Preclinical studies using cell lines transfected with human adrenoceptors showed that mirabegron is a selective agonist of the 3-adrenoceptor.
Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective erectile dysfunction doctors san antonio cheap 20mg cialis amex, randomised trial in paediatric renal transplantation erectile dysfunction doctors in brooklyn cheap cialis 10mg with amex. Steroid avoidance or withdrawal regimens in paediatric kidney transplantation: a meta-analysis of randomised controlled trials impotence organic cialis 5mg mastercard. Corticosteroid use and growth after pediatric solid organ transplantation: a systematic review and meta-analysis erectile dysfunction pills otc discount 5mg cialis free shipping. Safety and efficacy of a calcineurin inhibitor avoidance regimen in pediatric renal transplantation erectile dysfunction drugs nz discount cialis 5mg otc. Five-year experience using sirolimus-based, calcineurin inhibitor-free immunosuppression in pediatric renal transplantation. Conversion to sirolimus in pediatric renal transplant patients: a single-center experience. Cytomegalovirus infection in pediatric renal transplantation and the impact of chemoprophylaxis with (Val-) ganciclovir. Insights in transplanting complex pediatric renal recipients with vascular anomalies. Intraoperative management and early postoperative outcomes of pediatric renal transplants. Surgical site and early urinary tract infections in 1000 kidney transplants with antimicrobial perioperative prophylaxis. Impact of everolimus and low-dose cyclosporin on cytomegalovirus replication and disease in pediatric renal transplantation. Incidence and risk factors of early surgical complications in young renal transplant recipients: a persistent challenge. Association between slow and delayed graft function with graft outcomes in pediatric and adolescent deceased donor kidney transplant recipients. A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors. Assessing the value of ureteral stent placement in pediatric kidney transplant recipients. Immune desensitization allows pediatric blood group incompatible kidney transplantation. Late acute rejection: incidence, risk factors, and effect on graft survival and function. Decreased chronic cellular and antibody-mediated injury in the kidney following simultaneous liver-kidney transplantation. Induction therapy, rejection, and graft outcomes in pediatric and adolescent kidney transplant recipients. Lymphocyte-depleting induction therapy lowers the risk of acute rejection in African American pediatric kidney transplant recipients. Three-yr safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. Effect of immunosuppressive therapy on cardiovascular risk factor prevalence in kidney-transplanted children: comparative study. Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Protocol biopsies in pediatric renal transplant recipients on cyclosporine versus tacrolimus-based immunosuppression. Outcomes of two-drug maintenance immunosuppression for pediatric renal transplantation: 10-yr follow-up in a single center. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Five-year outcome in pediatric patients with mycophenolate mofetil-based renal transplantation. Mycophenolate mofetil-induced reversal of glomerular filtration loss in children with chronic allograft nephropathy. Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Improved gastrointestinal symptom burden after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in kidney transplanted children. Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients. Minimum mycophenolic acid levels are associated with donor-specific antibody formation. Severe neutropenia in children after renal transplantation: incidence, course, and treatment with granulocyte colony-stimulating factor. Pediatric kidney recipients may benefit from monitoring for donor-specific antibodies. The treatment of acute antibody-mediated rejection in kidney transplant recipients-a systematic review. The treatment of antibody-mediated rejection in kidney transplantation: an updated systematic review and metaanalysis. Acute and chronic antibody-mediated rejection in pediatric kidney transplantation. Eculizumab to treat antibody-mediated rejection in a 7-year-old kidney transplant recipient. Infection-related hospitalizations over 30 years of follow-up in patients starting renal replacement therapy at pediatric age. Infection-related hospitalization rates in pediatric versus adult patients with end-stage renal disease in the United States. Children after renal transplantation hospitalized for fever: is empirical antibiotic treatment always justified Increased urologic complications in children after kidney transplants for obstructive and reflux uropathy. Risk factors for urinary tract infection after renal transplantation and its impact on graft function in children and young adults. Outcome of treated and untreated asymptomatic bacteriuria in renal transplant recipients. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Cytomegalovirus serology and replication remain associated with solid organ graft rejection and graft loss in the era of prophylactic treatment. Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients. Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: Long-term results after 7 years of a randomized clinical trial. Tolerability of up to 200 days of prophylaxis with valganciclovir oral solution and/or film-coated tablets in pediatric kidney transplant recipients at risk of cytomegalovirus disease. Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Adolescents are more likely to develop posttransplant lymphoproliferative disorder after primary Epstein-Barr virus infection than younger renal transplant recipients. Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. The efficacy of valganciclovir for prevention of infections with cytomegalovirus and Epstein-Barr virus after kidney transplant in children. Epidemiology and outcome of chronic high Epstein-Barr viral load carriage in pediatric kidney transplant recipients. Conversion from tacrolimus/mycophenolic acid to tacrolimus/leflunomide to treat cutaneous warts in a series of four pediatric renal allograft recipients. Intravenous pentamidine for Pneumocystis carinii/ jiroveci pneumonia prophylaxis in pediatric transplant patients. Steroid-free immunosuppression since 1999: 129 pediatric renal transplants with sustained graft and patient benefits. Lipoprotein profile changes in children after renal transplantation in the modern immunosuppression era. Metabolic syndrome in children with chronic kidney disease and after renal transplantation. Increasing incidence of new-onset diabetes after transplant among pediatric renal transplant patients. New-onset diabetes after transplantation: results from a double-blind early corticosteroid withdrawal trial. Hypomagnesemia and increased risk of new-onset diabetes mellitus after transplantation in pediatric renal transplant recipients. Post-transplant malignancy after pediatric kidney transplantation: retrospective analysis of incidence and risk factors in 884 patients receiving transplants between 1963 and 2015 at the University of Minnesota. Post-transplantation lymphoproliferative disorder in pediatric kidney-transplant recipients - a national study. Donor or recipient origin of posttransplant lymphoproliferative disorders following solid organ transplantation. Skin cancer risk education in pediatric solid organ transplant patients: an evaluation of knowledge, behavior, and perceptions over time. Prevalence and predictors of blood transfusion after pediatric kidney transplantation. Anemia and markers of erythropoiesis in pediatric kidney transplant recipients compared to children with chronic renal failure. Chronic norovirus infection among solid organ recipients in a tertiary care hospital, the Netherlands, 2006-2014. Predictors of persistent diarrhea in norovirus enteritis after solid organ transplantation. Recurrent glomerulonephritis after kidney transplantation: risk factors and allograft outcomes. Success with plasmapheresis treatment for recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients. Membranoproliferative glomerulonephritis recurrence after kidney transplantation: using the new classification. Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Pediatric kidney transplantation in the developing world: challenges and solutions. Epidemiology and management of hypertension in paediatric and young adult kidney transplant recipients in the Netherlands. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Longitudinal relations between obesity and hypertension following pediatric renal transplantation. Improved long-term outcomes after renal transplantation associated with blood pressure control. Ambulatory blood pressure, left ventricular hypertrophy, and allograft function in children and young adults after kidney transplantation. Changes of blood pressure and left ventricular mass in pediatric renal transplantation. Risk factors for cardiovascular disease in children and young adults after renal transplantation. High prevalence of the metabolic syndrome and associated left ventricular hypertrophy in pediatric renal transplant recipients. Evaluation of arterial structure and function in pediatric patients with end-stage renal disease on dialysis and after renal transplantation. Subclinical atherosclerosis and related risk factors in renal transplant recipients. Lifestyle intervention to improve quality of life and prevent weight gain after renal transplantation: design of the 391. How many times can parvovirus B19-related anemia recur in solid organ transplant recipients Mineral metabolism in European children living with a renal transplant: a European society for paediatric nephrology/european renal association-European dialysis and transplant association registry study. Vitamin D deficiency and parathyroid hormone levels following renal transplantation in children. Prophylactic ureteric stents in renal transplant recipients: a multicenter randomized controlled trial of early versus late removal. Urological complications and vesicoureteral reflux following pediatric kidney transplantation. Urological complications following kidney transplantation in pediatric age: a single-center experience. Endoscopic treatment of symptomatic refluxing renal transplant ureteroneocystostomies in children. Endoscopic antireflux surgery leading to obstruction in pediatric renal transplant patients. Surgical correction of vesico-ureteric reflux for recurrent febrile urinary tract infections after kidney transplantation.
None of the above Answer: e Rationale: Overall effexor xr impotence order cialis, complications from renal biopsies range from 1% to 6% (see Table 68 erectile dysfunction diabetes purchase 2.5mg cialis mastercard. The most common complications reported are retroperitoneal hematoma and gross hematuria erectile dysfunction world statistics buy cheap cialis 2.5 mg online. All the above Answer: h Rationale: All the above have been published techniques for peritoneal dialysis catheter placement erectile dysfunction medicine name in india buy cialis 10mg without prescription. Finally impotence 10 buy 10mg cialis mastercard, we will provide a mechanistic overview of acute kidney graft rejection and immunosuppressive drugs. The clinical aspects of acute kidney graft rejection are covered in greater depth in Chapter 70. Antigen presentation is an integral component of the normal immune response that helps protect against infectious agents and maladapted cells, such as cancer cells. Large numbers of alloreactive T cells are present in all individuals, including transplant recipients, since thymic maturation of T cells deletes only autoreactive T cells without affecting alloreactive T cells. Proteins that are damaged or dysfunctional are targeted for degradation by the addition of ubiquitin tags in a process called ubiquitination. Polyubiquitinated proteins are recognized by the 19S complex, allowing them to move toward the proteolytic core for degradation. This process is responsible for degradation of 75% to 95% of intracellular proteins. The indirect pathway is thought to be activated in the long term after transplantation and may play an important role in promoting alloantibody production and chronic antibody-mediated allograft rejection. However, under certain inflammatory conditions, such as chronically rejecting allografts, structures reminiscent of lymphoid organs can form within allografts. These structures, called tertiary lymphoid organs, allow antigen presentation within the allograft, thus favoring the production of allo- and autoantibodies19,21 that are important in rejection. However, a second signaling pathway, Signal 2, needs to be triggered for T-cell activation and acquisition of effector function. Since the initial description of co-signaling pathways in the late 1980s, more than 25 different types of cosignaling pathways have been characterized. Three subtypes are involved in immunogenic responses and rejection: Th1, Th17, and Tfh. Interferon- produced by Th1 cells also induces the production of complementactivating antibodies by B cells, therefore recruiting an additional mechanism of allograft rejection. Th17 cells have been implicated in many autoimmune diseases in addition to transplant rejection. Their suppressive activity can inhibit a number of immunogenic reactions, including allograft rejection. Key surface molecules in activation of A, T effector cells and B, T regulatory cells (Tregs). T cells: soldiers and spies-the surveillance and control of effector T cells by regulatory T cells. Hence the importance of antibodies and B cells as mediators of rejection was forgotten or dismissed until the turn of the 21st century, when standardization of C4d staining for kidney allograft biopsies-a readout of complement activation by immune complexes- reactivated the field of antibody-dependent rejection. B cells exert a number of important immunologic functions; the most studied is the production of antibodies that can bind protein, peptide, and carbohydrate antigens (as opposed to T cells that react exclusively to antigenic peptides). B cells also express different surface markers depending on their state of maturation and differentiation. Most peripheral B cells are produced in the bone marrow and referred to as B2 cells. A minor B-cell population, known as B1 cells, are found not only in the pleural and peritoneal cavities but also in small numbers in the spleen. It is currently unclear whether B1 cells arise from a unique progenitor or from a progenitor common to both B1 and B2 cells. B2 cells are formed in the bone marrow and develop from pro-B cells, to pre-B cells, to immature B cells, which are released into the periphery. Following antigen encounter, B cells obtain T-cell help and enter the germinal center. Here they undergo class switch recombination and affinity maturation, a process involving iterative cycles of somatic hypermutation and proliferation. Dark-blue bars represent high expression, light-blue bars intermediate expression. These cells are likely to arise from multiple B-cell subsets (B1, transitional and marginal zone). They differentiate into either plasmablasts, memory B cells, or long-lived plasma cells following antigenic interaction and maturation within lymph nodes. These B cells then move to the border between the follicle and the T-cell zone, where they present antigen to a cognate. This first phase of activation can result in the differentiation of B cells into short-lived plasmablasts that produce low-affinity IgM antibodies, or the formation of a germinal center that will allow B-cell differentiation into either memory B cells or long-lived plasma cells that are responsible for the production of high-affinity antibodies. Antibodies are heterodimeric protein structures composed of a light chain and a heavy chain. There are five different human Ig isotypes (IgM, IgG, IgA, IgE, and IgD), which differ in the structure of the constant region. The antigen-binding site is composed of the variable regions of the heavy and light chains. Both chains contain a constant region and a variable region that undergoes recombination and somatic hypermutation. B1 cells reside within pleural and peritoneal cavities (and in smaller numbers in the spleen). B2 cells are formed in the bone marrow and develop from pro-B cells, to pre-B cells, through to immature B cells, which are released into the periphery. Following this interaction, the fate of the B cell lies between two pathways: 1) To become a short-lived extrafollicular plasmablast or 2) to enter the germinal center, undergo rounds of somatic hypermutation and selection to generate class-switched memory B cells or plasma cells. Mounting evidence suggests that B-cell activation, maturation, and antibody production can also occur within tertiary lymphoid structures developing within allografts. These structures are found in association with chronic inflammatory conditions, including autoimmune disorders, infection, cancer, and transplantation. They have been reported in animal models of rejection and in chronically rejected human renal and cardiac allografts. However, if the production of long-lived plasmablasts or memory B cells is established prior to transplantation because of allosensitizing events, such as pregnancy or prior transplantation, the need for T-cell help is bypassed. Autoantibodies have also been associated with either increased risk of acute rejection or reduced long-term allograft survival,42 as will be discussed in detail later in this chapter. The role of T-cell help in the production of these autoantibodies remains unclear. The classical pathway is activated when C1q binds to IgG or IgM antibodies present within immune complexes. The general order of complement fixing activity for antibodies is IgM>IgG3>IgG1>IgG2IgG4. IgE antibodies are noncomplement fixing, whereas IgA can activate the alternative, but not classical pathway. The binding of C1q to complementfixing antibodies leads to interactions with the serine proteases C1r and C1s, allowing for the cleavage of C4 and C2, and the formation of the multiprotein complex and C3 convertase, C4b2a. C4d staining, as used in the diagnosis of antibody-mediated rejection, is a read-out of C4 cleavage, and is considered a good marker of classical pathway activation. Like the classical pathway, the lectin pathway leads to the formation of the C4b2a C3 convertase and is therefore an additional source of positive C4d staining. The lectin pathway is thought to play an important role in ischemia-reperfusion injury. Increased activation of the alternative pathway occurs in the presence of various factors associated with tissue injury, including microparticles, platelet surfaces, and endotoxins. C3 convertases (either C4b2a or C3bBb) cleave C3 into C3a, which has proinflammatory and chemotactic functions, and C3b, which in turn cleaves C5. This leads to the formation of C5a, another potent chemotactic and proinflammatory mediator, and C5b. The latter interacts with distal complement components C6 to C9, leading to the formation of a lytic complex, C5b-9, that subsequently creates a pore in the plasma membrane of the target cell. Factor H accelerates degradation of key components of the alternative pathway and serves as a cofactor for factor I. C1 esterase inhibitor and C4b binding protein interfere with the activation of the classical pathway. The complement system is activated by one of three major pathways: classical, lectin, or alternative. The alternative pathway is initiated by direct binding of C3b to activating surfaces. All three pathways converge at the production of the central complement component C3. That is, all pathways form enzyme complexes (classical or alternative convertases) that cleave either C3 (into C3a and C3b) or C5 (into C5a and C5b). C5b triggers the terminal pathway by creating a pore in the target cell membrane via the formation of the membrane attack complex (C5b-C9). Soluble complement effectors C3a and C5a are detected by specific cell receptors thereby promoting inflammation. Complement inhibition occurs via a variety of molecules ultimately inhibiting C3 and C5 convertase or blocking the formation of the membrane attack complex (C5b-C9). Collectively, these changes are thought to favor neointimal thickening and mononuclear leukocyte infiltration. In a cohort of stable pediatric kidney transplant recipients, an enrichment in autoantibodies directed at antigenic targets from the renal pelvis and medulla, areas that are particularly sensitive to ischemia, was observed when pre- and posttransplant sera were compared. Indeed, since the first clinical histocompatibility testing was defined in 1969,100 the laboratory has grown to play a critical role in transplant decision making and allocation science. We will describe how these platforms can support humoral immunologic risk assessment that can be translated into clinical action with the goals of increasing transplant access, and reducing allograft damage related to immunologic incompatibility, optimizing both equity and utility. Indeed, any degree of mismatch between a donor and a recipient can stimulate an alloimmune response in the absence of enough immunosuppression, leading to subclinical and clinical rejection. As such, the immunogenicity of the class I molecule is defined by the polymorphism in this single chain. It warrants mention that the sequencing methods are not suitable for deceased donor typing, as they can take several days to complete; these are more commonly employed for recipient typing and living donor typing when used. The lymphocytes of the individual to be typed were then mixed with all serum samples in the panel in the presence of complement and a vital dye. Field 2 (in this example 01) identifies a precise allele, with at least 1 amino acid difference in the mature protein that distinguishes it from all other alleles in the allele group. Additionally, a suffix may be appended to the allele name (in this example N) indicating a variant of expression of the final protein product, where N represents Null or No expression; L indicates Low expression; S indicates a molecule that is Secreted and Soluble but not present on cell surfaces; C is assigned to alleles producing products only detected in the Cytoplasm; A indicates Aberrant expression, where the expression is not confirmed; and Q is assigned to Questionable, where the impact of the mutation on expression is not confirmed but has been seen in other alleles. For practical purposes in solid organ transplantation, only the first two fields have clinical impact in so far as they determine the protein to be considered in mismatching and antibody production. Additionally, the N or L suffix is important in transplantation, as where a protein has null or low expression it may not have any (null) or reduced (low) relevance in immunogenicity or antibody specificity considerations. Indeed, most commonly at the present time molecular typing in kidney transplantation is reported at only the first field level unless the specific allele is needed to quantify differences between a donor and recipient or to interpret a specific antibody pattern as donor specific or not. In the case where either a recipient or donor is homozygous for one or more antigens, there is a difference in mismatches depending on which direction the mismatches are considered. Consultation with histocompatibility specialists should be sought to determine the level of resolution needed in any given case. At present, the major limitation to some methods that result in a high level of resolution is that several days may be required to obtain a result, which is prohibitive in deceased donor transplantation workup and allocation; this, however, is anticipated to change with the rapid improvement of methods and platforms. Rather, when interpreting molecular results, the clinician should be sure to note whether allele level typing (second field resolution) is in fact necessary to interpret immunologic risk, either at the eplet mismatch level or antibody-antigen interaction level. Consultation with Histocompatibility specialists should be sought out to determine the level of resolution needed in any given case. We note that antibodies can form to self-eplets,126 but only when the surrounding epitope is non-self. There is much interest in determining which eplet differences carry the greatest risk of adverse outcome, but such data are currently not yet available. There is insufficient evidence available at this time to allocate organs strictly based on eplet load or eplet matching. It is important to acknowledge that if the mismatches in a given pair are greater, then the immunologic potential for alloimmune recognition and response is also greater. The clinician should use this information to refine the risk assessment along a continuum. It is essential that these data sets be large and as complete at all loci as possible so that the calculation Table 69. Further, this allows estimating access to transplantation because of antibody profile. Patently clear, however, is that both sensitive and specific antibody detection as well as identification methods are critical in guiding both the interventions and treatments for better outcomes, at all times during the transplant patient lifecycle. A bead is determined to be positive when its fluorescence is above the threshold level validated by the laboratory and manufacturer. Also analyzed on flow cytometric platforms, up to 100 unique beads per class can be tested simultaneously. The percentage of the cells in the panel which are lysed is an estimate of the percentage of donors from that population against whom the recipient has cytotoxic antibodies (IgG1 or IgG3 of sufficiently high titer to initiate the complement cascade).
Buy cialis on line amex. Chantix Commercial - SNL.
- Singh BM, Strobos RJ. Epilepsia partialis continua associated with nonketotic hyperglycemia: clinical and biochemical profile of 21 patients. Ann Neurol. 1980;8(2):155-160.
- Roth A, Elkayam U. Acute myocardial infarction associated with pregnancy. J Am Coll Cardiol. 2008;52(3):171-80.
- Broderick J, Connolly S, Feldmann E, et al: Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group, Stroke 38:2001-2023, 2007.
- Al-Mubarak N, Roubin GS, Vitek JJ, et al: Microembolization during carotid stenting with the distal-balloon antiemboli system, Int Angiol 21:344-348, 2002.
- Boeckh M. Current antiviral strategies for controlling cytomegalovirus in hematopoietic stem cell transplant recipients: prevention and therapy. Transpl Infect Dis. 1999;1:165-178.
- Hashitani H, Bramich NJ, Hirst GD: Mechanisms of excitatory neuromuscular transmission in the guinea-pig urinary bladder, J Physiol 524(Pt 2):565n579, 2000.
- Grande PO, Asgeirsson B, Nordstrom CH. Physiologic principles for volume regulation of a tissue enclosed in a rigid shell with application to the injured brain. J Trauma Acute Care Surg. 1997;42(5S):23S-31S. 92.