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By I. Akascha. Grace College.

In adult females discount plendil line, too much vitamin A can increase the risk for hip fracture—apparently by blocking the ability of vitamin D to enhance calcium absorption purchase plendil cheap online. Therapeutic Uses The only indication for vitamin A is prevention or correction of vitamin A deficiency buy generic plendil 10mg on line. Contrary to earlier hopes, it is now clear that vitamin A, in the form of beta-carotene supplements, does not decrease the risk for cancer or cardiovascular disease. In fact, in a study comparing placebo with dietary supplements (beta-carotene plus vitamin A), subjects taking the supplements had a significantly increased risk for lung cancer and overall mortality. Vitamin D Vitamin D plays a critical role in calcium metabolism and maintenance of bone health. The classic effects of deficiency are rickets (in children) and osteomalacia (in adults). Studies suggest that vitamin D may protect against arthritis, diabetes, heart disease, autoimmune disorders, and cancers of the colon, breast, and prostate. However, in a 2011 report—Dietary Reference Intakes for Calcium and Vitamin D—an expert panel concluded that, although such claims might eventually prove true, the current evidence does not prove any benefits beyond bone health. Vitamin E (Alpha-Tocopherol) Vitamin E (alpha-tocopherol) is essential to the health of many animal species but has no clearly established role in human nutrition. Observational studies of the past suggested that vitamin E protected against cardiovascular disease, Alzheimer disease, and cancer. Moreover, there is evidence that high-dose vitamin E may actually increase the risk for heart failure, cancer progression, and all-cause mortality. However, only four stereoisomers are found in our blood, all of them variants of alpha-tocopherol. The vitamin is also found in nuts, wheat germ, whole-grain products, and mustard greens. Accordingly, this limit should be exceeded only when there is a need to manage a specific disorder (e. Symptoms of deficiency include ataxia, sensory neuropathy, areflexia, and muscle hypertrophy. Potential Benefits Vitamin E has a role in protecting red blood cells from hemolysis. The higher dose associated with halting macular degeneration carries substantial risk, as detailed in the discussion that follows. Potential Risks High-dose vitamin E appears to increase the risk for hemorrhagic stroke by inhibiting platelet aggregation. These results are consistent with the theory that high doses of antioxidants may cause cancer or accelerate cancer progression. Studies have also linked high-dose vitamin E therapy with an increased risk for death, especially in older people. Finally, high-dose vitamin E (in combination with vitamin C) can blunt the beneficial effects of exercise on insulin sensitivity. Forms and Sources of Vitamin K Vitamin K occurs in nature in two forms: (1) vitamin K, or phytonadione1 (phylloquinone), and (2) vitamin K. Two other forms2 —vitamin K 4 (menadiol) and vitamin K 3 (menadione)—are produced synthetically. At this time, phytonadione is the only form of vitamin K available for therapeutic use. For most individuals, vitamin K requirements are readily met through dietary sources and through vitamin K synthesized by intestinal bacteria. Because bacterial colonization of the gut is not complete until several days after birth, levels of vitamin K may be low in newborns. Pharmacokinetics Intestinal absorption of the natural forms of vitamin K (phytonadione and vitamin K ) is adequate only in the presence of bile salts. Because the natural forms of vitamin K require bile salts for their uptake, any condition that decreases availability of these salts (e. Malabsorption syndromes (sprue, celiac disease, cystic fibrosis of the pancreas) can also decrease vitamin K uptake. Other potential causes of impaired absorption are ulcerative colitis, regional enteritis, and surgical resection of the intestine. Disruption of intestinal flora may result in deficiency by eliminating vitamin K–synthesizing bacteria. In infants, diarrhea may cause bacterial losses sufficient to result in deficiency. Consequently, to rapidly elevate prothrombin levels and reduce the risk for neonatal hemorrhage, the American Academy of Pediatrics and the Centers for Disease Control and Prevention recommend that all infants receive a single injection of phytonadione (vitamin K ) immediately after delivery. This previously routine prophylactic1 intervention has recently been challenged by parents who believe that the risks outweigh benefits. Subsequent to increases in parents declining prophylaxis, there has been an increase in life-threatening vitamin K deficiency bleeding in recent years. As discussed in Chapter 44, the anticoagulant warfarin acts as an antagonist of vitamin K and thereby decreases synthesis of vitamin K–dependent clotting factors. As a result, warfarin produces a state that is functionally equivalent to vitamin K deficiency. If the dosage of warfarin is excessive, hemorrhage can occur secondary to lack of prothrombin. Hyperbilirubinemia When administered parenterally to newborns, vitamin K derivatives can elevate plasma levels of bilirubin, thereby posing a risk for kernicterus. The incidence of hyperbilirubinemia is greater in premature infants than in full-term infants. Although all forms of vitamin K can raise bilirubin levels, the risk is higher with menadione and menadiol than with phytonadione. Therapeutic Uses and Dosage Vitamin K has two major applications: (1) correction or prevention of hypoprothrombinemia and bleeding caused by vitamin K deficiency and (2) control of hemorrhage caused by warfarin. Vitamin K Replacement As discussed, vitamin K deficiency can result from impaired absorption and from insufficient synthesis of vitamin K by intestinal flora. For children and adults, the usual dosage for correction of vitamin K deficiency ranges between 5 and 15 mg/day. To prevent hemorrhagic disease in neonates, it is recommended that all newborns be given an injection of phytonadione (0. Warfarin Antidote Vitamin K reverses hypoprothrombinemia and bleeding caused by excessive dosing with warfarin, an oral anticoagulant. Preparations and Routes of Administration Phytonadione (vitamin K ) is available in 5-mg tablets, marketed as Mephyton,1 and in parenteral formulations (2 and 10 mg/mL) sold generically. For example, this might be indicated in management of life- threatening bleeding due to vitamin K antagonists (e. Water-Soluble Vitamins The group of water-soluble vitamins consists of vitamin C and members of the vitamin B complex: thiamine, riboflavin, niacin, pyridoxine, pantothenic acid, biotin, folic acid, and cyanocobalamin. They are grouped together because they were first isolated from the same sources (yeast and liver). Vitamin C is not found in the same foods as the B vitamins and hence is classified by itself. Two compounds—pangamic acid and laetrile—have been falsely promoted as B vitamins.

To learn the principles ofnutritional support specifically designed for the modu­ lation of host infammatory and immune responses cheap plendil online. Thesevere infam­ matory response in pancreatitis can generate large fuid shifts between the intravas­ cular and extravascular space leading to hemodynamic instability as well as edema and respiratory failure purchase 2.5 mg plendil mastercard. Patients with severe pancreatitis require aggressive fuid resuscitation to maintain adequate intravascular volume to support end-organ perf­ sion order plendil 10mg. This type of lung injury requires prolonged mechanical respiratory support beyond the initial resuscitation phase. In addition, his initial hypotension may have decreased his end-organ perfsion, which can lead to acute kidney injury. If his pancreatitis is due to alcohol, he may also have a poor baseline nutritional status due to chronic excess alcohol consumption. Additionally, he may have defciencies that would ben­ efit fom specific vitamin and mineral supplementation in addition to caloric and pro­ tein provision. Enteral nutritional support will target the delivery of 25 to 30 kcal/kg of nonprotein calories and 1. Close monitoring to avoid hyperglycemia (glucose > 140-160) should be implemented. Similarly, if nasogastric feeding is initiated, the patient should be closely monitored for signs of intolerance such as abdominal distension, and/or high gastric residual volumes (>500 mL). The increased metabolic response continues into a later anabolic phase of tissue healing. The goals of nutrition therapy are to modify (most cases down-regulate) the metabolic response to stress, to prevent oxidative cellular injury, and to up-regulate the host immune responses. In the majority of critically ill patients, it is practical, safe, and less expensive to utilize enteral nutrition over parenteral nutrition. Results from the various clinical trials comparing enteral versus parenteral nutrition in critically ill patients have shown that enteral nutrition is associated with the reduction in infectious compli­ cations, specifically central-line infections and pneumonia. Enteral nutrition is also associated with cost savings from reduced adverse events and savings from reduced hospital length ofstay. Therefore, it is generally advisable to withhold enteral feeding until the patients are fully resuscitated. Enteral nutrition utilizes the gut barrier to control water and electrolyte absorp­ tion. It also supports the functional integrity of the gut by maintaining tight junc­ tions between the intraepithelial cells, stimulating blood fow, and inducing the release of trophic endogenous agents (ie, cholecystokinin, gastrin, bombesin, and bile salts). Furthermore, the structural integrity of the gut, including villous height and mass ofsecretory IgA-producing immunocytes, is better maintained with enteral nutrition. In a previously healthy patient with no evidence of malnutrition, the use of parenteral nutrition may be withheld until after 7 to 10 days of hospitalization without nutrition. This is mostly due to concerns with infectious complications associated with parenteral nutrition. If, however, there is preexisting protein-calorie malnutrition and enteral nutrition support is not feasible, it is appropriate to initi­ ate parenteral nutrition much earlier after adequate resuscitation has taken place. This can also be measured via indirect calorimetry with the aid of a respiratory therapist. These markers by themselves have too low specifcity, but may, together along with body weight changes, provide an estimate of general nutrition status. Enteral nutrition should be started within 24 to 48 hours following admission, or as soon as fluid resuscitation is completed and the patient is hemodynamically stable. Feeding started within this time frame is associated with less gut permeability and diminished activation and release of infammatory cytokines; early enteral feed­ ing has also been shown to reduce infectious morbidity and hospital length of stay. The use of "trickle" or trophic feeds may prevent mucosal atrophy, but has not been shown to improve outcomes from the standpoint of immune modulation. Gastric residuals <500 mL in the absence of other signs of intolerance are acceptable and do not increase the risk of aspiration or pneumonia. In critically ill patients, protein is the most important macronutrient for supporting immune function and wound healing. Assessment of the adequacy of protein nutrition is estimated from nitrogen balance (needs to be 1. Phosphate levels should be monitored closely and replaced when needed in respiratory failure patients for optimal pulmonary function. Patients with respiratory fail­ ure canreceive calorically dense formulations if fuid restriction is needed. Thiamine and folate supplementation for individuals with history of chronic alcohol abuse is important. Formulations with low glucose concentrations are available for diabetics as well to improve glycemic control. Special considerations regarding enteral nutrition should be made for patients with renal failure. These patients also require the standard enteral formulations described previously with continued adherence to the protein and calorie provisions as before. If significant electrolyte abnormalities develop, formulations with appropriate electrolyte profiles may be considered. Three meta-analyses showed that use of enteral nutrition compared to paren­ teral nutrition reduces infectious morbidity, hospital length of stay, need for surgical interventions, multiple organ failure, and mortality. Outcome benefits are seen in patients with acute pancreatitis when enteral nutrition is initiated within 24 to 48 hours. There has been no significant diference seen in outcomes of feeding by the gastric versus jejunal route; however, jejunal feeding may be better tolerated in these patients as severe pancreatitis can be associated with poor gastric emptying. Which of the following patients is the best candidate for enteral rather than parenteral nutrition? A 62-year-old malnourished man with an obstructing esophageal cancer about to undergo an lvor-Lewis esophagectomy. A 75-year-old healthy man who underwent an uncomplicated right hemi­ colectomy for a malignancy 7 days ago. A 26-year-old man with multiple gunshot wounds to the abdomen and extensive small bowel injury who has just undergone extensive small bowel resection and now has only 45 em of small bowel left and no ileoce­ cal valve. A 60-year-old woman who underwent a subtotal gastrectomy for stage 2 adenocarcinoma of the stomach 8 days ago and has developed an anasto­ motic leak. Both enteral and parenteral nutrition help preserve structural integrity of the gut. The cost savings of enteral over parenteral nutrition is from the direct cost of the cheaper generic enteral solutions versus the more expensive parenteral nutrition solutions. In patients with severe acute pancreatitis, enteral rather than parenteral nutrition is the preferred method of nutrition.

After application buy 10mg plendil otc, testosterone is absorbed rapidly into the skin and then slowly into the blood cheap plendil uk. Axiron is supplied as an alcohol-based solution in a metered-dose pump that delivers 30 mg of testosterone per actuation cheap 5mg plendil free shipping. Dosing is done by pumping the liquid onto an applicator (supplied with the pump) and then applying the liquid to clean, dry, intact skin of the underarm—and not to anyplace else. If an underarm deodorant or antiperspirant is used, it should be applied before applying testosterone (to avoid contaminating the deodorant or antiperspirant dispenser). After 14 days or longer, blood levels of testosterone are measured, and dosage is adjusted up or down as indicated. Like the testosterone gels, testosterone topical solution can be transferred to others through skin-to-skin contact, posing a risk to women and children. That is, Axiron users should wash their hands after every application, cover the application site with clothing after the solution has dried, and wash the application site before anticipated skin-to-skin contact with another person. Women and children should avoid contact with skin where Axiron was applied and should wash contaminated skin if accidental contact with an application site occurs. Nasal Gel Testosterone nasal gel [Natesto] is the newest formulation approved for testosterone administration. Because the drug is administered nasally, patients with nasal disorders or abnormalities (e. There has not been adequate testing for interactions with other nasally administered drugs. These include rhinorrhea, epistaxis, and nasopharyngitis; however, these tend to be modest effects. Administration instructions are supplied with the drug; however, it is important that the provider be aware of these in order to answer patient questions. The pump is inserted into the nostril with the tip aimed toward the lateral nostril wall. As the tip is withdrawn, it should be wiped against the lateral nostril wall to ensure that any remaining gel is distributed to the nostril. After administration in both nostrils, the nose should be lightly massaged below the nasal bridge. The patient should avoiding blowing or sniffing for at least 1 hour after administration. Implantable Testosterone Pellets Testosterone pellets [Testopel] are long-acting formulations indicated for male hypogonadism and delayed puberty. The pellets are implanted subdermally in the hip area or abdominal wall lateral to the umbilicus. About one third of the dose is absorbed the first month, one fourth the second month, and one sixth the third month. Testosterone Buccal Tablets Testosterone buccal tablets [Striant], approved for male hypogonadism, produce steady blood levels of testosterone. Tablets are applied to the gum area just above the incisor tooth, and are designed to stay in place until removed. To ensure good adhesion, tablets should be held in place (with a finger over the lip) for 30 seconds. The recommended dosage is 1 tablet every 12 hours, alternating sides of the mouth with each dose. If a tablet falls out before 8 hours, it should be replaced with a new one for the remainder of the dosing interval. If a tablet falls out after 8 hours, it should be replaced with a new one, and the next scheduled dose should be skipped (i. Adverse effects, which are usually transient, include local irritation, bitter taste, and taste distortion. It has been hypothesized that transfer of testosterone from buccal routes may occur through saliva transfer during kissing. Unfortunately, these preparations produce testosterone blood levels that vary widely: testosterone levels are higher than normal immediately after dosing and decline to lower than normal before the next dose. As a result, patients may experience significant variations in libido, energy, and mood. Androgen (Anabolic Steroid) Abuse by Athletes Many athletes take androgens (anabolic steroids) and androgen precursors to enhance athletic performance. The potential benefits of this practice, although substantial, are accompanied by significant risks. All of these drugs are regulated as controlled substances, making their use without a prescription illegal. Steroid use is especially prevalent among baseball players, football players, weight lifters, discus throwers, shot-putters, and bodybuilders. This includes professionals as well as athletes in college, high school, and junior high. Use is not limited to males: some females also take them, despite masculinizing effects. Exogenous androgens can significantly increase muscle mass and strength in males and females of all ages when given in sufficiently large doses. After 10 weeks, one study showed that testosterone treatment produced a 7-pound increase in muscle mass in subjects who did not exercise and a 13-pound increase in subjects who exercised and took the drug. In contrast, exercise in the absence of exogenous testosterone produced only a 4-pound increase in muscle mass. Because most of the androgens that athletes take are 17-alpha-alkylated compounds, hepatotoxicity (cholestatic hepatitis, jaundice, hepatocellular carcinoma) is an ever-present risk. In females, androgens can cause menstrual irregularities and virilization (growth of facial hair, deepening of the voice, decreased breast size, uterine atrophy, clitoral enlargement, and male-pattern baldness); baldness, growth of facial hair, and voice change may be irreversible. In boys and girls, androgens promote premature epiphyseal closure, reducing attainable adult height. There have been very few controlled studies to measure psychological effects of androgens; however, in the controlled studies undertaken, dosages of androgens were less than those typically taken by athletes. Surveys of athletes who engage in anabolic steroid use indicate an association with risky behavior and aggression; however, it is possible that these were inherent traits of the surveyed athletes regardless of steroid use. Characteristics include preoccupation with androgen use and difficulty in stopping use. When androgens finally are discontinued, an abstinence syndrome can develop similar to that produced by withdrawal of alcohol, opioids, and cocaine. This organization is dedicated to promoting, coordinating, and monitoring the fight against use of anabolic steroids and other banned substances in sports. Identifying High-Risk Patients Androgens are contraindicated for pregnant women, for men who have prostate cancer or breast cancer, and for enhancing athletic performance. Transdermal Gel and Solution Advise patients to wash their hands after applying the gel and to cover the site of application with clothing (to prevent transferring testosterone to others). Instruct patients not to shower or swim for several hours (to avoid washing the drug off). Warn users of the topical solution to avoid being near flames until the liquid has evaporated.

He r p re g - nancy was unremarkable and she states that she had no medical problems buy cheap plendil 5mg line. He r d e live r y w a s co m p lic a t e d b y p o s t p a r t u m h e m o rrh a g e re q u irin g c u re t t a g e of the uterus and a blood transfusion of four units of erythrocytes plendil 10 mg discount. She denies taking medications or hav- in g h e ad ach e s or visu al ab n orm alit ie s plendil 2.5mg visa. Mechanism: Pregnancy-associated enlargement of the anterior pituitary gland and hypotension leading to hemorrhage into t he anterior pituit ary gland. Other complications that are likely with this condition: An t er ior p it u it ar y in su f- ficien cy, su ch as h yp ot h yr oid ism or ad r en ocor t ical in su fficien cy. Know the other tropic hormones that may be affected by anterior pituitary necrosis. Co n s i d e r a t i o n s This patient developed amenorrhea from the time of her vaginal delivery that was complicat ed by postpartum hemorrhage. The pat ient also underwent a ut erine curett age in t he t reat ment of the postpartum bleeding. In this setting, there are two explanations: (1) Sheehan syndrome and (2) int rauterine adhesions (Asherman syndrome). Sheehan syndrome is caused by hypot ension in t he postpartum period, leading to hemor- rhagic necrosis of the anterior pituitary gland. Asherman syndrome is caused by the uterine curettage, which damages the decidua basalis layer, rendering the endomet rium unresponsive. The key t o different iat ing bet ween Sheehan syn- drome and intrauterine adhesions is to assess for whether or not the anterior pituitary is functioning, and whether the outflow tract (uterus) is responsive to hormonal therapy. For instance, since this patient’s history was “unable to breast- feed aft er delivery,” it would suggest t hat t he ant erior pituit ary was not funct ion- ing (lack of prolact in). H ad t he pat ient been able t o breastfeed, t he most likely diagnosis would have been int raut erine synechiae. T his pat ient was given a com- bination oral contraceptive agent, and if the endometrium were responsive to the hormonal t herapy, t hen proliferat ion of t he endomet rium should occur followed by stabilization of the endometrium with the progestin component, and then fin ally bleed in g wh en the placebo pills are t aken (d ays 21– 28). From a more pathophysi- ologic standpoint, it is the amount of bleeding that results in, or threatens to result in, hemodynamic inst abilit y if left unabat ed. However, in a nonlactating woman, when no menses resumes by 12 weeks after delivery, then pathology must be suspected. Overall, the most common cause of amenorrhea in the reproductive years is pregnancy. If the patient does not have a history of postpartum hemorrhage, evaluation of hypothalamic causes, such as hypothyroidism or hyper- prolactinemia, is often fruitful. Polycystic ovarian syndrome is characterized by estrogen excess wit hout progesterone, obesit y, hirsut ism, and glucose intolerance. Polycystic ovarian syndrome should be suspected in patients with obesity, hirsutism, and oligomenorrhea. When women are hypoestrogenic, then two broad cat egor ies of cau ses are com m on : hypothalamic/ pituitary diseases or ovarian fail- ure. Distinguishing between these two entities involves assessing whether the patient has normal or abnormal anterior pituitary function, or some evidence of unresponsiveness of the outflow tract to hormonal treatment (Table 51– 1). The treatment of Sheehan syndrome consists of replacement of hormones, such as thy- roxine, cortisol, and mineralocorticoid, and estrogen and progestin therapy. Intra- uterine adhesions are treated by hysteroscopic resection of the scar tissue. Which of t he following is a feature of int raut erine synech iae (Asherman syndrome)? C au sed b y an isch em ic n ecr o sis of the p o st er io r p it u it ar y glan d C. W hich of the following is the best description of the mecha- nism of intrauterine synechiae (Asherman syndrome)? Intrauterine adhesions are associated with a biphasic basal temperature ch ar t that r eflect s n or mal pit u it ar y fu n ct ion an d n or mal ovu lat ion. This indicat es t he presence of progest erone, which elevat es the t emperature. It is wit h Sheehan syndrome, and not with Asherman syndrome, that due to anterior pituit ary hemorrhagic necrosis, t he pat ient is unable to breastfeed aft er delivery, has a monophasic basal body t emperat ure chart, and has low cor t isol levels. Sheehan syndrome involves the anterior pituitary undergoing hemor- rhagic necrosis after a hypotensive episode, usually in the setting of post- partum hemorrhage. The anterior pituitary is, therefore, unable to secrete prolactin among a few other hormones. A patient may have an associated hypotensive episode, and not a hypertensive one, in t heir peripartum period caused by t he post - partum hemorrhage. In Asherman syndrome, large patches of endometrium are defective because of intrauterine adhesions. The endometrium is unresponsive, so estrogen exposure will have no effect on the lining of the uterus, and therefore, cannot pose a risk for endometrial hyperplasia. Pituitary engorgement occurs during pregnancy due to the hypertrophy and hyperplasia of lactotrophs. There is no associated increase in vascular supply, so when postpartum hemorrhage occurs, the anterior pituitary is particularly vulnerable to ischemia. It does not directly induce int raut erine synech iae; h owever, if t he pat ient undergoes a dilat ion and curett age for management of the t rophoblast ic disease, Asherman syn- drome may develop. T his setting increases the patient’s risk of endometrial hyperplasia or endometrial cancer. Osteoporosis is a risk in hypoestrogenic st ates, and this patient has estrogen excess, so osteoporosis is not a concern; in fact, bone mineral density is usually quite good. Up o n fu rt h e r q u e st io n in g, sh e h a s a lso n o t ice d a n in cre a se in fa cia l h a ir a n d a cn e fo r m a n y ye a rs. Sh e d e n ie s a n y h ist o ry o f m e d i- cal problems and has a strong family medical history of diabetes. Sh e is n o t e d t o h a ve so m e h irsu t ism a n d a ca n t h o sis n ig rica n s (o f n e ck a n d in n e r t h ig h s). Therapeutic plan: Regulate menstrual cycles with combination oral contra- cept ives an d scr een for met abolic abn or m alit ies (diabet es, lipid pan el, et c). The diagnostic criteria require two out of the three following signs and symptoms: o ligo - menorrhea/ amenorrhea, hyperandrogenism (not otherwise explained), or evidence of small multiple ovarian cysts on t ransvaginal ultrasound. She has chronic menstrual cycle irregularities, obesity, and signs of hyperandrogenism (acne, hirsutism). After exclusion of secondary causes of hyperandrogenism (lat e onset congenit al adre- nal hyperplasia, hyperprolactinemia, adrenal/ ovarian tumors, Cushing syndrome, thyroid disorders), the diagnosis can be made. When the patient does not desire a pregnancy, her menstrual cycles are best regulated with combined oral contraceptive pills. She should be assessed for metabolic abnormalities, as this pat ient is at high risk for chronic condit ions such as t ype 2 diabetes and car diovascu lar disease.

It can cause percent concentration in the administered air that pro- chest wall (truncal) rigidity because of interactions in the duces no response to surgical incision in 50% of the striatum buy generic plendil 2.5mg line. Answers A cheap plendil 5mg online, C buy discount plendil 10mg line, and D are measures of the azolam, C, ketamine, D, propofol, or E, thiopental. In contrast, affective disorders are emotional distur- about 1% of the world’s population. Its hallmarks are delu- bances in which the mood is excessively low (depression) or sions, hallucinations, disorganized thinking, and emotional high (mania). Several forms of the disease, including para- have been made in the treatment of these disorders. The noid, disorganized, and catatonic forms, are differentiated newer antipsychotic drugs used to treat schizophrenia and on the basis of symptoms. Delusions Affective fattening Disorganized speech Lack of motivation Dopamine Hypothesis Disorganized thinking Lack of pleasure (anhedonia) Many hypotheses exist regarding the biologic basis of Hallucinations Poverty of speech (alogia) schizophrenia. According to the dopamine hypothesis, schizophrenia results from abnormalities in dopamine neu- Insomnia Social isolation rotransmission in mesolimbic and mesocortical neuronal pathways (Box 22-2). Much of the evidence supporting this hypothesis is based on the clinical effects of agents that alter dopaminergic transmission. As shown in the accompanying fgure, numerous dopamine pathways are found in the brain. There are several mesocorti- ing those listed previously) block dopamine D2 receptors in cal pathways. Decreased activity in the pathway that the mesolimbic pathway to the nucleus accumbens, and this goes from the midbrain to the prefrontal lobe cortex alleviates the positive symptoms of schizophrenia. The pathway from the sub- stantia nigra to the striatum is involved in the coordina- tion of body movements. Second, drugs that act by increasing the in an interrogation room, waving his handgun, and yelling neuronal release of dopamine (amantadine) or by blocking incoherent statements such as “They aren’t going to take the reuptake of dopamine (drugs such as amphetamines and me alive! He was ronal release of dopamine, can be studied by measuring the overheard talking and arguing with himself in the locker concentration of the principal metabolite of dopamine, room that morning, and the partner says they almost got into a fght just minutes ago because the partner wouldn’t homovanillic acid, in the cerebrospinal fuid. Although ele- agree to shoot him when he insisted that he “wouldn’t be vated levels of homovanillic acid are not found in patients hurt and was immortal. Evidence corner cowering in fear, they forcibly enter the room, disarm also exists for a dopamine receptor defect in schizophrenic him, and inject haloperidol into his thigh. Positive emission tomography scanning using D2 to the locked ward of a psychiatric hospital and diagnosed receptor ligands has revealed that schizophrenic patients with paranoid schizophrenia. These fndings lend overall support to the dopa- Schizophrenia affects about 1 in 100 males and can be one of the most dangerous of all mental disorders, as it causes mine hypothesis, although it is clear from the clinical effec- those it affects to lose touch with reality. In the paranoid form of this Antipsychotic Drugs disorder, schizophrenics develop delusions of persecution or Antipsychotic drugs are agents that reduce psychotic personal grandeur. The frst sign of paranoid schizophrenia symptoms and improve the behavior of schizophrenic usually surfaces at ages 15 to 30, and schizophrenia is much patients. Antipsychotic drugs were also called neuroleptic more common in males than females. There is no cure, but drugs because they suppress motor activity and emotional the disorder can be controlled with antipsychotic medica- tions such as haloperidol. The accidental discovery of the antipsychotic acute psychotic episodes as it is rapidly absorbed and has properties of chlorpromazine in the early 1950s began a a high bioavailability after intramuscular injection, with new era in the treatment of schizophrenia and stimulated plasma levels reaching their maximum within 20 minutes research concerning the neurobiology of mental illness and after injection. Nearly 40 years later, the introduc- tion of clozapine had an equally important impact. Drug Properties Pharmacologic Effects Mechanism of Action The mechanisms by which the blockade of dopamine and The antipsychotic drugs interact with multiple neurotrans- serotonin receptors alleviates the symptoms of schizophrenia mitter systems. As shown the drugs cause an increase in dopamine synthesis, release, in Figure 22-1, an excellent correlation exists between the and metabolism. This probably represents a compensatory clinical potency of these drugs and their in vitro affnity for response to the acute blockade of postsynaptic dopamine D2 receptors. Whereas antagonism of D2 receptors in meso- receptors produced by antipsychotic drugs. Over time, con- limbic pathways is thought to repress the positive symptoms tinued dopamine receptor blockade leads to inactivation of of schizophrenia, blockade of D2 receptors in the basal dopaminergic neurons and produces what has been called ganglia is believed to be responsible for the parkinsonian and depolarization blockade. The clinical potency of the typical antipsychotic drugs 1 10 100 1000 10,000 is highly correlated with their in vitro affnity for Average daily clinical dose (mg) D2 (but not D1) receptors. Antagonism of Eventually the reduction in dopamine release caused by brain H1 receptors produces drowsiness and weight gain. It is a life-threatening condition may increase dopamine release in these pathways. In the characterized by muscle rigidity, elevated temperature mesocortical pathway, this action may alleviate the negative (>38° C), altered consciousness, and autonomic dysfunction symptoms of schizophrenia. Neuroleptic malignant syndrome Adverse Effects is managed by immediately discontinuing treatment with In the peripheral autonomic nervous system, antipsychotic the offending antipsychotic drug, administering dantrolene drugs also blockmuscarinicreceptors andα1-adrenoceptors, to prevent further muscle abnormality (see Chapter 21), and thereby causing the adverse effects described in Tables 22-1 providing supportive care. In addition, stronger warnings of active and inactive metabolites before they are excreted in were issued concerning the potential risk for abnormal the urine, and they have elimination half-lives ranging from motor movements or withdrawal effects in neonates of 20 to 30 hours (see Table 22-3). After therapy is initi- Indications ated, the positive symptoms of schizophrenia usually subside Antipsychotic agents are primarily used to treat schizophre- in 1 to 3 weeks. Patients become less agitated and experi- nia and other forms of psychosis, including drug-induced ence fewer auditory hallucinations. Grandiose or paranoid psychosis and psychosis associated with the manic phase of delusions subside and can disappear completely in some bipolar disorder. At the same time, sleep- patients, including those with dementia and severe mental ing and eating patterns become normalized, and behavioral retardation. Because the phenothiazines have antiemetic improvement occurs in the form of decreased hostility, activity, some of them are used in the management of nausea combativeness, and aggression. Antipsychotic drugs were traditionally classifed on the basis Chlorpromazine and thioridazine are considered low- of their chemical structure, but they are also classifed potency agents, fuphenazine has a slightly greater potency, according to whether they display typical or atypical phar- and haloperidol is a high-potency antipsychotic agent. The most common adverse effects pro- also considered frst-generation antipsychotic agents, and duced by typical antipsychotic drugs are summarized in the atypical antipsychotic drugs are second-generation Table 22-2. Patients with akathisia, or Typical Antipsychotic Agents motor restlessness, feel compelled to pace, shuffe their feet, or Numerous typical antipsychotics are available for the treat- shift positions and are unable to sit quietly. The four sonism resembles idiopathic Parkinson disease and is char- representative examples discussed in detail here are chlor- acterized by rigidity, bradykinesia, and tremor. Concurrent use of a β-adrenoceptor antagonist or an antidepressant may increase serum levels of both drugs. Concurrent use of a β-adrenoceptor antagonist or an antidepressant may increase serum levels of both drugs. Concurrent use of a β-adrenoceptor antagonist may increase serum levels of both drugs. Concurrent use of a β-adrenoceptor antagonist or an antidepressant may increase serum levels of both drugs. Patients with dystonia can experience which develops during long-term dopamine receptor severe reactions, such as oculogyric crisis (a condition in antagonism (see Chapter 18).

Reduced Therapeutic Effects The interaction between propranolol and albuterol represents a detrimental inhibitory interaction 10mg plendil for sale. Propranolol discount 5 mg plendil otc, a drug for cardiovascular disorders cheap plendil american express, can act in the lung to block the effects of albuterol. Reduced Adverse Effects The use of naloxone to treat morphine overdose is an excellent example of a beneficial inhibitory interaction. When administered in excessive dosage, morphine can produce coma, profound respiratory depression, and eventual death. Creation of a Unique Response Rarely, the combination of two drugs produces a new response not seen with either agent alone. When alcohol and disulfiram are combined, a host of unpleasant and dangerous responses can result; however, these effects do not occur when disulfiram or alcohol is used alone. Basic Mechanisms of Drug-Drug Interactions Drugs can interact through four basic mechanisms: (1) direct chemical or physical interaction, (2) pharmacokinetic interaction, (3) pharmacodynamic interaction, and (4) combined toxicity. Direct Chemical or Physical Interactions Some drugs, because of their physical or chemical properties, can undergo direct interaction with other drugs. Frequently, the interaction produces a precipitate; however, direct drug interactions may not always leave visible evidence. Because drugs can interact in solution, it is essential to consider and verify drug incompatibilities when ordering medications. Pharmacokinetic Interactions Drug interactions can affect all four of the basic pharmacokinetic processes. That is, when two drugs are taken together, one may alter the absorption, distribution, metabolism, or excretion of the other. Altered Absorption Drug absorption may be enhanced or reduced by drug interactions. There are several mechanisms by which one drug can alter the absorption of another. For example, when epinephrine is injected together with a local anesthetic, the epinephrine causes local vasoconstriction, thereby reducing regional blood flow and delaying absorption of the anesthetic. Altered Distribution There are two principal mechanisms by which one drug can alter the distribution of another: (1) competition for protein binding and (2) alteration of extracellular pH. When two drugs bind to the same site on plasma albumin, coadministration of those drugs produces competition for binding. As a result, binding of one or both agents is reduced, causing plasma levels of free drug to rise. However, because the newly freed drug usually undergoes rapid elimination, the increase in plasma levels of free drug is rarely sustained or significant unless the patient has liver problems that interfere with drug metabolism or has renal problems that interfere with drug excretion. A drug with the ability to change extracellular pH can alter the distribution of other drugs. For example, if a drug were to increase extracellular pH, that drug would increase the ionization of acidic drugs in extracellular fluids (i. As a result, acidic drugs would be drawn from within cells (where the pH was below that of the extracellular fluid) into the extracellular space. The ability of drugs to alter pH and thereby alter the distribution of other drugs can be put to practical use in the management of poisoning. For example, symptoms of aspirin toxicity can be reduced with sodium bicarbonate, a drug that elevates extracellular pH. By increasing the pH outside cells, bicarbonate causes aspirin to move from intracellular sites into the interstitial fluid and plasma, thereby minimizing injury to cells. Altered Metabolism Altered metabolism is one of the most important—and most complex— mechanisms by which drugs interact. Some drugs increase the metabolism of other drugs, and some drugs decrease the metabolism of other drugs. Drugs that increase the metabolism of other drugs do so by inducing synthesis of hepatic drug-metabolizing enzymes. Drugs that decrease the metabolism of other drugs do so by inhibiting those enzymes. When it is essential that an inducing agent is taken with another medicine, dosage of the other medicine may need adjustment. For example, if a woman taking oral contraceptives were to begin taking phenobarbital, induction of drug metabolism by phenobarbital would accelerate metabolism of the contraceptive, thereby lowering its level. If drug metabolism were increased enough, protection against pregnancy would be lost. To maintain contraceptive efficacy, dosage of the contraceptive should be increased. Conversely, when a patient discontinues an inducing agent, dosages of other drugs may need to be lowered. If dosage is not reduced, drug levels may climb dangerously high as rates of hepatic metabolism decline to their baseline (noninduced) values. The interactions of ketoconazole (an antifungal drug) and cyclosporine (an expensive immunosuppressant) provide an interesting case in point. If ketoconazole is combined with cyclosporine, the serum drug level of cyclosporine will rise. Although inhibition of drug metabolism can be beneficial, as a rule inhibition has undesirable results. That is, in most cases, when an inhibitor increases the level of another drug, the outcome is toxicity. Accordingly, when a patient is taking an inhibitor along with his or her other medicines, you should be alert for possible adverse effects. Unfortunately, because the number of possible interactions of this type is large, keeping track is a challenge. The safest practice is to check for drug interactions in one of the reliable software applications that are widely available. Altered Renal Excretion Drugs can alter all three phases of renal excretion: filtration, reabsorption, and active secretion. Glomerular filtration can be decreased by drugs that reduce cardiac output: a reduction in cardiac output decreases renal perfusion, which decreases drug filtration at the glomerulus, which in turn decreases the rate of drug excretion. By altering urinary pH, one drug can alter the ionization of another and thereby increase or decrease the extent to which that drug undergoes passive tubular reabsorption. Finally, competition between two drugs for active tubular secretion can decrease the renal excretion of both agents. Pharmacodynamic Interactions By influencing pharmacodynamic processes, one drug can alter the effects of another. Pharmacodynamic interactions are of two basic types: (1) interactions in which the interacting drugs act at the same site and (2) interactions in which the interacting drugs act at separate sites. Pharmacodynamic interactions may be potentiative or inhibitory and can be of great clinical significance. Interactions at the Same Receptor Interactions that occur at the same receptor are almost always inhibitory. Inhibition occurs when an antagonist drug blocks access of an agonist drug to its receptor.

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