By M. Fadi. Lyme Academy of Fine Arts. 2019.
The spleen is frequently enlarged buy proscar on line amex prostate 32, and the ascites buy generic proscar from india androgen hormone gel, fluid within the peritoneal cavity cheap proscar amex prostate cancer 5k pittsburgh, is due to liver insufficiency. Death may ensue as a result of bleeding from esophageal varices or bacterial peritonitis of the ascitic fluid. The liver is covered with visceral peritoneum over most of its surface and is sus- pended by several mesenteric structures called ligaments. The falciform ligament (with the round ligament of the liver, the adult remnant of the umbilical vein, in its free margin) is reflected onto the anterior abdominal wall and divides the liver into apparent right and left anatomical lobes. As the falciform ligament passes onto the superior surface of the liver, the two layers of peritoneum diverge to the right and to the left, creating the anterior layers of the coronary ligaments. These pass to the right and to the left to the extremes of the superior liver surface, turn back on themselves (creating the triangular ligaments), and turn posteriorly to form the posterior layers of the coronary ligaments. In this manner, an area devoid of visceral peritoneum is created, the bare area of the liver. The posterior layers of the coro- nary ligaments converge to form the lesser omentum, which passes from the visceral surface of the liver to the lesser curvature of the stomach (hepatogastric ligament) and the first part of the duodenum (hepatoduodenal ligament). The liver is divided anatomically into four lobes by external landmarks and is delineated on the visceral surface by fissures and fossae, which form the letter H (see Figure 23-1). The left side of the H is formed by the fissure for the round ligament and the ligamentum venosum (adult remnant of the ductus venosus); the left lobe is to the left of this fissure. The crossbar of the H is the porta hepatis, through which the hepatic artery, portal vein, and nerves enter the liver and the bile ducts and lymphatics exit. Appendix fibrosa Inferior vena cava Esophageal impression Bare area of the liver Caudate lobe Coronary ligament Gastric impression Portal vein Suprarenal impression Hepatic artery Renal impression Porta hepatis Common hepatic duct Cystic duct Edge of lesser omentum Duodenal impression Quadrate lobe Round ligament Colic impression Gallbladder figure 23-1. The left portal lobe is the left anatomical lobe, quadrate lobe, and the remainder of the caudate lobe. The portal lobes are supplied by lobar branches of the hepatic artery, portal vein, and bile ducts. Although lacking external landmarks, the portal lobes are further divided functionally into hepatic segments. The liver receives a dual blood supply; approximately 30 percent of the blood entering the organ is from the hepatic artery, and 70 percent is from the portal vein. The proper hepatic artery is a branch of the common hepatic artery, one of the three major branches of the celiac artery. As it approaches the liver, it divides into right and left hepatic branches that enter the liver and divide into lobar, seg- mental, and smaller branches. Eventually, blood reaches the arterioles in the portal areas at the periphery of the hepatic lobules and, after providing oxygen and nutri- ents to the parenchyma, drains into the hepatic sinusoids. The majority of blood entering the liver is venous blood rich in nutrients and molecules absorbed by the gastrointestinal organs. Intrahepatic branches of the portal vein follow the arteries to the portal areas, where portal venules empty into the sinusoids from which mol- ecules are extracted and added. This short, wide vein ascends within the hepatoduodenal ligament, posterior to the bile duct and hepatic artery, and enters the liver through the porta hepatis. Portacaval (systemic) venous anastomoses occur at sites where blood may ulti- mately drain into the portal system and/or the vena caval system. If venous flow through the portal system is prevented by liver disease, for example, the absence of valves within the portal system veins allows reverse flow. This dilates the smaller veins, and blood is drained by veins emptying into the vena cavae. This occurs at several sites and may produce clinical signs or symptoms (Table 23-1). This is due to dilatation of the anastomosis between which of the following pairs of veins? The left hepatic artery supplies the left and quadrate lobes and a portion of the caudate lobe. He has been under significant job-related stress and has been self-medicating himself with over-the-counter antacids, with some relief. He states that his stools have changed in color over the previous 2 months and now are intermittently dark and tarry in consistency. His stools have become dark and tarry, which upon examination contain occult blood. The dark and tarry stools reflect blood in the stools; that is, hemoglobin has been converted to melena. If the stomach is the site, a biopsy is usually performed to assess concurrent malignancy. Treatment includes a histamine-blocking agent, proton pump inhibitor, and antibiotic therapy. The bacterium Helicobacter pylori has been implicated in most cases of peptic ulcer disease. If an ulcer occurs in the duodenum, the posterior wall of the ampulla of the duodenum (duodenal cap) is the usual site. The gastroduodenal artery lies posterior to the duodenum at this point and is at risk in the event of ulcer perforation. This continuation of the esophagus is a large, intraperitoneal, saccular organ that is suspended by the mesentery-like greater and lesser omenta. The stomach is divided anatomically into a cardia, fundus, body, and pylorus (pyloric antrum and canal with sphinc- ter) and has greater and lesser curvatures. The greater omentum attaches to the greater curvature and drapes inferiorly to form a double-layer apron anterior to the abdominal cavity contents. The greater omentum is subdivided into gastrocolic, gastrosplenic, splenorenal, and gastrophrenic ligament portions. The lesser omentum is attached to the lesser curvature and first part of the duodenum and extends to the visceral surface of the liver. With the stomach, it forms the anterior boundary of the omental bursa (lesser sac). The lesser omentum is divided into hepatogastric and hepatoduodenal ligaments; the latter form the anterior boundary of the epiploic foramen (of Winslow; see Figure 24-1). The stomach is richly supplied by five sets of arteries, all of which are branches of the celiac artery (trunk). The celiac artery arises from the abdominal aorta opposite the upper portion of L1. Ascending branch of left gastric artery Left gastric Splenic artery artery Short gastric Inferior phrenic artery artery Celiac artery Spleen Ascending hepatic artery Proper hepatic artery Left gastroepiploic Right gastric artery artery Gastroduodenal artery Posterior superior pancreaticoduodenal artery Pancreatic branches Anterior superior pancreaticoduodenal artery Right gastroepiploic artery Inferior pancreatico- duodenal artery Epiploic arteries Superior mesenteric (omental branches) artery figure 24-1. After sending small branches to the esophagus, it curves inferiorly within the lesser omentum, parallel to the lesser curvature, to which numerous gastric branches are provided. The splenic artery is a large, tor- tuous branch of the celiac that passes to the left, along the superior margin of the pancreas, to reach the spleen.
The disorder is characterized by abnormal oral thermy proscar 5 mg with mastercard androgen hormone nausea, a condition in which the body temperature tends to and facial movements (e discount 5mg proscar with amex man health magazine india. In later stages discount proscar 5mg otc prostate oncologycom, abnormal limb and truncal thermia (including heat stroke) or hypothermia. Investigators believe that high doses of thioridazine can cause pigmentary retinopa- tardive dyskinesia results from supersensitivity to dopamine, thy and cardiac toxicity. Acute extrapyramidal (compulsive use of obscene words, particularly those related effects (akathisia, pseudoparkinsonism, and dystonias) that to feces), and echolalia (repetition of another person’s words are caused by typical antipsychotic drugs can be managed by or phrases). Besides treatment of schizophre- activity; and amantadine, an agent that increases dopamine nia, some members of this class are approved for the treat- release in the basal ganglia and can be used in conjunction ment of acute manic episodes associated with bipolar with an anticholinergic drug. It seems likely that its thera- tardive dyskinesia, which are sometimes reversible. This results clozapine is associated with signifcant sedation and auto- in signifcant improvement in many patients. These adverse reactions are caused by approved for the treatment of tardive dyskinesia, but some antagonism of histamine, muscarinic, and α1-adrenoceptors. Its pharmacologic properties are similar to those of by antipsychotics and other drugs existing as substrates for clozapine, but olanzapine causes fewer autonomic side the same cytochrome P450 isozymes. The most common adverse reactions to olan- weeks and is useful for treating patients who are not compli- zapine are sedation and weight gain. Olanzapine is also available in combination with of the most widely used typical antipsychotics agents is hal- the antidepressant fuoxetine (see later) in a formulation operidol. Haloperidol has properties similar to those of fu- (Symbyax) indicated for treatment-resistant depression. Its pharmacologic properties are similar to those long-acting depot preparation for intramuscular administra- of olanzapine, but it appears to cause less sedation, more tion. Its effects on treating both the positive In addition to its use in treating psychoses (e. This syndrome In some patients, risperidone elevates levels of serum pro- is characterized by facial and vocal tics, coprolalia lactin. A newer agent, ase- Bipolar Disorder napine, also acts like risperidone but is formulated as a Bipolar disorder (previously called manic-depressive disor- sublingual tablet. This disorder differs from major depression in to treat irritability in autistic children. Paliperidone is the that periods of mania alternate or occur simultaneously with major active metabolite of risperidone and shares its phar- depressive symptoms. Paliperidone is available in a once-a-day formula- self-esteem (grandiosity), increased talking (pressure of tion using osmotic drug-release technology to deliver a con- speech), racing thoughts (fight of ideas), increased social or trolled amount of drug throughout the 24-hour period and work activity, and decreased need for sleep. All typical antipsychotic intensifes, some patients experience psychotic symptoms drugs appear to be equally effective when used in equipotent such as delusions. The highly sedat- Typically, the manic phase occurs just before or just after ing drugs are no more effective than the less-sedating drugs a depressive episode. In many patients, depressive and manic in calming agitated patients, and the less-sedating drugs are episodes last several weeks or months. In some patients, no more effective than the highly sedating drugs in treating however, the episodes change within hours or days (rapid withdrawn patients. Several controlled trials indicate that low-dose regimens are as effec- Biogenic Amine Hypothesis tive as high-dose regimens and produce fewer side effects. According to the biogenic amine hypothesis, mood disor- The atypical antipsychotic drugs are an appealing choice ders result from abnormalities in serotonin, norepinephrine, for the treatment of schizophrenia, and they may become or dopamine neurotransmission. The serotonergic system is activated during effective against the negative symptoms of schizophrenia. It is believed that patients with chronic schizophrenia, however, have not yet impaired serotonin neurotransmission can decrease cortical been obtained. Noradrenergic fbers that chotic drug, many patients exhibit some alleviation of posi- project from the locus ceruleus to the cerebral cortex can also tive symptoms and an improvement in socialization, mood, play a role in depression, as can dopaminergic fbers inner- and self-care habits. Antipsychotic medication is usually continued for mediator of biologic rhythms, is known to suppress the at least 12 months after the remission of acute psychotic activity of serotonergic neurons. At that time, a low-dose regimen or gradual excess melatonin production contributes to the development withdrawal of medication should be considered in order to of depression. This hypothesis is particularly relevant to sea- reduce the probability of developing tardive dyskinesia. Abnormalities in melatonin and sero- drawal symptoms such as insomnia, nightmares, nausea, tonin metabolism can also contribute to the sleep distur- vomiting, diarrhea, restlessness, salivation, and sweating. The primary drugs used in their tion of serotonin, and this leads to down-regulation of treatment are antidepressant drugs and mood-stabilizing presynaptic autoreceptors. If administration begins and causes an immediate increase in patients fail to respond to these drugs, monoamine oxidase the synaptic concentration of serotonin and norepinephrine. The blockade is also believed to trigger a series of adaptive Because depressed patients might attempt suicide, the changes in norepinephrine and serotonin neurotransmission. Over time, the increased synaptic concen- boxed warnings highlighting the risk of increased tration of serotonin can cause down-regulation of presyn- suicidal thoughts and behavior in children, adolescents, aptic autoreceptors and thereby increase the fring rate of and adults. Clomipramine is particu- often administered at bedtime, when their sedative effects larly effective in treating patients with obsessive-compulsive can have the added beneft of promoting sleep. Some antidepressants are benefcial in the manage- lower the seizure threshold and can induce seizures at thera- ment of certain sleep disorders, including somnambulism, peutic as well as toxic serum concentrations. In patients with enuresis, antidepressants appear to including hypotension and sinus tachycardia; excessive seda- increase the awareness of the need to urinate and thereby tion; and seizures. The type of arrhythmia also have a role in the treatment of chronic pain syndromes that occurs with an overdose can be treated by the intrave- because of their mood-elevating effect and analgesic nous administration of sodium bicarbonate. Secondary amines block norepinephrine uptake more than they block serotonin reuptake, and this is Tricyclic Antidepressants especially true of desipramine. They block serotonin reuptake to a greater highly effective in the treatment of depression and several extent than do secondary amines. They also produce more other disorders, but they are associated with a high incidence sedation and autonomic side effects than do secondary of adverse effects. The type of amine group determines the selectivity Selective Serotonin Reuptake Inhibitors of the pharmacologic action. Fluoxetine (Prozac), is one of the most popular drugs for the treatment of depression, and the frst drug approved for the treatment of bulimia nervosa; it is Drug Properties also effective in the management of anorexia nervosa and Pharmacokinetics. The drug is well absorbed the gut after oral administration and are extensively metabo- orally and is converted to an active metabolite, norfuox- lized by cytochrome P450 isozymes. This long converted to an active metabolite that has an even longer duration of action can be a disadvantage if severe adverse half-life. It can impair the regulation of blood glucose levels and have much less effect on the reuptake of norepinephrine. It can also cause a syndrome of inap- Their effcacy in the treatment of depression supports the propriate antidiuretic hormone secretion, characterized by hypothesis that serotonin dysfunction plays a signifcant persistent hyponatremia and elevated urine osmolality. Fluvoxamine is approved for the treatment and long-term effects of serotonin reuptake inhibition are of obsessive-compulsive disorder but has also been used to illustrated in Figure 22-2.
This treatment was tylcholine in peripheral tissues and the brain and thereby repeated after 20 minutes best buy for proscar prostate cancer zytiga forums, and his symptoms gradually sub- counteracts manifestations of atropine toxicity purchase proscar without prescription androgen hormone target organ. He should be reserved for persons with serious central nervous continued to improve over the next 36 hours and was toxicity such as hallucinations and seizures cheap 5mg proscar visa mens health total body workout. Atropine and scopolamine pine and other muscarinic receptor antagonists act as potent are distributed to the central nervous system, where they can inhibitors of secretions in the upper and lower respiratory block muscarinic receptors and produce both sedation tract. Muscarinic receptor blockers relax gastrointesti- followed by a slower and longer-lasting sedative effect. With nal muscle, except sphincters, and reduce intestinal motility, higher doses of atropine, patients can experience an acute Chapter 7 y Acetylcholine Receptor Antagonists 65 confusional state known as delirium. Higher doses of mus- Chapter 24, muscarinic receptor blockers are also used in the carinic antagonists sometimes cause hallucinations. Atropine and glycopyrrolate (see later) sweating, which can reduce heat loss and lead to hyperther- are used in two other clinical contexts. The increased body temperature prevent muscarinic side effects when cholinesterase inhibi- can cause cutaneous vasodilatation, and the skin can become tors are given to patients with myasthenia gravis. To obtain a relatively localized effect setting, supranormal doses may be required to counteract the on ocular tissues, muscarinic receptor blockers are adminis- large concentrations of acetylcholine that have accumulated tered via topical instillation of a solution or ointment. These at acetylcholine synapses, and the atropine dosage must be drugs are typically used to produce mydriasis and facilitate titrated to the patient’s response. They late will not counteract the effects of nicotinic receptor can also be used to produce cycloplegia and permit the activation caused by cholinesterase inhibition. The muscle accurate determination of refractive errors, especially in weakness resulting from nicotinic receptor stimulation can be younger patients with strong accommodation. Atropine can be used to treat sinus primarily responsible for the pharmacologic effects of atro- bradycardia in cases in which the slow sinus rhythm reduces pine. Formulations of hyoscyamine for oral or sublingual the cardiac output and blood pressure and produces symp- administration are used to treat intestinal spasms and other toms of hypotension or ischemia. Atropine is usually given intravenously for this purpose, but Semisynthetic and Synthetic Muscarinic it can be injected endotracheally if a vein is not accessible. Receptor Antagonists In patients with symptomatic atrioventricular block, atro In the search for a more selective muscarinic receptor anta- pine or glycopyrrolate can be used to increase the atrioven- gonist, investigators have developed a large number of tricular conduction velocity. Because of its bronchodilat- pharmacologic effects of these agents are similar to those ing effects, atropine was once used to treat asthma and other of atropine, their unique pharmacokinetic properties are obstructive lung diseases. For example, it impairs ciliary activity, thereby reducing the clearance of Ipratropium and Tiotropium mucus from the lungs and causing accumulation of viscid Ipratropium (Atrovent) and tiotropium (Spiriva), qua- material in the airways. As discussed later in this chapter, ternary amine derivatives of atropine, are administered by ipratropium is now used instead of atropine to treat obstruc- inhalation to patients with obstructive lung diseases. Atropine and other muscarinic receptor Because these drugs are not well absorbed from the lungs blockers are used to reduce salivary and respiratory secre- into the systemic circulation, they produce few adverse tions and thereby prevent airway obstruction in patients who effects. For example, unlike atropine, they do not impair the are receiving general anesthetics. This makes used for this purpose today (see the section on other them particularly useful in treating patients with asthma, indications). Atropine and and uses of these compounds are discussed more thoroughly related drugs are used to relieve intestinal spasms and pain in Chapter 27. As dis- dine, darifenacin, solifenacin, and trospium are used to cussed later, a selective muscarinic M1 receptor blocker, reduce the four major symptoms of overactive bladder: pirenzepine, is available in some countries to treat peptic daytime urinary frequency, nocturia (frequent urination at ulcer disease. Compared mulation of scopolamine can be used to prevent motion with other muscarinic receptor antagonists, darifenacin, soli- sickness. The skin patch slowly releases scopolamine over a fenacin, tolterodine, and trospium appear to have a more period of 3 days and is thought to work by blocking acetyl- selective action on the urinary bladder and may cause fewer choline neurotransmission from the vestibular apparatus to adverse effects such as dry mouth and blurred vision. Low doses preferentially inhibit secretions, and the paralytics or muscle relaxants) bind to the muscle type of drug is administered preoperatively to inhibit excessive sali- nicotinic acetylcholine receptor and inhibit neurotransmis- vary and respiratory tract secretions. It is also used during sion at skeletal neuromuscular junctions, causing muscle anesthesia to inhibit the secretory and vagal effects of cho- weakness and paralysis. A new formulation of and the other consisting of the depolarizing blocker glycopyrrolate (Cuvposa) was recently approved to reduce succinylcholine. The neuromuscular blocking agents are chronic severe drooling in patients aged 3 to 16 years with extremely dangerous compounds, because they can produce neurologic conditions such as cerebral palsy. The neuromuscular blockers are primar- Tropicamide ily responsible for the rare occurrence of “anesthesia aware- Tropicamide is a synthetic drug that was developed for ness” during surgery, because they can render a patient topical ocular administration as a mydriatic (pupillary immobile without affecting mental status. It is given just before ophthalmoscopy to facilitate examination of the peripheral retina. It has a short dura- Nondepolarizing Neuromuscular tion of action (about 1 hour) and is often preferable to Blocking Agents atropine and scopolamine for short-term mydriasis. The nondepolarizing neuromuscular blocking agents, also known as curariform drugs, include Pirenzepine atracurium, cisatracurium, pancuronium, rocuronium, Pirenzepine, a muscarinic receptor antagonist that is selec- and vecuronium. One of the original drugs, tubocurarine, tive for M1 receptors, was developed to reduce vagally stimu- was extracted from plants used by native South Americans lated gastric acid secretion in patients with peptic ulcers. Curare is another blocks M1 receptors on paracrine cells and inhibits the name for the arrow poisons and their chemical derivatives. Pirenz- The curariform drugs are not well absorbed from the gut epine is available in Canada and Europe but not in the and do not cross the blood-brain barrier. The pharmacologic The acetylcholine nicotinic receptor antagonists include properties of curariform drugs are listed in Table 7-1. These ganglionic blocking agents and neuromuscular blocking drugs are positively charged quaternary amines having an agents. The nondepolarizing neu- Drugs that block autonomic ganglia were among the frst romuscular blocking agents are administered only by the drugs to be developed for reducing excessive activity of the intravenous route. Chapter 7 y Acetylcholine Receptor Antagonists 67 the specifc isomer known as cisatracurium spontaneously respiratory tract so as to enable ventilation and endoscopic decomposes by nonenzymatic chemical (Hoffman) degrada- procedures (e. Hence, cisatracurium is the preferred paralytic agent neuromuscular blocking agents, the degree of neuromuscular for critically ill patients with impaired hepatic and renal blockade can be determined by monitoring the contraction function. In patients with normal renal and hepatic function, of a small limb muscle in response to nerve stimulation. The selection of a nondepolarizing agent of action comparable to that of vecuronium and rocuronium. The curariform drugs act as relative duration of action and the degree of drug-induced competitive antagonists of acetylcholine at nicotinic changes in blood pressure and heart rate. Atracurium, cisa receptors in skeletal muscle, and this accounts for their tracurium, rocuronium, and vecuronium provide an inter- muscle-relaxing effects. After a curariform drug is adminis- mediate duration of action (30 to 60 minutes). With the tered, it frst paralyzes the small and rapidly moving muscles exception of atracurium, which can cause histamine release of the eyes and face and then paralyzes the larger muscles at higher doses, the intermediate-acting drugs have minimal of the limbs and trunk.
In both cases order proscar with a visa prostate meds, to prevent the long-term complications of gluco- cor t icoid excess (diabet es proven 5mg proscar prostate cancer 35 years old, h yper t en sion buy discount proscar 5mg online prostate cancer with bone metastasis, obesit y, ost eoporosis, cat aract s), pat ient s should not be overt reated. St r e s s Do s e St e r o id s When a patient has adrenal insufficiency or adrenal suppression due to chronic superphysiologic cort icost eroid use (equivalent of prednisone 15 mg/ d for 3 weeks or longer during the prior 12 months), then stress dose steroids are needed for event s such as surgery, acute illness. D o u b le the p r ed n iso n e the n igh t b efo r e an d h old h er st er o id s the d ay of the surgery. Use of cyclophosphamide in lieu of corticosteroids for 2 weeks following surgery t o promot e wound h ealing. Aut oimmune adrenalit is is the most common cause of primar y adrenal in suf- ficien cy. Su r gical excision of the ad r en al glan d s would r esu lt in pr im ar y ad r e- nal insufficiency. H emorrhage of the adrenal glands is more common in the sett ing of sepsis and another cause of primary adrenal insufficiency. A stress dose of corticosteroids is important to prevent adrenal insuffi- cien cy before sur ger y. Cor t isol levels var y t h r ou gh ou the d ay, an d are on ly u sefu l wh en elevat ed t o exclude adrenal insufficiency. The family has noted that for approximately the past 2 months, the patient has become progressively fatigued and absentminded, and she has developed loss of appetite and weight loss. She has been getting up to urinate several times per night and complains of thirst; however, a glucose test for diabetes in her doctor’s office was negative. This morn- in g, sh e lo st h e r b a la n ce b e ca u se sh e fe lt “lig h t -h e a d e d ” a n d fe ll, la n d in g o n h e r le ft a rm. Ph ysica l e xa m in a t io n is n o t a b le fo r a n e ld e rly, t h in wo m a n in m ild d is- tress as a result of pain. Heart and lung examinations are normal, and carotid auscultation reveals no bruits. Examination of her extremities is sig- nificant only for deformity of the left mid-humerus with swelling. The radiologist calls you to confirm the fracture of the mid-left humerus but also states that there is the suggestion of some lytic lesions of the proximal humerus and recommends a skull film (Figure 50–1). She has a 2-month history of fatigue, absent mindedness, loss of appetite and weight, and nocturia. In addit ion t o t he fracture seen on x-r ay, sh e also h as lyt ic lesion s of the pr oxim al h u m er u s. Most likely diagnosis: Hypercalcemia with pathologic fracture of the left humerus. Co n s i d e r a t i o n s The patient presents with acute confusion, fatigue, and lethargy, all symptoms of hypercalcemia, consistent with the calcium level of 13 mg/ dL. The first step in therapy should be intravenous saline to restore volume status and facilitate urinary calciu m excr et ion. G iven the r apidit y of on set of symp t oms, weigh t loss, age, an d presence of lytic bone lesions, the first concern should be for malignancy, such as multiple myeloma, or bony metastases from an undiagnosed cancer. Both serum and urine elect rophoresis would help to ident ify the presence of a monoclonal gam- mopathy. O ther causes include granulomatous disorders such as sarcoidosis and tuberculosis; less commonly, hypercalcemia may be the presentation of intoxication with vitamin A, vitamin D, or calcium-contain- ing ant acids, or may occur as a side effect of t h erapies wit h drugs such as lit h ium or thiazide diuretics. Genetic conditions such as familial hypocalciuric hypercalcemia and hyperparat hyroidism as part of a mult iple endocrine neoplasia syndrome are less common causes. Thedifferentialdiagnosiscan benarrowed based on thechronicityof thepatient’s presentation and the presence or absence of other symptoms and signs. Most patients have no symptoms with mild hyper- calcem ia less t h an 12 g/ d L, except p er h aps some p olyu r ia an d d eh yd r at ion. The symptoms of hyperparathyroidism can be remembered as stones (kidney), moans (abdominal pain), groans (myalgias), bones (bone pain), and psychiatric overtones (mental status changes). Diagnosis can be established by finding hyper- calcem ia, h yp oph osph at em ia, an d in ap pr opr iat ely elevat ed P T H levels. Pat ient s wit h primary hyperparathyroidism may be t reated surgically with parat hyroidec- tomy if the patient is symptomatic, if the calcium is greater than 1 mg/ dL above upper limit of normal, if less than 50 years old, or if there is significantly decreased bone mineral density (T score < – 2. However, a patient presenting with acute onset of symptomatic hypercalcemia is more likely t o have a malignancy. M u lt iple myeloma, lymph oma, an d leu kemia all can present wit h hypercalcemia, as can solid tumors such as breast, lung, and kidney cancers. Some of these cancers cause elevated calcium levels by stimulating osteoclast activity through direct bone marrow invasion (multiple myeloma, leu- kemia, and breast cancer). In this case scenario, checking electrolytes to assess acid-base status and renal fu n ct ion are imp or t ant t est s t o con sid er. If mult iple myeloma is sus- pected, serum and urine electrophoresis for monoclonal antibody spikes should be examined. Radiographs showing lytic or blastic lesions may be helpful; finally, a bone marrow biopsy may be considered. Patients typically present with lytic bone lesions, hypercalcemia, renal insufficiency, anemia, an d an elevat ed globu lin fract ion on serum chemist ries, which, if separated by elect rophoresis, shows a monoclonal pro- liferation (M-spike). The diagnosis of multiple myeloma requires laboratory and clin ical cr it er ia: a monoclonal antibody spike in the serum, or light chains in the urine, and more than 10%clonal plasma cells in the bone marrow, and end-organ damage such as lytic bone lesions. M G U S is much more common t h an myeloma, affecting up to 1% of the population more than 50 years, or up to 10% of people older than age 75. Some patients with myeloma wit h no bone lesions or other end-organ damage have an indolent course (“smolder- ing myeloma”) and can be observed without treatment for many years if asymptom- at ic. Therapy for symptomatic multiple myeloma includes evaluat ion for aut ologous st em cell t ransplant, and induct ion chemot herapy wit h h igh-dose pulsed dexa- methasone, in combination with thalidomide or lenalidomide, and bortezomib. Which of the fol- lowing t h erapies is useful for immediat e t reat ment of the hypercalcemia? H e is clinically dehydrated, his serum calcium level is 14 mg/ dL, and his creatinine level is 2. An asymptomatic, most likely chronically elevated calcium level is most likely caused by primar y h yperparat h yroidism due t o a parat h yroid adenoma. The hypercalcemia is presumed to be chronic because she has osteoporo- sis and is premenopausal. Familial hypocalciuric hypercalcemia can also lead to elevated serum calcium and low serum phosphate levels, but is usually asymptomat ic and is far more rare than primary hyperparat hyroidism. Bisphosphonates are helpful in controlling hypercalcemia through inhi- bition of osteoclastic bone reabsorption. Dexamethasone, in combination wit h thalidomide, is useful in t reat ment of t he myeloma, wit h a slower effect on the calcium level. Erythropoietin is inappropriate and is used to increase synt hesis of red blood cells in t hose wit h renal failure. It is appropriat e t o t reat ch r on ic h epat it is B an d as an adjuvant t o su r gical t r eat m ent for malign ant melanoma. Both sarcoidosis and lymphoma can present with cough, dyspnea, and hilar adenopathy on chest x-ray.
Some drugs is composed of representatives of medical and pharmacy are found to have other clinical uses after the drug has been colleges and societies from each state buy cheap proscar 5 mg on line prostate foundation. These indications are known as information on the chemical analysis of drugs and indicates unlabeled or “off-label” uses buy 5 mg proscar prostate cancer xenograft mouse model. In some cases generic proscar 5mg with visa prostate oncology 360, manufacturers will 110% of the labeled amount of acetylsalicylic acid (aspirin). This was done for tion and many other aspects of drug product composition the antidepressant bupropion, the exact same drug mar- and analysis. Postmarketing surveillance is particularly Amendments to the Food, Drug, and Cosmetic Act. One type concerns drug safety and effcacy determined to be unsafe for use without the supervision of and regulates the processes by which drugs are evaluated, a designated health care professional. The other type focuses on the pre been marketed for a period of time or if it is found to be vention of drug abuse. The Act was passed in response to the The KefauverHarris Amendments were passed in 1962, sale of patent medicines, often by so-called “snake-oil sales- largely in response to reports of severe malformations in men,” which contained toxic or habit-forming ingredients. Nevertheless, the shocking pictures regulate fraudulent advertising, the legislation was only par- from Europe of deformed babies spurred Congress to tially successful in eliminating unsafe drug products. Examples are drugs Chapter 4 y Drug Development and Safety 37 used for the treatment of urea cycle enzyme defciencies, synthesis of this potent and rapid-acting derivative of mor- Gaucher disease, homocystinuria, and other rare metabolic phine. The Har- Drug Price Competition and Patent Term rison Narcotics Act had a profound and controversial effect Restoration Act on the treatment of substance abuse in that it prohibited The Drug Price Competition and Patent Term Restora physicians from administering opioid drugs to drug- tion Act of 1984 extended the patent life of drug products dependent patients as part of their treatment program. Believing that the drug abuse problem required a new range (usually ±20%), the generic drug may be approved for approach, members of Congress passed the Comprehensive marketing. The cost of such a study is relatively small com- Drug Abuse Prevention and Control Act of 1970. Note that many states have legalized the medical use of marijuana, although federally it is still illegal to use marijuana for medicinal purposes. Examples are hemolytic anemia, thrombocytope- Adverse effects, or side effects, can be classifed with respect nia, and drug-induced lupus erythematosus. The deposition caused by excessive pharmacologic activity are the most of antigen-antibody complexes in vascular endothelium predictable and are often the easiest to prevent or counteract. An example is the severe skin rash seen in patients unpredictable, because its occurrence depends on the drug with a life-threatening form of drug-induced immune vas- susceptibility of the individual patient, the drug dosage, culitis that is known as Stevens-Johnson syndrome. Hypersensitivity reactions are reactions are delayed hypersensitivity reactions that are responsible for a large number of adverse organ system mediated by sensitized lymphocytes. These reactions occur frequently with some drugs ampicillin-induced skin rash that occurs in patients with but only rarely with others. Excessive Pharmacologic Effects Adverse Effects on Organs Drugs often produce adverse effects by the same mechanism In some cases the adverse effects and therapeutic effects of that is responsible for their therapeutic effect on the target a drug are caused by different mechanisms. For example, atropine may cause dry mouth and patients taking aspirin, the adverse reaction such as hyper- urinary retention by the same mechanism that reduces ventilation that leads to respiratory alkalosis is caused by gastric acid secretion in the treatment of peptic ulcer, namely, adverse effects that do not appear to be mediated by the by muscarinic receptor antagonism. This type of adverse drug’s primary mechanism of action, which is inhibition of effect may be managed by reducing the drug dosage or by prostaglandin synthesis. A variety of drugs (Table 4-2) substituting a drug that is more selective for the target organ. Patients receiving these Hypersensitivity reactions, or drug allergies, are respon- drugs should be monitored with appropriate laboratory sible for a large number of organ toxicities that range in tests. For example, hepatotoxicity may be detected by severity from a mild skin rash to major organ system failure. The antigen and antibody subsequently interact with body tissues to produce a wide Hematopoietic Toxicity variety of adverse effects. Bone marrow toxicity, one of the most frequent types of In the Gell and Coombs classifcation system, allergic drug-induced toxicity, may manifest as agranulocytosis, reactions are divided into four general types, each of which anemia, thrombocytopenia, or a combination of these (pan- can be produced by drugs. The effects are often reversible when the drug is hypersensitivity reactions that are mediated by immuno- withdrawn, but they may have serious consequences before globulin E antibodies. Chapter 4 y Drug Development and Safety 39 agranulocytosis may succumb to a fatal infection before the Other Organ Toxicities problem is recognized. Many drugs, such as chloramphenicol, are believed to Some drugs, such as opioid analgesics, cause respiratory cause hematopoietic toxicity by triggering hypersensitivity depression via their effects on the brain stem respiratory reactions directed against the stem cells in bone marrow or centers. Chloramphenicol also produces a reversible monary fbrosis, so patients who are being treated with these form of anemia by blocking the action of the enzyme fer- agents should have periodic chest radiographs and blood gas rochelatase and thereby preventing the incorporation of iron measurements to detect early signs of fbrosis. Anthracy- The most serious form of hematopoietic toxicity is aplas cline anticancer drugs, such as doxorubicin (Adriamycin), tic anemia, which may be associated with several types of produce adverse cardiac effects that resemble congestive blood cell defciencies and lead to pancytopenia. This can result in muscle pain and by administration of hematopoietic growth factors (see sometimes leads to rhabdomyolysis and renal failure. Skin rashes of all varieties, including macular, papular, maculopapular, and urticarial rashes, may be produced by Hepatotoxicity drug hypersensitivity reactions. A mild skin rash may dis- A large number of drugs produce liver toxicity, either via an appear with continued drug administration. Nevertheless, immunologic mechanism or via their direct effect on the because rashes may lead to more serious skin or organ toxic- hepatocytes. Liver toxicity can be classifed as cholestatic or ity, they should be monitored carefully. Cholestatic hepatotoxicity is often caused by a hypersensitivity mechanism producing infammation Idiosyncratic Reactions and stasis of the biliary system. Hepatocellular toxicity is Idiosyncratic reactions are unexpected drug reactions caused sometimes caused by a toxic drug metabolite. For example, acetaminophen and isoniazid have toxic metabolites that patients who have glucose-6-phosphate dehydrogenase may cause hepatitis. With many hepatotoxic drugs, elevated defciency may develop hemolytic anemia when they are serum transaminase levels may provide an early indication exposed to an oxidizing drug such as primaquine or to a of liver damage, and levels should be monitored during the sulfonamide. If transaminase levels exceed three times the rently with another drug or with food. Unfor- may be caused by changes in the pharmaceutical, pharma- tunately, some patients have developed acute hepatic failure codynamic, or pharmacokinetic properties of the affected even when serum transaminase levels have been monitored drug (Table 4-3). In recent years, several drugs such as trogli tazone, used to treat diabetes, have been removed from the Pharmaceutical Interactions market as a result of excessive cases of fatal hepatic failure. Pharmaceutical interactions are caused by a chemical reac- tion between drugs before their administration or absorp Nephrotoxicity tion. Pharmaceutical interactions occur most frequently Renal toxicity is caused by various drugs, including several when drug solutions are combined before they are given groups of antibiotics. For example, if a penicillin solution and an classifed according to site and mechanism and include aminoglycoside solution are mixed, they will form an inso- interstitial nephritis, renal tubular necrosis, and crystal luble precipitate, because penicillins are negatively charged luria (the precipitation of insoluble drug in the renal and aminoglycosides are positively charged. Nephrotoxicity often reduces drug clearance, drugs are incompatible and should not be combined before thereby elevating plasma drug concentrations and leading they are administered.