Current concepts in clinical therapeutics: asthma

The epidemiology, etiology, pathophysiology, diagnosis, and treatment of asthma are reviewed, and the major drugs used in treating asthma are discussed in depth. In terms of morbidity, mortality, and economic impact, asthma is a serious disease. About nine million Americans suffer from it, and in a recent year nearly 2000 people died from it. The underlying mechanism of asthma appears to be a hyperreactivity of the airways to certain stimuli, including environmental irritants, exercise, and psychological factors. The symptoms of asthma are caused by spasm of airway smooth muscle, increased mucus secretion, and inflammation. Asthma may be classified as intermittent (patients with extended symptom-free periods) or chronic (patients with frequent exacerbations). Diagnosis of asthma relies heavily on a comprehensive patient history confirmed with objective physiologic data. Acute or intermittent asthma should be treated first with inhaled beta 2 agonists such as albuterol or terbutaline. Corticosteroids should be started if the response to the beta 2 agonists is inadequate, and theophylline may be used while waiting for the steroids to exert an effect. Adequate hydration, correction of metabolic acidosis, and oxygen are essential supportive measures. Theophylline appears to be the best noncorticosteroid for chronic asthma, although cromolyn is an acceptable alternative. Sympathomimetic bronchodilator therapy and corticosteroids may be needed adjunctively. Immunotherapy is indicated in patients with chronic asthma caused by specific allergens and poorly controlled on theophylline or cromolyn. Asthma is best managed using multiple pharmacologic agents in response to specific events and symptoms, making optimal therapy difficult to achieve and sometimes difficult to define.     

Current concepts in clinical therapeutics: testicular cancer

The incidence and epidemiology, pathophysiology, diagnosis and staging, and therapy of testicular cancer are reviewed. Although relatively rare, testicular cancer is an important disease because it is the first disseminated solid tumor occurring in adults for which truly effective therapy has been developed. More than 90% of testicular neoplasms are of germ-cell origin; about 40% of cases involve pure seminoma, 15%-20% are pure embryonal carcinoma, and the rest are of mixed types. Clinically, the major distinction is between pure seminoma and other types because of therapeutic differences. Most men with testicular neoplasms initially complain of a painless testicular mass. Surgical exploration follows, with orchiectomy and complete excision of the spermatic cord if a neoplasm is documented. Seminoma is a highly radiosensitive tumor, and overall cure rates now approach 95%-98%. Combination therapy with cisplatin has been effective in treating patients with extensive disease. Nonseminomatous testicular cancer patients who do not have metastases are treated with a traditional orchiectomy and retroperitoneal lymph-node dissection; about 10% of patients will relapse and must be treated with antineoplastic agents. Patients with disseminated disease require systemic treatment with cisplatin-based combination drug therapy. Reduction of toxicity and identification of patients who can be spared extensive treatment are the current thrusts of research; efficacy is excellent for several regimens. Major advances have been made over the last two decades in curing patients with testicular cancer.     

Current concepts in clinical therapeutics: pressure sores

The etiology, pathophysiology, clinical presentation, prevention, management, and complications of pressure sores are reviewed. Three specific patient populations are at high risk of developing pressure sores: spinal-cord-injury, geriatric long-term-care, and orthopedic patients. Pressure sores usually develop at bony prominences on the body as a result of four etiologic elements: pressure, shearing forces, friction, and moisture. Excessive pressure causes poor tissue perfusion, which is normally compensated for by shifts in body position. However, in these patient populations, various abnormalities prevent patients from recognizing or compensating for this pressure. Once a lesion forms, it may progress through four stages marked by worsening necrosis, infection, and tissue loss. The best treatment of pressure sores is prevention. Various mechanical devices may assist the patient in decreasing or distributing pressure, but quality nursing care is essential for debilitated or disabled patients. If a pressure sore develops, treatment should focus on (1) eliminating local pressure, (2) cleaning and removing necrotic tissue, (3) creating a tissue-growth environment, and (4) treating factors that retard wound healing. Drug therapy includes agents for chemical cleansing and debridement of pressure sores and systemic antibiotics for complications such as septicemia or osteomyelitis. Despite efforts to improve treatment of pressure sores, prevention remains the best treatment.     

Current concepts in clinical therapeutics: Parkinson's disease

The etiology, pathophysiology, diagnosis and clinical presentation, and clinical management of Parkinson's disease are reviewed. The cause of Parkinson's disease, a progressive, degenerative neurologic motor disorder, is unknown. Both endogenous and environmental factors appear to play a role. The clinical features of parkinsonism result from a depletion in dopaminergic transmission in the corpus striatum; the dopamine deficiency is caused by a loss of melanin-containing nerve cells within the substantia nigra and locus ceruleus. In the remaining neurons, hyalin-like masses called Lewy bodies increase in number, but the importance of this is unclear. The diagnosis of Parkinson's disease is based on the clinical presentation of the patient, which initially includes sensory complaints of aching pains, paresthesias, numbness, and coldness. As the disease progresses, the four classic symptoms become prominent: tremor, rigidity, bradykinesia, and postural difficulties. Drug therapy is the cornerstone of clinical management of Parkinson's disease, but no treatment has been found that will retard or reverse the disease. Therapy is usually initiated with anticholinergic agents such as biperiden hydrochloride or trihexyphenidyl hydrochloride with or without amantadine. The mainstay of therapy is levodopa, which is used in combination with dopa decarboxylase inhibitors to decrease the peripheral conversion of levodopa to dopamine. Bromocriptine is a dopamine agonist useful in treating Parkinson's disease. Therapy, which must continue for life, eventually becomes less effective or completely ineffective in all patients. Drug therapy has improved greatly the functional ability of patients with Parkinson's disease, but new agents that can extend the length of effective treatment or reverse the disease are needed.     

Current concepts in clinical therapeutics: intra-abdominal infections

The etiology, pathophysiology, clinical presentation, and treatment of the two major types of intra-abdominal infections--peritonitis and abscesses--are described. Peritonitis of infectious origin is the acute response of the peritoneum to microorganisms; it is classified as primary (when the source of bacteria is not apparent) or secondary (usually involving perforation of a hollow structure of the GI tract with subsequent release of microbes). Peritonitis results in mortality because of fluid shifts and endotoxins that may cause hypovolemia and shock. Abscesses, purulent collections of fluid physically separated from the surrounding tissues, are the result of chronic inflammation following failure of the body to eradicate a pathogen completely. Secondary intra-abdominal infections are often polymicrobial because of the diversity of organisms in the GI tract. The size of bacterial inocula and the number and types of species present substantially affect patient outcome. The patient with peritonitis usually presents in acute distress, with generalized abdominal pain and faint bowel sounds. The presentation of the patient with intra-abdominal abscess is more variable and less dramatic; pain and fever may be present. The treatment of these infections requires the coordinated use of prompt surgical intervention, support of vital functions, and appropriate antimicrobial therapy. Surgical procedures are used to stop continuing bacterial contamination of the peritoneum, remove foreign material from the abdomen, and drain purulent collections; it is the foundation of treating most types of intra-abdominal infections. Aggressive fluid therapy is required to assure adequate intravascular volumes in most patients. Generally, antimicrobial coverage for both aerobes and anaerobes must be started before culture results are available. Antimicrobial therapy for specific types of infections is given in the article. Surgical procedures are the foundation of treatment of most intra-abdominal infections; antimicrobial agents active against aerobic gram-negative bacilli and anaerobes are important adjuncts.     

Current concepts in clinical therapeutics: congestive heart failure

The epidemiology and etiology, pathophysiology, diagnosis, and treatment of congestive heart failure (CHF) are reviewed. CHF affects as many as 4 million Americans and is one of the most prevalent causes of death in hospitalized patients. Major risk factors for developing CHF include advanced age, male sex, hypertension, coronary artery disease, smoking, hypercholesterolemia, diabetes mellitus, and rheumatic heart disease. Heart failure results from decreased intrinsic myocardial contractility caused by one or more of three changes: (1) altered adrenergic nervous system function, (2) impaired delivery of calcium to contractile elements in the heart, and (3) reduced myosin-ATPase activity in the myocardium. The disease is progressive, and no intervention has yet been found to stop it effectively. CHF is diagnosed based on subjective signs and symptoms and objective assessment using auscultation, ECG, chest roentgenogram, laboratory tests, and noninvasive and invasive tests. Treatment of CHF begins with restriction of physical activity and sodium intake. Pharmacologic interventions start with either digitalis glycosides or thiazide diuretics; both may be used concomitantly as the disease progresses. Current studies are focusing on the use of angiotensin-converting enzyme inhibitors as first-line agents for CHF. When CHF worsens, loop diuretics are substituted for or added to the thiazide diuretics, and vasodilators are added to reduce the workload on the heart. Other inotropic agents, including the new bipyridine derivatives, may also be used. In patients not responding to these and other aggressive therapeutic interventions, cardiac transplantation is the only option. Despite advances in management of CHF, little improvement in overall survival has been demonstrated, and no intervention has stopped or reversed the progression of CHF.     

Current concepts in clinical therapeutics: acute myocardial infarction

The epidemiology and etiology, pathophysiology, diagnosis, clinical presentation, complications, and treatment of acute myocardial infarction (AMI) are reviewed. Major risk factors for AMI include age, sex (men greater than women), family history, race, hyperlipidemia, hypertension, cigarette smoking, diabetes mellitus, and diet. AMI occurs when there is a prolonged decrease in oxygen supply to the myocardium caused by coronary thrombosis or coronary vascular spasm. Traditional drug treatment of uncomplicated AMI includes oxygen, laxatives, and analgesics. For analgesia, narcotic agonists are generally preferred, although intravenous nitroglycerin is of value for both reducing infarct size and relieving pain. Fibrinolytic therapy is also indicated in these patients. Low-dose heparin should be initiated on admission to the hospital. Beta-adrenergic blocking agents have proven useful in reducing the incidence of ventricular fibrillation and sudden death. Antiplatelet agents may also be used to decrease long-term mortality. Recent studies have focused on reduction of infarct size using agents such as beta blockers, calcium-channel blockers, nitroglycerin, and thrombolytics. Revascularization procedures are required in some patients to re-establish adequate coronary perfusion. Most patients who survive AMI initially have a relatively uncomplicated clinical course. An increasing number of therapeutic interventions are available for acute and chronic treatment of AMI.     

Current concepts in clinical therapeutics: ischemic cerebrovascular disease

The classification, epidemiology, pathophysiology, diagnosis, and treatment of ischemic cerebrovascular disease (ischemic stroke) are reviewed, and the major drugs used in the prevention of this disease are discussed. Ischemic stroke is a major problem in terms of morbidity and mortality because of the high prevalence of atherosclerosis in the United States population. The pathogenesis of cerebral ischemia is multifactorial, beginning with an atherosclerotic plaque on the arterial wall that may result in stenosis or ulceration with subsequent thrombosis or embolization. Platelets may adhere to the exposed arterial wall endothelium, stimulating further platelet aggregation and accumulation of leukocytes and fibrin. Consequences of cerebral ischemia include transient ischemic attacks and brain infarcts. Diagnosis is based mainly on patient history and ancillary radiologic studies. Treatment of ischemic cerebrovascular disease is primarily preventive, since the brain has limited capacity to recover neurologic function after an infarction. Transient ischemic attacks are treated with either antiplatelet agents, anticoagulants, or surgery. Treatment of stroke is also preventive, although anticoagulation is sometimes used to prevent stroke progression. Agents that may reverse neurologic impairment following an acute stroke, such as prostacyclin, calcium-channel blockers, and opiate antagonists, are being investigated. Antiplatelet therapy is indicated in subsets of patients with cerebral vascular insufficiency. Anticoagulation therapy, if needed, should be given for only three to four months.     

Current concepts in clinical therapeutics: peptic ulcer disease

The epidemiology, pathophysiology, diagnosis, clinical presentation, and treatment of peptic ulcer disease (PUD) are reviewed. PUD occurs commonly, with about 4 million Americans affected in a year. Cigarette smoking, aspirin use, and prolonged corticosteroid use are associated with PUD. The disease's etiology is multifactorial; the long-held assumption that ulcers develop solely because of increased gastric acid secretion is no longer valid. Although duodenal ulcer patients are frequently hypersecretors of acid, gastric ulcer patients more commonly have defective mechanisms for protecting the mucosal lining from acid, pepsin, and other agents. PUD is best diagnosed using an upper gastrointestinal roentgenographic series or using endoscopy. The clinical presentations, which involve epigastric abdominal pain that is relieved by food, milk, or antacids, may aid in diagnosis but are not usually definitive. Treatment is designed to relieve symptoms, heal the ulcer, prevent recurrences, and prevent complications. Of the four currently available drug treatments (cimetidine, ranitidine, antacids, and sucralfate), the treatment of first choice is cimetidine or ranitidine for four or six weeks, respectively, for duodenal and gastric ulcer patients. Antacids should be used as needed for pain, and the patient should be reassessed at the end of this period. For most patients, neither cimetidine nor ranitidine is demonstrably superior to one another. Several agents are under investigation in the U.S., including other H2-receptor antagonists (famotidine and nizatidine), proton-pump inhibitors (omeprazole), prostaglandins (misoprostol, arbasprostil, enprostil, and trimoprostil), antimuscarinic agents (pirenzepine), and tricyclic antidepressants (doxepin and trimipramine). peptic ulcer disease is an important disease. It is best treated with H2-receptor antagonists supplemented with antacids as needed for pain.     

Current concepts in the treatment of rheumatoid arthritis

The treatment of RA is complex and often frustrating. The pathologic process of RA is composed of acute inflammation, chronic immunologic phenomenon, and chronic connective tissue degradation. It is important to understand not only the pathophysiology of RA but also the mechanism of action of our therapeutic drugs so that treatment can be tailored to affect the important aspects of the process leading to end-organ damage. Despite the many drugs available, therapy is still unsatisfactory. Many drugs work in only certain patients. This could be secondary to variability in the disease state or to difference in drug metabolism. A better understanding of both disease and therapeutic agents may lead to better use of our present agents and development of new, more effective treatment modalities.     

Current concepts in clinical therapeutics: anxiety disorders, Part 1

The diagnosis, epidemiology, classification and clinical presentation, pathophysiology, and treatment of anxiety disorders are reviewed. Anxiety disorders, among the most common mental disorders, must be differentiated from medical diseases with anxious symptoms. A complete physical and mental status examination, as well as a thorough knowledge of the patient's medical, psychiatric, and drug history are required. Epidemiologic studies indicate an incidence of 4-8% in the United States. There are four categories of anxiety disorders: phobic disorders, anxiety states, posttraumatic stress disorders, and atypical anxiety disorders. Several psychoanalytic, behavioral, and cognitive theories have been advanced to explain the pathophysiologic mechanisms causing anxiety disorders. Of most interest are the biological theories involving the catecholamine neurotransmitter norepinephrine and the benzodiazepine receptor. Proper treatment for anxiety disorders involves nonpharmacologic and pharmacologic approaches. The benzodiazepines are widely used and are the mainstay of drug treatment for patients with situational anxiety and generalized anxiety disorder. However, problems with sedation, complications of drug withdrawal, and patients' fear of drug dependency may limit clinical usefulness. Buspirone is the first nonbenzodiazepine anxiolytic to be introduced in the United States in more than 25 years. Its unique role in treating anxiety, compared with the benzodiazepines, may include less sedation, minimal drug abuse potential, and fewer withdrawal symptoms upon drug discontinuation. Nonpharmacologic therapy is used extensively in the treatment of phobic disorders (simple and social phobia). Important advances in the diagnosis and treatment of anxiety disorders have been made. An accurate diagnosis is essential for optimal management. Unfortunately, many anxious patients do not seek treatment and some do not receive the most appropriate treatment.     

Approaches to the treatment of early rheumatoid arthritis with disease-modifying antirheumatic drugs

This paper reviews recent approaches to treatment of early rheumatoid arthritis (RA) with disease-modifying antirheumatic drugs (DMARDs). The literature on treatment the early RA published between 1995 and 2007 was accessed through the PubMed database from the National Library of Medicine. Keywords were 'early rheumatoid arthritis', 'disease-modifying antirheumatic drugs', 'biologic agents' and 'combination therapy'. Only results of trials on human subjects that directly measured the effects of DMARDs or biological agents on clinical, laboratory parameters and radiological progression of early RA were selected. Combination therapy suppresses RA activity and radiological progression more effectively than monotherapy. If better control of RA is evident after 3–6 months of treatment with the combination of DMARDs, one must still decide whether to stop the first DMARD, stop the second, or continue with the combination. Combination therapy biological agents (infliximab, adalimumab) with methotrexate and etanercept therapy alone may induce remission in many patients with early RA. It is a method of choice in patients with an adverse prognosis. The main indications for combination therapy 'standard' DMARDs or combination 1 DMARDs with a biological agent are such variables as detection of a shared epitope, increase of concentration of anticyclic citrullinated peptide antibodies, rheumatoid factor, C-reactive protein, 28-joint disease activity score, Sharp score and presence of erosion in joints. The majority of rheumatologists believe that patients with RA should be treated with DMARDs earlier rather than later in the disease process. Further trials should establish the optimal approaches to early RA therapy.     

Current concepts in clinical therapeutics: drug therapy in acute renal failure

The etiology and classification, pathophysiology, diagnosis, clinical course, and drug therapy of acute renal failure (ARF) are reviewed. ARF, a rapid reduction in kidney function that results in decreased glomerular filtration rate and tubular function, is caused by many different factors and can cause multiple organ dysfunction. The major causes of ARF are classically divided into three broad categories: (1) prerenal, or hypoperfusion states, (2) intrarenal, or intrinsic renal parenchymal disease, and (3) post-renal, or urinary obstructive disorders. The underlying pathogenic abnormality is renal tubular cell damage in patients with prerenal azotemia; vascular and glomerular damage is often secondary to immunologic mechanisms. Interstitial nephritis, often drug-induced, results from an immunologically mediated inflammatory renal response. Obstructive nephropathy results from partial or complete blockade of urine flow. Diagnosis relies heavily on patient history and physical examination; laboratory data, renal imaging, and sometimes renal biopsy results can yield important clues. The clinical course of ARF consists of four phases: insult and onset, maintenance, diuresis, and recovery. Morbidity and mortality are high. Drug therapy is directed at preventing or reversing the renal lesion before ARF becomes established and supporting the patient to allow the body to correct the lesion once it occurs. Prevention of prerenal azotemia and intrarenal disease is directed at identifying patients at risk, minimizing nephrotoxicity, and maintaining adequate urine output. In patients with established renal failure, an appropriate intravascular volume and pressure must be re-established and underlying problems must be corrected. Fluid, electrolyte, and acid-base balance are critical, and other serious effects on the gastrointestinal and neurologic systems must be addressed. Even though morbidity and mortality remain unacceptably high in patients with acute renal failure, promising progress has been made during the last 20-30 years.     

Current concepts in clinical therapeutics: bacterial meningitis in infants and children

The epidemiology and incidence, etiology, pathogenesis and pathophysiology, clinical presentation, diagnosis, principles of therapy, and treatment of bacterial meningitis in infants and children are reviewed. Bacterial meningitis is a major cause of morbidity and mortality, and most cases occur in children less than five years old. Haemophilus influenzae type b, Neisseria meningitidis, and Streptococcus pneumoniae are the major pathogens involved. Bacteremia or colonization of the upper-respiratory-tract epithelium often precedes meningitis. Defense mechanisms are poor in the cerebrospinal fluid; once an organism penetrates the blood-brain barrier, infection may follow quickly. Clinical signs and symptoms are somewhat nonspecific, with lethargy, restlessness, and poor feeding prominent; diagnosis often relies on the patient history along with preliminary results of lumbar punctures. Therapy is based on pharmacologic and pharmacodynamic principles concerning the available antimicrobial agents, the blood-brain barrier, and supportive therapy. Effective antimicrobial therapy requires attainment of adequate bactericidal activity in the cerebrospinal fluid; penetration of agents into the brain depends on their physico-chemical characteristics. Antibiotic therapy must generally be started before culture results are available, making empiric therapy based on the child's age, history, and underlying conditions important. Established therapeutic agents include penicillins, aminoglycosides, and chloramphenicol, though newer expanded-spectrum cephalosporins such as cefuroxime, ceftriaxone, and cefotaxime are being used with increasing frequency. However, the use of these newer, more potent antimicrobial agents have not appreciably altered associated morbidity and mortality. Aggressive supportive care and evaluation of newer nonantibiotic treatments should be addressed in future studies of bacterial meningitis in infants and children.     

Current concepts in clinical therapeutics: major affective disorders, Part 1

The epidemiology, pathophysiology, diagnosis and clinical features, and treatment of unipolar (depressive) and bipolar (manic-depressive) affective disorders are described. Disturbances of mood are the most common psychiatric disorders in adults, with 18-23% of women and 8-11% of men having at least one major depressive episode. Genetic factors are important in both depression and manic-depressive illness. Depression is characterized by a persistent dysphoric mood accompanied by feelings of sadness or hopelessness nearly every day for at least two weeks. The essential feature of a manic episode is an elevated, expansive, or irritable mood associated with symptoms such as hyperactivity and lack of judgment. Treatment involves nonpharmacologic and pharmacologic interventions. Psychotherapy in patients with depression is most useful in improving social functions, while antidepressant drugs reduce relapse rates. Electroconvulsive therapy is indicated in depressed patients at immediate risk of suicide or extreme incapacitation. Tricyclic antidepressants (amitriptyline, imipramine, doxepin, notriptyline, desipramine, trimipramine), second-generation antidepressants (maprotiline, amoxapine, trazodone, bupropion), monoamine-oxidase inhibitors (phenelzine, isocarboxazid, tranylcypromine, pargyline), and lithium are useful in treating patients with affective disorders. Tricyclic agents are the mainstay of treatment for depression; newer second-generation agents should be used in specific subgroups of patients. Lithium is the drug of choice for prophylaxis in bipolar patients, whereas combinations of lithium and tricyclic agents are useful during acute episodes of depression in bipolar patients. Major affective disorders occur commonly and require a careful balance of pharmacologic and nonpharmacologic interventions for proper therapy.     

Tachykinin receptor modulators: novel therapeutics for rheumatoid arthritis

The activation of a cellular immune response in a genetically susceptible individual is widely recognised as a main step in triggering rheumatoid arthritis (RA). The tachykinins, substance P (SP) and neurokinin A (NKA), can play a major role in different immune diseases. In patients with inflammatory joint disease, elevated levels of SP have been demonstrated in the synovial fluid of affected joints. It is well known that SP and, to a lesser extent, NKA are deeply involved in the processing of nociceptive signals and exert many pro-inflammatory actions, which may be elicited by an increased neuronal neurokinin release in arthritis; the mechanism behind this increase remains to be fully elucidated. Different observations suggest that one approach to the treatment of RA might be to inhibit the local effects of neurokinins in the affected joints. This review will summarise the more relevant aspects of this topic.     

Tachykinin receptor modulators: novel therapeutics for rheumatoid arthritis

The activation of a cellular immune response in a genetically susceptible individual is widely recognised as a main step in triggering rheumatoid arthritis (RA). The tachykinins, substance P (SP) and neurokinin A (NKA), can play a major role in different immune diseases. In patients with inflammatory joint disease, elevated levels of SP have been demonstrated in the synovial fluid of affected joints. It is well known that SP and, to a lesser extent, NKA are deeply involved in the processing of nociceptive signals and exert many pro-inflammatory actions, which may be elicited by an increased neuronal neurokinin release in arthritis; the mechanism behind this increase remains to be fully elucidated. Different observations suggest that one approach to the treatment of RA might be to inhibit the local effects of neurokinins in the affected joints. This review will summarise the more relevant aspects of this topic.