By T. Frithjof. Bastyr University.

The most common are nausea buy provera american express menstrual bleeding for a month, vomiting buy cheap provera menopause rash, fatigue order provera 2.5 mg overnight delivery questions menstrual cycle, anorexia buy provera now menstrual 6 days early, taste disturbance, and hematologic deficits: anemia, leukopenia, and thrombocytopenia. Romidepsin can harm the developing fetus and hence should not be used during pregnancy. In contrast to vorinostat, romidepsin has not been associated with pulmonary embolism. Romidepsin binds with receptors for estrogen and can thereby reduce the effects of estrogen-containing contraceptives. Ipilimumab Ipilimumab [Yervoy] is indicated for unresectable or metastatic melanoma. By promoting T-cell activation and proliferation, ipilimumab can cause severe or fatal immune-mediated effects. Among these are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathies (both motor and sensory), and endocrinopathies (e. If a severe immune-mediated reaction is diagnosed, ipilimumab should be immediately and permanently discontinued, and patients should be treated with high-dose systemic glucocorticoids. Interferon Alfa-2b Interferons are naturally occurring proteins with complex antiviral, anticancer, and immunomodulatory actions. Release of endogenous interferons is triggered by viral infections and other stimuli. Interferons are active against a variety of solid tumors and hematologic malignancies. Discussion here is limited to two interferons: interferon alfa-2b [Intron A] and peginterferon alfa-2b [Sylatron]. Anticancer effects of interferon alfa-2b are thought to result from two basic processes: (1) enhancement of host immune responses and (2) direct antiproliferative effects on cancer cells. Both processes are mediated by binding of interferon alfa-2b to cell-surface receptors, with resultant increased expression of certain genes and reduced expression of others. In addition, it can cause0 proliferating cells to differentiate into nonproliferative mature forms. The most common is a flu- like syndrome characterized by fever, fatigue, myalgia, headache, and chills. Other common effects include anorexia, weight loss, diarrhea, abdominal pain, dizziness, and cough. Prolonged or high-dose therapy can cause fatigue, cardiotoxicity, thyroid dysfunction, and bone marrow suppression, manifesting as neutropenia and thrombocytopenia. Neuropsychiatric effects—especially depression—are a serious concern, owing to a risk for death by suicide. The pharmacology of interferon alfa-2b and peginterferon alfa-2b is discussed in Chapter 78. Because severe adverse effects occur often, the drug must be administered in a hospital that has an intensive care facility; a specialist in cardiopulmonary or intensive care medicine must be available. These powerful immunostimulant actions are believed to underlie antitumor effects. Therapeutic Use Aldesleukin has two approved uses: metastatic renal cell carcinoma and metastatic melanoma. Among patients with renal cell cancer, 4% respond completely and 11% respond partially. About 70% of each dose undergoes preferential uptake by the liver, kidneys, and lungs. Renal enzymes convert the drug into inactive metabolites, which are excreted in the urine. Effects seen most frequently are fever and chills, nausea and vomiting, hypotension, anemia, diarrhea, altered mental status, sinus tachycardia, impaired renal function, impaired liver function, pulmonary congestion, dyspnea, and pruritus. This potentially fatal reaction is characterized by hypotension and reduced organ perfusion (secondary to loss of vascular tone and extravasation of plasma proteins and fluid). The vaccine is approved for primary and relapsed carcinoma in situ of the bladder, in both the presence and absence of associated papillary tumors. Instillation in the bladder produces a local inflammatory response that, by an unknown mechanism, promotes regression of tumors in the urothelial lining. Adverse Effects The most common adverse effects, which result from bladder irritation, are dysuria, urinary frequency, urinary urgency, and hematuria. Accordingly, the vaccine is contraindicated for (1) immunocompromised patients (e. All materials employed during administration should be disposed of in plastic bags labeled “Infectious Waste. Other Noncytotoxic Anticancer Drugs Glucocorticoids The basic pharmacology of the glucocorticoids is discussed in Chapter 56. To benefit patients with cancer, dosages must be high, and hence, with long-term use, adverse effects are a concern. Specific indications are acute and chronic lymphocytic leukemias, Hodgkin disease, non- Hodgkin lymphomas, and multiple myeloma. Glucocorticoids are beneficial in these cancers because they are directly toxic to lymphoid tissues: high-dose therapy causes suppression of mitosis, dissolution of lymphocytes, regression of lymphatic tissue, and cell death. In addition to their use against lymphoid-derived cancers, glucocorticoids are used to manage complications of cancer and cancer therapy. Specific benefits include suppression of chemotherapy-induced nausea and vomiting, reduction of cerebral edema (caused by brain metastasis and irradiation to the brain), reduction of pain (caused by nerve compression or edema), and suppression of hypercalcemia in patients with steroid-responsive tumors. Retinoids Retinoids are derivatives of retinol (vitamin A) that bind to and activate retinoid receptors. In their active state, retinoid receptors regulate the proliferation and differentiation of cells, both normal and neoplastic. When alitretinoin is added to Kaposi sarcoma cells in culture, it inhibits their growth. The drug should be applied only to cutaneous Kaposi sarcoma lesions, not to normal skin. After application, the area should be allowed to dry for 3 to 5 minutes before putting clothing over it. Local reactions— erythema, scaling, irritation, rash, and dermatitis—occur in 25% to 77% of patients. Although photosensitivity has not been reported with alitretinoin, exposing the treated area to sunlight or sunlamps should nonetheless be minimized. Accordingly, women using alitretinoin should avoid getting pregnant (even though systemic absorption of alitretinoin appears to be minimal). Bexarotene Mechanism and Use Bexarotene [Targretin] is indicated for oral therapy of cutaneous T-cell lymphoma in patients who have been refractory to prior systemic therapy. Like alitretinoin, bexarotene is an analog of vitamin A (retinol) and can activate retinoid receptors. Sixty percent of patients have significant elevations in total cholesterol and low-density lipoprotein cholesterol. Bexarotene frequently causes headache, asthenia, leukopenia, anemia, infection, rash, and photosensitivity. Unfortunately, although tretinoin can be very effective, it can also cause severe toxicity, and hence the benefits of treatment must be carefully weighed against the risks. The drug appears to work by reversing the blockade on myeloid differentiation and apoptosis and by inhibiting angiogenesis. Common side effects include nausea, vomiting, diarrhea, fatigue, edema, hyperglycemia, dyspnea, cough, rash, headache, and dizziness. An electrocardiogram should be obtained before treatment and at least weekly thereafter. In contrast to cytotoxic anticancer drugs, arsenic trioxide does not cause alopecia or mucositis. Denileukin can cause life-threatening hypersensitivity reactions and hence must be administered in a facility equipped for cardiopulmonary resuscitation. After the drug is bound, the diphtheria toxin moiety inhibits protein synthesis, causing cell death within hours. Prominent symptoms are hypotension, back pain, dyspnea, vasodilation, rash, chest pain, and tachycardia. Denileukin can cause potentially fatal capillary leak syndrome, characterized by hypoalbuminemia, edema, and hypotension. Serum albumin should be monitored, and, if it falls below 3 g/dL, the next round of treatment should be postponed. Symptoms include fever or chills, asthenia, nausea and vomiting, myalgia, and arthralgia. Denileukin can cause eye damage, manifesting as a decrease in color vision and vision acuity. Thalidomide Thalidomide [Thalomid] is a drug with complex pharmacologic actions, including the ability to cause severe birth defects. In the United States thalidomide has two approved indications: (1) erythema nodosum leprosum, a complication of leprosy; and (2) multiple myeloma, a cancer of the bone marrow. Anticancer effects are thought to derive from (1) effects on the immune system and (2) inhibition of angiogenesis. Compared with cytotoxic anticancer drugs, thalidomide is relatively well tolerated but can cause clinically important neuropathy, sedation, and constipation. In patients with multiple myeloma, the drug has caused deep vein thrombosis and pulmonary embolism. Like thalidomide, lenalidomide is teratogenic in primates and thus must not be used during pregnancy. To reduce risk, the drug is available only through a restricted distribution program, known as RevAssist, similar to the S. Progestins Two progestins can be employed to treat cancer: medroxyprogesterone acetate [Depo-Provera] and megestrol acetate [Megace].

It is also associated with a risk of life- which appears to increase the absorption of ergotamine and threatening retroperitoneal generic 10mg provera mastercard womens health 28 day fat blaster, pleural cheap provera 2.5mg amex breast cancer forum, and cardiac valve may also exert a mild vasoconstrictive effect that helps fbrosis generic 2.5 mg provera fast delivery menstruation tissue. The intranasal preparation provera 10mg with mastercard women's health center keokuk iowa, which was recently with periodic chest x-rays to detect early signs of fbrosis, approved by the U. It is moderately effective in preventing occurrence of given with an antiemetic drug, such as the dopamine recep- migraines with few adverse effects. It is further contraindicated in persons with coronary artery disease or discussed in Chapter 5. A rebound head- Numerous drugs can be used to terminate a migraine head- ache can last several days, and hospitalization may be ache after it has begun. To Chapter 29 y Drugs for Headache Disorders 311 prevent cumulative toxicity, daily use of ergotamine should According to some clinical trials, the newer triptans have be avoided. Concomitant use of ergot alkaloids and rates of headache recurrence are lower (30% for newer trip- β-adrenoceptor antagonists can cause severe peripheral tans versus 40% for sumatriptan). Naratriptan has a longer ischemia resulting from α-adrenoceptor–mediated vasocon- half-life than sumatriptan, and this may explain its lower striction that is unopposed by β2-adrenoceptor–mediated rate of headache recurrence. The incidence of adverse effects appears to ous and includes naratriptan, rizatriptan, and zolmitrip- be similar for all triptan drugs. Although these four triptans have amassed the most The triptans have been reported to cause abnormal tin- data on their effectiveness in aborting a migraine attack, gling or burning sensations (paresthesias) in the skin on newer agents, such as frovatriptan, almotriptan, and ele- various parts of the body. The newer triptans are similar to they can be mistaken for a serious adverse effect by the sumatriptan, but their improved pharmacokinetic properties patient. Almotriptan has the Triptan drugs can cause coronary vasospasm and should distinction of being the frst and only triptan agent to be not be used in patients with a history of angina pectoris, approved for use in both adults and adolescents. As used for the acute treatment of migraine headache pain in with ergots, triptan agents can increase blood pressure, so adolescents age 12 to 17 years with a history of migraine they should not be given to patients with uncontrolled attacks with or without aura usually lasting 4 hours or more hypertension. Combination formulations of sumatriptan are achieved most rapidly with subcutaneous acetaminophen, butalbital (a barbiturate), and caffeine are administration and least rapidly with oral administration. Relief of migraine usually takes an hour when sumatriptan Isometheptene, an agent that acts as a sympathomimetic, is given subcutaneously using an autoinjector (Alsuma) but can terminate migraine headaches. In comparison with sumat- Opioid analgesics can relieve the pain of migraine head- riptan, these newer triptan drugs are more lipophilic, have aches, but their use should be reserved for patients in whom higher oral bioavailabilities, and achieve higher concentra- other agents are contraindicated or ineffective. Butorphanol acts as an migraine headache disorder, subcutaneously administered agonist at κ opioid receptors and a mixed agonist-antagonist sumatriptan was found to relieve 85% of migraine attacks at µ opioid receptors. These measures include 312 Section V y Pharmacology of the Respiratory and Other Systems appropriate patient education; the identifcation and avoid- describe a searing or burning pain that arises behind one eye, ance of factors that contribute to migraine attacks, including occurs without warning, and can be excruciating. Pain often particular foods, beverages, and environmental factors; bio- lasts from 15 minutes to 3 hours and usually occurs at the feedback and relaxation therapy; and psychotherapy. Unlike patients with migraine head- puncture and physiotherapy may be benefcial, but their aches, who are highly sensitive to movement and external effcacy has not been established in controlled, clinical trials. The effcacy of these agents varies from face to provide distraction from the pain. The incidence of patient to patient, however, so fnding a drug that works well cluster headache disorder is low, however; it affects less than is largely a matter of trial and error. For Drugs to prevent cluster headaches include verapamil example, β-blockers have negative effects on cardiac output, (see Chapter 11), and lithium (see Chapter 22). As with so they are usually less suitable than other drugs for competi- migraine headaches, cluster headaches can be aborted by tive athletes. Other the frequency of migraine attacks by at least 50%, and the agents that are effective in aborting cluster headaches include criteria for evaluating the effcacy of particular drugs should inhaled oxygen, intranasal lidocaine, and glucocorticoids. It usually takes 3 to 4 weeks of therapy before the aches are similar to those outlined previously for migraine beneft of a given drug is observed, so authorities recommend headaches. No available drug meets all of This common type of headache often responds to physio- these criteria. The newer serotonin agonists (triptans) appear logic approaches that correct cervical or dental alignment or to be less toxic and slightly more effective than the ergot visual refractive error. The optimal use of abortive treatment requires prudent This drug is usually tolerated well when therapy is initiated drug selection and reasonable restrictions on drug use to with a low dose at bedtime, and the dosage is gradually avoid toxicity or habituation. To evaluate the effects of drug therapy, the tion, and a unilateral, pulsatile headache. This stimulation causes cerebral vasocon- Cluster headaches are severe, unilateral, retro-orbital head- striction, inhibits the release of peptides and other aches that tend to group or cluster over time. Patients often mediators of infammation and vasodilation from Chapter 29 y Drugs for Headache Disorders 313 trigeminal neurons, and inhibits activation of the 5. A 35-year-old woman with a history of migraine reports trigeminal nucleus in the brain stem. Use (B) sumatriptan of ergots or triptans is contraindicated in patients with (C) dihydroergotamine coronary artery disease. Answers B through E have shown review Questions various degrees of effectiveness in preventing migraines in controlled studies. The answer is B: patients with uncontrolled hyperten- ness in the prophylactic treatment of migraine sion. Use of sumatriptan is contraindicated in which one of the Answers A and C through E are mechanisms of other following groups of patients? Verapamil is (B) patients with uncontrolled hypertension used for the treatment of migraine or, better stated, (C) patients with moderate to unresponsive severe the prophylactic treatment to prevent migraine attacks migraines because of its ability to block calcium channels and cause (D) patients with hepatic insuffciency vasodilation. Other answer choices are not the primary (E) patients with renal dysfunction mechanism of action of verapamil. Answer A, methysergide, is also an ergot but (C) antagonism at dopamine receptors is not used for acute treatment of migraine attacks. Verapamil is indicated for the treatment of migraine a dual-action opioid-antidepressant agent, helpful in because it has which one of the following effects? They are also used by Nonsteroidal Antiinfammatory Drugs millions on a daily basis for the occasional headache. In addition, many patients have extraarticular • Hydroxychloroquine (Plaquenil) manifestations, such as vasculitis, lymphadenopathy, and • Lefunomide (Arava) splenomegaly. Both humoral and cellular immune mechanisms are involved in the pathogenesis of the Drugs for Gout disease. These mechanisms include the cytokine-mediated Drugs to Prevent Gout Attacks activation of T and B lymphocytes and the recruitment and • Allopurinol (Zyloprim) activation of macrophages. The infammatory leukocytes • Febuxostat (Uloric) then release a variety of prostaglandins, cytotoxic com- • Pegloticase (Krystexxa) pounds, and free radicals that cause joint infammation • Rasburicase (Elitek) and destruction. The sites of action of selected antirheumatic Acuvail, Sprix), piroxicam (Feldene), nabumetone (Relafen), etodolac (Lodine), meloxicam (Mobic), diclofenac (Flector, Voltaren Gel, Zipsor), drugs are depicted in Figure 30-1 and discussed later. However, the A variety of medical disorders and injuries are characterized disease is not simply associated with the aging process. Her physician notes that disease can begin at any age but most often starts after age both right and left joints are affected and appear reddened 40 and before age 60. Pathogenesis of rheumatoid arthritis and sites of action of selected antirheumatic drugs. Methotrexate In this simplifed view of the immune system, den- Leflunomide dritic (antigen-presenting) cells phagocytose anti- gens and present them to T cells, thereby activating the T cells. Eventually the cartilaginous layer is com- pletely destroyed, leading to erosion and microfractures in the underlying bone. It is a sterile, viscoelastic solution prepared from A chicken combs (the feshy growths on top of chicken heads). The deposition of these crystals occurs as a consequence of hyperuricemia, which can result from overproduction or underexcretion of uric acid. Cancer chemotherapy can B also increase plasma uric acid by cell death and lysis, releas- ing purines into the plasma; the purines are subsequently catabolized to uric acid. Subsequent attacks of gout can be prevented by long-term therapy with a drug that either increases uric acid excretion or inhibits uric acid O O formation and thereby reduces the serum level of uric acid as discussed later. This decrease in the production of prostaglandins and other produces irreversible or noncompetitive inhibition. Prostaglandin Effects Prostaglandins play an important role in the development of pain, infammation, and fever. Prostaglandins are stimulating infammatory cell chemotaxis, causing vasodila- released from cells in response to chemical stimuli or phy- tion and increasing capillary permeability and edema. They sensitize sensory nerve endings to noci- Fever, defned as the elevation of body temperature to a ceptive stimuli and thereby amplify the generation of level above 37° C (98. They also promote tissue infammation by of hypothalamic thermoregulatory mechanisms. Some drug interactions are asso- including aspirin, ibuprofen, ketoprofen, and naproxen. For example, high Acetaminophen is a weak antiinfammatory agent, but it is doses of salicylates exert a hypoglycemic effect that can alter 318 Section V y Pharmacology of the Respiratory and Other Systems Shock, coma, respiratory and renal failure, and death Fever, dehydration, 20-30 g and metabolic acidosis Hyperventilation 10-20 g and respiratory alkalosis Antiinflammatory 6-10 g effect and tinnitus Analgesic and 3-6 g antipyretic effects 650-975 mg Antiplatelet effect 80-160 mg Figure 30-3. Relationship between the dosage of aspirin and the pharmacologic and toxic effects of the drug. The oral dosage of aspirin that is needed to inhibit renal dysfunction, and premature closure of the ductus platelet aggregation is somewhat lower than the oral dosage arteriosus. Figure 30-3 shows the relationship between the nized when they were identifed as the active ingredients of dosage of aspirin and the pharmacologic and toxic effects of willow bark and other plant materials used in folk medicine the drug. Aspirin soon slow its absorption rate, it does not signifcantly reduce its became widely used around the world as an analgesic, anti- bioavailability. This substance is then excreted in the urine, along children, the use of salicylates should be avoided, because with about 10% of free salicylate and a similar amount of the risk of Reye syndrome appears to be increased in virus- glucuronide conjugates.

Until recently order provera once a day women's health clinic melbourne pap smear, treatment was started with lifestyle measures alone; drugs were added only if these measures failed buy discount provera line menopause formula. As a result best provera 10 mg womens health research, glycemic control is established sooner purchase 2.5 mg provera otc channel 9 menopause diet, and the risk for long-term complications is lowered. As a result, it is common for people with type 2 diabetes to eventually require insulin therapy. Given the many drugs available for type 2 diabetes, how does one decide which drugs to use for a given patient? To treat type 2 diabetes, the position statement recommends a four-step approach: Step 1. The choice of agent is made in light of relative efficacy, hypoglycemia risk, tolerability, weight-related considerations, and cost. Again, the choice of regimen used is determined based on drug- and patient-specific considerations. If three-drug combination therapy that includes basal insulin fails to achieve treatment goals after 3 to 6 months, it is recommended to proceed to a more complex insulin regimen, usually in combination with one or more noninsulin medicines. Treatment should start at step 1 and then progress to steps 2, 3, and 4 if needed. Determining Appropriate Glycemic Goals In both type 1 and type 2 diabetes, it is important to determine appropriate glycemic goals for the individual based on his or her lifestyle and other patient- specific considerations. The process of maintaining glucose levels within a normal range, around-the-clock, is often referred to as “tight glycemic control. However, for many patients with type 2 diabetes, the risks of tight control may be greater than the benefits. Moreover, onset of ophthalmic problems was delayed, and progression of existing problems was slowed. Hence, with rigorous control of blood glucose, the high degree of morbidity and mortality traditionally associated with type 1 diabetes can be markedly reduced. Drawbacks The greatest concern of intensive therapy and strict glycemic goals is hypoglycemia. Because glucose levels are kept relatively low, even a modest overdose with insulin can cause blood glucose to fall too low, so the possibility of hypoglycemia increases. In addition, patients on intensive insulin therapy experienced greater weight gain (about 10 pounds, on average). Other disadvantages are greater inconvenience, increased complexity, and a need for greater patient motivation. Finally, the cost is higher: whereas traditional therapy costs about $1700/year, intensive therapy costs about $4000/year (for multiple daily injections) or $5800 (for continuous infusion with an insulin pump). Type 2 Diabetes In patients with type 2 diabetes, benefits of tight glycemic control are limited mainly to microvascular complications; tight control does little to reduce macrovascular complications, as evidenced by studies performed to date. Furthermore, benefits accrue more to younger adults with recent-onset disease than to older adults with well-established disease. As in type 1 diabetes, tight glycemic control poses a significant risk for hypoglycemia and weight gain. In one branch of the study, nonobese patients were given either intensive therapy or conventional therapy. Compared with patients in the conventional group, patients in the intensive group had a 12% reduction in total diabetes-related end points (cardiovascular, retinal, and renal damage). However, a reduction in microvascular complications (especially retinal damage) accounted for most of the benefit. Taken together, these four studies suggest that tight glycemic control is most appropriate for younger adults who have recent-onset type 2 diabetes and no cardiovascular complications. Because even short periods of hyperglycemia may increase the risk for complications, optimal therapy should be started as soon as diabetes is diagnosed. Intensive glycemic control may be inappropriate for patients with the following conditions: • Long-standing type 2 diabetes • Advanced microvascular or macrovascular complications • Extensive comorbid conditions • A history of severe hypoglycemia • Limited life expectancy For these patients, an A1c goal above 7% may be more appropriate than a goal below 7% (see Table 46. Monitoring Treatment We need monitoring to (1) determine whether glucose levels are being maintained in a safe range, both short term and long term, and (2) guide changes in treatment when the range is not satisfactory or safe. It is additionally used by most patients with type 2 diabetes using other therapies as well. Information on blood glucose concentration provides a guide for “fine-tuning” dosages of insulin and other antidiabetic drugs. A patient on metformin monotherapy may only need to check his or her blood sugar once per week, whereas a patient with type 1 diabetes on an intensive insulin regimen may check up to 8 times per day or more. Frequently used target values for blood glucose are 70 to 130 mg/dL before meals and 100 to 140 mg/dL at bedtime. Monitoring of Hemoglobin A1c Measurement of hemoglobin A1c—also called glycosylated hemoglobin or glycated hemoglobin—provides an index of average glucose levels over the prior 2 to 3 months. Glucose interacts spontaneously with hemoglobin in red blood cells to form glycosylated derivatives, the most prevalent being A1c. Because red blood cells have a long life span (120 days), levels of A1c reflect average glucose levels over an extended time. Hence, by measuring A1c every 3 to 6 months, we can get a picture of long-term glycemic control. Please note, however, that measuring A1c tells us nothing about acute, hour-to-hour swings in blood glucose. Although an A1c goal of below 7% is good for most patients, a less stringent goal (e. Our discussion of insulin is divided into three sections: physiology, preparations and administration, and therapeutic use. As indicated, insulin consists of two amino acid chains: the “A” (acidic) chain and the “B” (basic) chain. Enzymes clip off connecting peptide (C-peptide) to release active insulin, composed of two peptide chains (A and B) connected by two disulfide (S–S) bonds. Because C-peptide arises only from endogenous insulin, its presence in blood indicates that at least some pancreatic insulin is being made. Biosynthesis Insulin is synthesized in the pancreas by beta cells within the islets of Langerhans. Proinsulin consists of insulin itself plus a peptide loop that runs from the A chain to the B chain. In the final step of insulin synthesis, C-peptide is enzymatically clipped from the proinsulin molecule. Measurement of plasma C-peptide levels offers a way to assess residual capacity for insulin synthesis. Because commercial insulin preparations lack C- peptide, and because endogenous C-peptide is only present as a byproduct of insulin biosynthesis, the presence of C-peptide in the blood indicates the pancreas is still producing some insulin of its own. Secretion The principal stimulus for insulin release is a rise in blood glucose, and the most common cause of glucose elevation is eating a meal, especially one rich in carbohydrates. Under normal conditions, there is tight coupling between rising levels of blood glucose and increased secretion of insulin. Activation of beta -adrenergic receptors in the pancreas 2 promotes secretion of insulin. Conversely, activation of alpha-adrenergic receptors in the pancreas inhibits insulin release. Insulin promotes conservation of energy and buildup of energy stores, such as glycogen. First, it stimulates cellular transport (uptake) of glucose, amino acids, nucleotides, and potassium. Under the influence of insulin and other factors, glucose is converted into glycogen, amino acids are assembled into proteins, and fatty acids are incorporated into triglycerides. Metabolic Consequences of Insulin Deficiency Insulin deficiency puts the body into a catabolic mode. Hence, in the absence of insulin, glycogen is converted into glucose, proteins are degraded into amino acids, and fats are converted to glycerol (glycerin) and free fatty acids. Note that the catabolic effects resulting from insulin deficiency are opposite to the anabolic effects when insulin levels are normal. Insulin deficiency promotes hyperglycemia by three mechanisms: (1) increased glycogenolysis, (2) increased gluconeogenesis, and (3) reduced glucose utilization. The raw materials that allow increased gluconeogenesis are the amino acids and fatty acids produced by metabolic breakdown of proteins and fats. Reduced glucose utilization occurs because insulin deficiency decreases cellular uptake of glucose and decreases conversion of glucose to glycogen. Preparations and Administration There are many insulin preparations or formulations. Major differences concern time course, appearance (clear or cloudy), concentration, and route of administration. Because of these differences, insulin preparations cannot be used interchangeably. In fact, if a patient is given the wrong preparation, the consequences can be dire. Unfortunately, medication errors with insulins remain all too common, which explains why insulin appears on all lists of “high-alert” agents. Some products, referred to as human insulin, are identical to insulin produced by the human pancreas. Other products, referred to as human insulin analogs, are modified forms of human insulin. The analogs have the same pharmacologic actions as human insulin but have different time courses. Types of Insulin There are seven types of insulin: “natural” insulin (also known as regular insulin or native insulin) and six modified insulins.

After these interventions order 2.5mg provera menopause 2 periods a month, emergency visits related to cold and cough medications decreased significantly for children younger than 4 years provera 10 mg line women's health center kennesaw. U N I T X V I Gastrointestinal Drugs O U T L I N E Chapter 62 Drugs for Peptic Ulcer Disease Chapter 63 Laxatives Chapter 64 Other Gastrointestinal Drugs C H A P T E R 6 2 Drugs for Peptic Ulcer Disease Laura D order provera 10mg online breast cancer bras. Although peptic ulcers can develop in any region exposed to acid and pepsin generic 10mg provera amex womens health fitness, ulceration is most common in the lesser curvature of the stomach and the duodenum. Pathogenesis of Peptic Ulcers Peptic ulcers develop when there is an imbalance between mucosal defensive factors and aggressive factors (Fig. When aggressive factors outweigh mucosal defenses, gastritis and peptic ulcers result. Defensive Factors Defensive factors serve the physiologic role of protecting the stomach and duodenum from self-digestion. Conversely, when defenses are compromised, aggressive factors are able to cause injury. Bicarbonate Bicarbonate is secreted by epithelial cells of the stomach and duodenum. Most bicarbonate remains trapped in the mucus layer, where it serves to neutralize any hydrogen ions that penetrate the mucus. Bicarbonate produced by the pancreas is secreted into the lumen of the duodenum, where it neutralizes acid delivered from the stomach. If submucosal blood flow is reduced, the resultant local ischemia can lead to cell injury, thereby increasing vulnerability to attack by acid and pepsin. These compounds stimulate secretion of mucus and bicarbonate, and they promote vasodilation, which helps maintain submucosal blood flow. By taking up residence in the space between epithelial cells and the mucus barrier that protects these cells, the bacterium manages to escape destruction by acid and pepsin. In fact, the bacterium has been declared a type 1 carcinogen by the International Agency for Research on Cancer. By doing so, they can decrease submucosal blood flow, suppress secretion of mucus and bicarbonate, and promote secretion of gastric acid. Gastric Acid Gastric acid is an absolute requirement for peptic ulcer generation: in the absence of acid, no ulcer will form. In fact, in most patients with gastric ulcers, acid secretion is normal or reduced, and among patients with duodenal ulcers, only one third produce excessive amounts of acid. From these observations, we can conclude that, in most patients with peptic ulcers, factors in addition to acid must be involved. Zollinger-Ellison syndrome is the primary disorder in which hypersecretion of acid alone causes ulcers. The syndrome is caused by a tumor that secretes gastrin, a hormone that stimulates gastric acid production. Like gastric acid, pepsin can injure unprotected cells of the gastric and duodenal mucosa. Possible mechanisms include reduction of the beneficial effects of antiulcer medications, reduced secretion of bicarbonate, and accelerated gastric emptying, which would deliver more acid to the duodenum. Overview of Treatment Drug Therapy The goals of drug therapy are to (1) alleviate symptoms, (2) promote healing, (3) prevent complications (hemorrhage, perforation, obstruction), and (4) prevent recurrence. With the exception of antibiotics, the drugs employed do not alter the disease process. Because nonantibiotic therapies do not cure ulcers, the relapse rate after their discontinuation is high. Drug Selection Helicobacter pylori–Associated Ulcers In 1997, a National Institutes of Health Consensus Development Conference recommended that all patients with gastric or duodenal ulcers and documented H. To hasten healing and relieve symptoms, an antisecretory agent should be given along with the antibiotics. Evaluation We can evaluate ulcer healing by monitoring for relief of pain and by radiologic or endoscopic examination of the ulcer site. Unfortunately, evaluation is seldom straightforward because cessation of pain and disappearance of the ulcer rarely coincide: in most cases, pain subsides before complete healing. However, the converse may also be true: pain may persist even though endoscopic or radiologic examination reveals healing is complete. A Note About the Effects of Drugs on Pepsin Pepsin is a proteolytic enzyme that can contribute to ulcer formation. For example, treatment that produces a 99% reduction in gastric acidity will cause pH to rise from a base level of 1. To avoid activation of pepsin, drugs that reduce acidity should be administered in doses sufficient to raise gastric pH above 5. Nondrug Therapy Optimal antiulcer therapy requires implementation of nondrug measures in addition to drug therapy. The traditional “ulcer diet,” consisting of bland foods together with milk or cream, does not accelerate healing. Furthermore, there is no convincing evidence that caffeine-containing beverages (coffee, tea, colas) promote ulcer formation or interfere with recovery. A change in eating pattern may be beneficial: consumption of five or six small meals a day, rather than three larger ones, can reduce fluctuations in intragastric pH and may thereby facilitate recovery. Other Nondrug Measures Smoking is associated with an increased incidence of ulcers and also delays recovery. However, if the patient notes a temporal relationship between alcohol consumption and exacerbation of symptoms, then alcohol use should stop. Many people feel that reduction of stress and anxiety may encourage ulcer healing; however, there is no good evidence that this is true. Antibacterial Drugs Antibacterial drugs should be given to all patients with gastric or duodenal ulcers and confirmed infection with H. Antibiotics are not recommended for asymptomatic individuals who test positive for H. Antibiotics Employed The antibiotics employed most often are clarithromycin, amoxicillin, bismuth, metronidazole, and tetracycline. Furthermore, if these drugs are used alone, the risk for developing resistance is increased. Antibacterial activity is highest at neutral pH and hence can be enhanced by reducing gastric acidity with an antisecretory agent (e. Bismuth Bismuth compounds—bismuth subsalicylate and bismuth subcitrate—act topically to disrupt the cell wall of H. Tetracycline Tetracycline, an inhibitor of bacterial protein synthesis, is highly active against H. Because tetracycline can stain developing teeth, it should not be used by pregnant women or young children. Metronidazole Metronidazole [Flagyl] is very effective against sensitive strains of H. A disulfiram-like reaction can occur if metronidazole is used with alcohol, and hence alcohol must be avoided. Like metronidazole, tinidazole can cause a disulfiram-like reaction and hence must not be combined with alcohol. To minimize emergence of resistance, the guidelines recommend using at least two antibiotics, and preferably three. Eradication rates are good with a 10-day2 course and slightly better with a 14-day course. For patients with penicillin allergy, metronidazole can be substituted for amoxicillin. At this time, the efficacy of sequential therapy in North America has not been established. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. First, antibiotic regimens are complex, requiring the patient to ingest as many as 12 pills a day. At one time, cimetidine was the most frequently prescribed drug in the United States. P ro t o t y p e D r u g s Drugs for Peptic Ulcer Disease Antibiotic (for Helicobacter pylori) Amoxicillin/clarithromycin/omeprazole Histamine-2 Receptor Antagonist Cimetidine Proton Pump Inhibitor Omeprazole Mucosal Protectant Sucralfate Antacid Aluminum hydroxide/magnesium hydroxide Mechanism of Action Histamine acts through two types of receptors, named H and H. Activation of H receptors, which1 2 are located on parietal cells of the stomach (Fig. By blocking H receptors, cimetidine reduces both the volume of2 gastric juice and its hydrogen ion concentration. Cimetidine suppresses basal acid secretion and secretion stimulated by gastrin and acetylcholine. Because cimetidine produces selective blockade of H receptors, the drug cannot suppress2 symptoms of allergy. When the drug is taken orally, food decreases the rate of absorption but not the extent. Hence, if cimetidine is taken with meals, absorption will be slowed and beneficial effects prolonged. Although some hepatic metabolism takes place, most of each dose is eliminated intact in the urine. The half-life is relatively short (about 2 hours) but increases in patients with renal impairment. Therapeutic Uses Gastric and Duodenal Ulcers Cimetidine promotes healing of gastric and duodenal ulcers. Long-term therapy with low doses may be given as prophylaxis against recurrence of gastric and duodenal ulcers.