Patrizio Caturegli, M.D., M.P.H.

• Director, Hypophysitis Center
• Professor of Pathology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0009037/patrizio-caturegli

These episodes of transient thyrotoxicosis 676 Section Vii Endocrine Drugs contraindicated hiv infection rate in costa rica purchase cheap valtrex online, irradiation of the posterior orbit hiv infection first week symptoms 1000 mg valtrex amex, using well-collimated high-energy X-ray therapy hiv infection throat buy cheap valtrex 500 mg on-line, will frequently result in marked improvement of the acute process hiv infection rates in thailand buy valtrex 500mg online. Eyelid or eye muscle surgery may be necessary to correct residual problems after the acute process has subsided symptoms of hiv infection during pregnancy 1000 mg valtrex sale. Dermopathy Dermopathy or pretibial myxedema will often respond to topical corticosteroids applied to the involved area and covered with an occlusive dressing hiv infection cd4 discount valtrex 1000 mg fast delivery. Amiodarone-Induced Thyrotoxicosis In addition to those patients who develop hypothyroidism caused by amiodarone, approximately 3% of patients receiving this drug will develop hyperthyroidism instead. Thyrotoxicosis during Pregnancy Ideally, women in the childbearing period with severe disease should have definitive therapy with 131I or subtotal thyroidectomy prior to pregnancy in order to avoid an acute exacerbation of the disease during pregnancy or following delivery. Propylthiouracil (fewer teratogenic risks than methimazole) can be given in the first trimester, and then methimazole can be given for the remainder of the pregnancy in order to avoid potential liver damage. Other causes include germ-line or acquired mutations in genes involved in hormone synthesis, dietary goitrogens, and neoplasms (see below). However, treatment is necessary because of the severe metabolic stress the infant experiences. These medications are gradually reduced as the clinical picture improves and can be discontinued by 6­12 weeks. Benign lesions may be monitored for growth or symptoms of local obstruction, which would mandate surgical excision. Levothyroxine therapy is not recommended for the suppression of benign nodules, especially in iodine sufficient areas. The evaluation for recurrence of some thyroid malignancies often involves withdrawal of thyroxine replacement for 4­6 weeks-accompanied by the development of hypothyroidism. Stagnaro-Green A et al: the American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Vita R et al: A novel formulation of l-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations. Galli E, Pingitore A, Iervasi G: the role of thyroid hormone in the pathophysiology of heart failure: Clinical evidence. Nodules & Cancer (see Guidelines) Gharib H et al: Clinical review: Nonsurgical, image-guided, minimally invasive therapy for thyroid nodules. Makita N, Liri T: Tyrosine kinase inhibitor­induced thyroid disorders: A review and hypothesis. Radioactive iodine therapy and thyroidectomy are reasonable and effective strategies for definitive treatment of her hyperthyroidism, especially before becoming pregnant to avoid an acute exacerbation of the disease during pregnancy or following delivery. The examining physician discovers postural hypotension and moderate vitiligo (depigmented areas of skin) and obtains routine blood tests. The natural adrenocortical hormones are steroid molecules produced and released by the adrenal cortex. Inhibitors of the synthesis or antagonists of the action of the adrenocortical steroids are important in the treatment of several conditions. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. When a particular enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. The sensitivity of tissues to glucocorticoids is also circadian but inverse to that of cortisol, with low sensitivity in the late morning and high sensitivity in the evening and early night (lower panel). The half-life of cortisol in the circulation is normally about 60­90 minutes; it may be increased when hydrocortisone (the pharmaceutical preparation of cortisol) is administered in large amounts or when stress, hypothyroidism, or liver disease is present. Mechanism of Action Most of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors. These proteins are members of the superfamily of nuclear receptors, which includes steroid, sterol (vitamin D), thyroid, retinoic acid, and many other receptors with unknown or nonexistent ligands (orphan receptors). In the absence of the hormonal ligand, glucocorticoid receptors are primarily cytoplasmic, in oligomeric complexes with chaperone heatshock proteins (hsp). This variability suggests that this important class of steroid receptors has complex stochastic activities. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have increased surface activity and are useful in dermatology. The amino-terminal domain is involved in the transactivation activity of the receptor and increases its specificity. Some of the effects of glucocorticoids can be attributed to their binding to mineralocorticoid receptors. A mineralocorticoid effect of the higher levels of cortisol is avoided in some tissues (eg, kidney, colon, salivary glands) by expression of 11-hydroxysteroid dehydrogenase type 2, the enzyme responsible for biotransformation to its 11-keto derivative (cortisone), which has minimal action on aldosterone receptors. For example, recent studies implicate G protein-coupled membrane receptors in the response of glutamatergic neurons to glucocorticoids in rats. Such receptors are available for direct interactions with and effects on various membrane-associated or cytoplasmic proteins without the need for entry into the nucleus and induction of transcriptional actions. The major metabolic consequences of glucocorticoid secretion or administration are due to direct actions of these hormones in the cell. For example, the response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol and restored by physiologic amounts of this glucocorticoid. They stimulate phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and glycogen synthase and the release of amino acids in the course of muscle catabolism. Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone-sensitive lipase and thus lipolysis. The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation. Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and weakness and thinning of the skin. Anti-Inflammatory and Immunosuppressive Effects Glucocorticoids dramatically reduce the manifestations of inflammation. Inflammation, regardless of its cause, is characterized by the extravasation and infiltration of leukocytes into the affected tissue. The increase in neutrophils is due both to the increased influx into the blood from the bone marrow and to the decreased migration from the blood vessels, leading to a reduction in the number of cells at the site of inflammation. The effect on macrophages is particularly marked and limits their ability to phagocytose and kill microorganisms and to produce tumor necrosis factor-, interleukin-1, metalloproteinases, and plasminogen activator. Both macrophages and lymphocytes produce less interleukin-12 and interferon-, important inducers of Th1 cell activity, and cellular immunity. In addition to their effects on leukocyte function, glucocorticoids influence the inflammatory response by inhibiting phospholipase A2 thereby reducing the synthesis of arachidonic acid, the precursor of prostaglandins and leukotrienes, and of platelet-activating factor. Glucocorticoids cause vasoconstriction when applied directly to the skin, possibly by suppressing mast cell degranulation. They also decrease capillary permeability by reducing the amount of histamine released by basophils and mast cells. Antibody production can be reduced by large doses of steroids, although it is unaffected by moderate doses (eg, 20 mg/d of prednisone). The anti-inflammatory and immunosuppressive effects of these agents are widely useful therapeutically but are also responsible for some of their most serious adverse effects (see text that follows). Increased amounts of glucocorticoids often produce behavioral disturbances in humans: initially insomnia and euphoria and subsequently depression. Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the local immune response against Helicobacter pylori. Indeed, the structural and functional changes in the lungs near term, including the production of pulmonary surfaceactive material required for air breathing (surfactant), are stimulated by glucocorticoids. This has stimulated the development of many synthetic steroids with anti-inflammatory and immunosuppressive activity. They bind to the specific intracellular receptor proteins and produce the same effects but have different ratios of glucocorticoid to mineralocorticoid potency (Table 39­1). The synthetic corticosteroids (Table 39­1) are in most cases rapidly and completely absorbed when given by mouth. Alterations in the glucocorticoid molecule influence its affinity for glucocorticoid and mineralocorticoid receptors as well as its protein-binding affinity, side chain stability, rate of elimination, and metabolic products. In such individuals, minor noxious, traumatic, or infectious stimuli may produce acute adrenal insufficiency with circulatory shock and even death. Activity1 Agent Short- to medium-acting glucocorticoids Hydrocortisone (cortisol) Cortisone Prednisone Prednisolone Methylprednisolone Meprednisone Triamcinolone Paramethasone 2 2 2 AntiInflammatory Topical Salt-Retaining Equivalent Oral Dose (mg) Forms Available 1 0. Therapy consists of large amounts of parenteral hydrocortisone in addition to correction of fluid and electrolyte abnormalities and treatment of precipitating factors. In pregnancies at high risk for congenital adrenal hyperplasia, fetuses can be protected from genital abnormalities by administration of dexamethasone to the mother. The adrenal becomes hyperplastic and produces abnormally large amounts of precursors such as 17-hydroxyprogesterone that can be diverted to the androgen pathway, which leads to virilization and can result in ambiguous genitalia in the female fetus. When 17-hydroxylation is defective in the adrenals and gonads, hypogonadism is also present. However, increased amounts of 11-deoxycorticosterone are formed, and the signs and symptoms associated with mineralocorticoid excess-such as hypertension and hypokalemia-are also observed. Once the patient is * Names for the adrenal steroid synthetic enzymes include the following: P450c11 (11-hydroxylase), P450c17 (17-hydroxylase), P450c21 (21-hydroxylase). Protein loss may be significant and includes muscle wasting; thinning, purple striae, and easy bruising of the skin; poor wound healing; and osteoporosis. The dose must be reduced slowly to normal replacement levels, since rapid reduction in dose may produce withdrawal symptoms, including fever and joint pain. If adrenalectomy has been performed, long-term maintenance is similar to that outlined above for adrenal insufficiency. Primary generalized glucocorticoid resistance (Chrousos syndrome)-This rare sporadic or familial genetic condition is usually due to inactivating mutations of the glucocorticoid receptor gene. These increased levels may result in hypertension with or without hypokalemic alkalosis and hyperandrogenism expressed as virilization and precocious puberty in children and acne, hirsutism, male pattern baldness, and menstrual irregularities (mostly oligo-amenorrhea and hypofertility) in women. The therapy of this syndrome is high doses of synthetic glucocorticoids such as dexamethasone with no inherent mineralocorticoid activity. These doses are titrated to normalize the production of cortisol, cortisol precursors, and adrenal androgens. Aldosteronism-Primary aldosteronism usually results from the excessive production of aldosterone by an adrenal adenoma. This syndrome can also be produced in disorders of adrenal steroid biosynthesis by excessive secretion of deoxycorticosterone, corticosterone, or 18-hydroxycorticosterone-all compounds with inherent mineralocorticoid activity. When the disorder is mild, it may escape detection if serum potassium levels are used for screening. In these circumstances, it is advantageous to use a very potent substance such as dexamethasone because the use of small quantities reduces the possibility of confusion in the interpretation of hormone assays in blood or urine. For example, if complete suppression is achieved by the use of 50 mg of cortisol, the urinary 17-hydroxycorticosteroids will be 15­18 mg/24 h, since one third of the dose given will be recovered in urine as 17-hydroxycorticosteroid. Treatment of the mother with large doses of glucocorticoid reduces the incidence of respiratory distress syndrome in infants delivered prematurely. When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone, 12 mg, followed by an additional dose of 12 mg 18­24 hours later, is commonly used. A study of over 10,000 infants born at 23 to 25 weeks of gestation indicated that exposure to exogenous corticosteroids before birth reduced the death rate and evidence of neurodevelopmental impairment. Corticosteroids and Nonadrenal Disorders the synthetic analogs of cortisol are useful in the treatment of a diverse group of diseases unrelated to any known disturbance of adrenal function (Table 39­2). The usefulness of corticosteroids in these disorders is a function of their ability to suppress inflammatory and immune responses and to alter leukocyte function, as previously described (see also Chapter 55). Therefore, chronic therapy with these drugs should be undertaken with great care and only when the seriousness of the disorder warrants their use and when less hazardous measures have been exhausted. In general, attempts should be made to bring the disease process under control using medium- to intermediate-acting glucocorticoids such as prednisone and prednisolone (Table 39­1), as well as all ancillary measures possible to keep the dose low. Examples Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, temporal arteritis Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis Acquired hemolytic anemia, acute allergic purpura, leukemia, lymphoma, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple myeloma Acute respiratory distress syndrome (sustained therapy with moderate dosage accelerates recovery and decreases mortality) Acute respiratory distress syndrome, sepsis Arthritis, bursitis, tenosynovitis Toxicity the benefits obtained from glucocorticoids vary considerably. Use of these drugs must be carefully weighed in each patient against their widespread effects on every part of the organism. However, insomnia, behavioral changes (primarily hypomania), and acute peptic ulcers are occasionally observed even after only a few days of treatment. The rate of development is a function of the dosage and the genetic background of the patient. In the face, rounding, puffiness, fat deposition, and plethora usually appear (moon facies). Similarly, fat tends to be redistributed from the extremities to the trunk, the back of the neck, and the supraclavicular fossae. The continuing breakdown of protein and diversion of amino acids to glucose production increase the need for insulin and over time result in weight gain; visceral fat deposition; myopathy and muscle wasting; thinning of the skin, with striae and bruising; hyperglycemia; and eventually osteoporosis, diabetes, and aseptic necrosis of the hip. The clinical findings associated with certain disorders, particularly bacterial and mycotic infections, may be masked by the corticosteroids, and patients must be carefully monitored to avoid serious mishap when large doses are used. The administration of such compounds has been associated with nausea, dizziness, and weight loss in some patients. These effects are treated by changing drugs, reducing dosage, and increasing potassium and protein intake. Long-term therapy with intermediate- and long-acting steroids is associated Disorder Allergic reactions Collagen-vascular disorders Eye diseases Gastrointestinal diseases Hematologic disorders Systemic inflammation Infections Inflammatory conditions of bones and joints Nausea and vomiting Neurologic disorders A large dose of dexamethasone reduces emetic effects of chemotherapy and general anesthesia Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to minimize cerebral edema in the postoperative period), multiple sclerosis Prevention and treatment of rejection (immunosuppression) Aspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome, sarcoidosis Nephrotic syndrome Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis fungoides, pemphigus, seborrheic dermatitis, xerosis Malignant exophthalmos, subacute thyroiditis Hypercalcemia, mountain sickness Organ transplants Pulmonary diseases Renal disorders Skin diseases Thyroid diseases Miscellaneous and a tuberculin test, since glucocorticoid therapy can reactivate dormant tuberculosis. The presence of diabetes, peptic ulcer, osteoporosis, and psychological disturbances should be taken into consideration, and cardiovascular function should be assessed. In dosages of 45 mg/m2/d or more of hydrocortisone or its equivalent, growth retardation occurs in children.

From a clinical perspective hiv infection rates by county purchase valtrex cheap, cisatracurium has all the advantages of atracurium with fewer adverse effects hiv infection versus aids cheap valtrex 500 mg on-line. Gantacurium is currently in phase 3 clinical trials and not yet available for widespread clinical use hiv infection rate united states buy genuine valtrex. Preclinical and clinical data indicate gantacurium has a rapid onset of effect and predictable duration of action (very short coconut oil antiviral generic 500mg valtrex otc, similar to succinylcholine) that can be reversed with neostigmine or more quickly (within 1­2 minutes) hiv infection rates for tops buy discount valtrex line, with administration of l-cysteine hiv infection rates over time buy cheap valtrex line. Depolarizing Relaxant Drugs the extremely short duration of action of succinylcholine (5­10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively. Given the rarity of these genetic variants, plasma cholinesterase testing is not a routine clinical procedure but may be indicated for patients with a family history of plasma cholinesterase deficiency. Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (ie, 150 minutes). Drug Isoquinoline derivatives Atracurium Cisatracurium Tubocurarine Steroid derivatives Pancuronium Rocuronium Vecuronium Depolarizing agent Succinylcholine 1 2 Elimination Spontaneous1 Mostly spontaneous Kidney (40%) Kidney (80%) Liver (75­90%) and kidney Liver (75­90%) and kidney Plasma ChE2 (100%) Clearance (mL/kg/min) Approximate Duration of Action (minutes) Approximate Potency Relative to Tubocurarine 6. This action further weakens neuromuscular transmission and diminishes the ability of the acetylcholinesterase inhibitors (eg, neostigmine, edrophonium, pyridostigmine) to antagonize the effect of nondepolarizing muscle relaxants. One consequence of the surmountable nature of the postsynaptic blockade produced by nondepolarizing muscle relaxants is the fact that tetanic stimulation (rapid delivery of electrical stimuli to a peripheral nerve) releases a large quantity of acetylcholine and is followed by transient posttetanic facilitation of the twitch strength (ie, relief of blockade). Bottom, left: A nondepolarizing blocker, eg, rocuronium (yellow), is shown as preventing the opening of the channel when it binds to the receptor. In the double-burst pattern, three stimuli are applied at 50 Hz, followed by a 700 ms rest period and then repeated. In the posttetanic potentiation pattern, several seconds of 50 Hz stimulation are applied, followed by several seconds of rest and then by single stimuli at a slow rate (eg, 0. Succinylcholine reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate, and this in turn spreads to the adjacent membranes, causing contractions of muscle motor units. The upper trace was recorded in the presence of a low concentration of succinylcholine; the downward deflections represent openings of the channel and passage of inward (depolarizing) current. In contrast to the nondepolarizing drugs, this so-called phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors. The adjunctive use of neuromuscular blocking drugs makes it possible to achieve adequate muscle relaxation for all types of surgical procedures without the cardiorespiratory depressant effects produced by deep anesthesia. The standard approach for monitoring the clinical effects of muscle relaxants during surgery uses peripheral nerve stimulation to elicit motor responses, which are visually observed by the anesthesiologist. With single-twitch stimulation, a single supramaximal electrical stimulus is applied to a peripheral nerve at frequencies from 0. Tetanic stimulation consists of a very rapid (30­100 Hz) delivery of electrical stimuli for several seconds. During a partial nondepolarizing blockade, tetanic nerve stimulation is followed by an increase in the posttetanic twitch response, so-called posttetanic facilitation of neuromuscular transmission. During intense neuromuscular blockade, there is no response to either tetanic or posttetanic stimulation. The reappearance of the first response to twitch stimulation after tetanic stimulation reflects the duration of profound (clinical) neuromuscular blockade. To determine the posttetanic count, 5 seconds of 50 Hz tetany is applied, followed by 3 seconds of rest, followed by 1 Hz pulses for about 10 seconds (10 pulses). In general, larger muscles (eg, abdominal, trunk, paraspinous, diaphragm) are more resistant to neuromuscular blockade and recover more rapidly than smaller muscles (eg, facial, foot, hand). However, subtle evidence of residual muscle paralysis detected using a neuromuscular monitor may last for another hour, increasing the likelihood of adverse outcomes, eg, aspiration and decreased hypoxic drive. Of the currently available nondepolarizing drugs, rocuronium has the most rapid onset time (60­120 seconds). As paralysis develops rapidly (< 90 seconds), the arm, neck, and leg muscles are initially relaxed followed by the respiratory muscles. Succinylcholine can cause cardiac arrhythmias, especially when administered during halothane anesthesia. This transient bradycardia can be prevented by thiopental, atropine, ganglionic-blocking drugs, and by pretreating with a small dose of a nondepolarizing muscle relaxant (eg, rocuronium). Cardiovascular Effects Vecuronium, cisatracurium, and rocuronium have minimal, if any, cardiovascular effects. The other nondepolarizing muscle relaxants (ie, pancuronium and atracurium) produce cardiovascular effects that are mediated by autonomic or histamine receptors (Table 27­3). Tubocurarine and, to a lesser extent, atracurium can produce hypotension as a result of systemic histamine release, and with larger doses, ganglionic blockade may occur with tubocurarine. Pancuronium causes a moderate increase in heart rate and a smaller increase in cardiac output, with little or no change in systemic vascular resistance. Although pancuronium-induced tachycardia is primarily due to a vagolytic action, release of norepinephrine from adrenergic nerve endings and blockade of neuronal uptake of norepinephrine may be secondary mechanisms. Bronchospasm may be produced by neuromuscular blockers that release histamine (eg, atracurium), Other Adverse Effects of Depolarizing Blockade A. The exact time course of receptor proliferation is unknown; therefore, it is best to avoid the use of succinylcholine in these cases. Increased Intraocular Pressure Administration of succinylcholine may be associated with the rapid onset of an increase in intraocular pressure (< 60 seconds), peaking at 2­4 minutes, and declining after 5 minutes. Drug Isoquinoline derivatives Atracurium Cisatracurium Tubocurarine Steroid derivatives Pancuronium Rocuronium1 Vecuronium Other agents Gallamine Succinylcholine 1 Effect on Autonomic Ganglia Effect on Cardiac Muscarinic Receptors Tendency to Cause Histamine Release None None Weak block None None None None Stimulation None None None Moderate block Slight None Strong block Stimulation Slight None Moderate None None None None Slight Allergic reactions have been reported. Despite the increase in intraocular pressure, the use of succinylcholine for ophthalmologic operations is not contraindicated unless the anterior chamber is open ("open globe") due to trauma. Increased Intragastric Pressure In heavily muscled patients, the fasciculations associated with succinylcholine may cause an increase in intragastric pressure ranging from 5 to 40 cm H2O, increasing the risk for regurgitation and aspiration of gastric contents. This complication is more likely to occur in patients with delayed gastric emptying (eg, those with diabetes), traumatic injury (eg, an emergency case), esophageal dysfunction, and morbid obesity. Muscle Pain Myalgias are a common postoperative complaint of heavily muscled patients and those who receive large doses (> 1. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Other Neuromuscular Blocking Drugs the end plate-depolarizing effect of succinylcholine can be antagonized by administering a small dose of a nondepolarizing blocker. Although this dose usually reduces fasciculations and postoperative myalgias, it can increase the amount of succinylcholine required for relaxation by 50­90% and can produce a feeling of weakness in awake patients. This condition is treated with dantrolene and is discussed below under Spasmolytic Drugs and in Chapter 16. Many of the antibiotics Effects of Diseases & Aging on the Neuromuscular Response Several diseases can diminish or augment the neuromuscular blockade produced by nondepolarizing muscle relaxants. Its approval has been delayed over concerns that it may induce coagulopathy and hypersensitivity reactions. Sugammadex is a modified -cyclodextrin (a macro-ring structure with 16 polar hydroxyl groups facing inward and 8 polar carboxyl groups facing outward) that binds tightly to rocuronium in a 1:1 ratio. Sugammadex will bind to and can reverse effects of other steroidal neuromuscular blockers such as vecuronium and pancuronium, but to a lesser extent. Clinical trials studying the safety and efficacy of sugammadex have used doses varying between 0. Currently, three dose ranges are recommended: 2 mg/kg to reverse shallow neuromuscular blockade, 4 mg/kg to reverse profound blockade (1­2 posttetanic count), and 1 mg/kg for immediate reversal following administration of rocuronium. The sugammadexrocuronium complex is typically excreted unchanged in the urine within 24 hours in patients with normal renal function. However, due to the strong complex formation with rocuronium, no signs of recurrence of neuromuscular blockade have been noted up to 48 hours after use in such patients. Endotracheal tube placement ensures an adequate airway and minimizes the risk of pulmonary aspiration during general anesthesia. Control of Ventilation In critically ill patients who have ventilatory failure from various causes (eg, severe bronchospasm, pneumonia, chronic obstructive airway disease), it may be necessary to control ventilation to provide adequate gas exchange and to prevent atelectasis. Treatment of Convulsions Neuromuscular blocking drugs (ie, succinylcholine) are occasionally used to attenuate the peripheral (motor) manifestations of convulsions associated with status epilepticus, local anesthetic toxicity, or electroconvulsive therapy. A variety of pharmacologic agents described as depressants of the spinal "polysynaptic" reflex arc (eg, barbiturates [phenobarbital] and glycerol ethers [mephenesin]) have been used to treat these conditions of excess skeletal muscle tone. Although diazepam can be used in patients with muscle spasm of almost any origin (including local muscle trauma), it also produces sedation at the doses required to reduce muscle tone. The left half of the diagram shows an inhibitory reflex arc, which includes an intercalated inhibitory interneuron. Through reduced release of excitatory transmitters in both the brain and the spinal cord, baclofen suppresses activity of Ia sensory afferents, spinal interneurons, and motor neurons. It is rapidly and completely absorbed after oral administration and has a plasma half-life of 3­4 hours. Baclofen should be used with caution during pregnancy: although there are no reports of baclofen directly causing human fetal malformations, animal studies using high doses show that it causes impaired sternal ossification and omphalocele. Studies have confirmed that intrathecal administration of baclofen can control severe spasticity and muscle pain that is not responsive to medication by other routes of administration. This tolerance was not confirmed in a recent study and decreased response may represent unrecognized catheter malfunctions. Although a major disadvantage of this therapeutic approach is the difficulty of maintaining the drug delivery catheter in the subarachnoid space, risking an acute withdrawal syndrome upon treatment interruption, long-term intrathecal baclofen therapy can improve the quality of life for patients with severe spastic disorders. Adverse effects of high-dose baclofen include excessive somnolence, respiratory depression, and coma. Oral baclofen has been studied in many other medical conditions, including patients with intractable low back pain, stiff person syndrome, trigeminal neuralgia, cluster headache, intractable hiccups, tic disorder, gastroesophageal reflux disease, and cravings for alcohol, nicotine, and cocaine (see Chapter 32). Pregabalin is a newer analog of gabapentin that may also prove useful in relieving painful disorders that involve a muscle spasm component. In contrast to the 468 Section V Drugs That Act in the Central Nervous System centrally acting drugs, dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in the muscle fibers. After administration of one of the triggering agents, there is a sudden and prolonged release of calcium, with massive muscle contraction, lactic acid production, and increased body temperature. Local facial injections of botulinum toxin are widely used for the short-term treatment (1­3 months per treatment) of wrinkles associated with aging around the eyes and mouth. Most clinical studies to date have involved administration in one or two limbs, and the benefits appear to persist for weeks to several months after a single treatment. Adverse effects include respiratory tract infections, muscle weakness, urinary incontinence, falls, fever, and pain. While immunogenicity is currently of much less concern than in the past, experts still recommend that injections not be administered more frequently than every 3 months. As a result of its strong antimuscarinic actions, cyclobenzaprine may cause significant sedation, as well as confusion and transient visual hallucinations. The dosage of cyclobenzaprine for acute injury-related muscle spasm is 20­40 mg/d orally in divided doses. Metaxalone Generic, Skelaxin Methocarbamol Generic, Robaxin Orphenadrine Generic, Norflex, others Riluzole Generic, Rilutek Note: this drug is labeled only for use in amyotrophic lateral sclerosis. Llauradу S et al: Sugammadex ideal body weight dose adjusted by level of neuromuscular blockade in laparoscopic bariatric surgery. Part I: Definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Naguib M et al: Advances in neurobiology of the neuromuscular junction: Implications for the anesthesiologist. Krause T et al: Dantrolene-A review of its pharmacology, therapeutic use and new developments. Despite its adverse effects, succinylcholine has the fastest onset of action of any currently available skeletal muscle relaxant. Both burns and neurologic injuries result in the expression of extrajunctional acetylcholine receptors. He also notes a stooped posture, a tendency to drag his left leg when walking, and slight unsteadiness on turning. He is started on a dopamine agonist, which he seems to tolerate well, and the dose is gradually built up to the therapeutic range. Tremor consists of a rhythmic oscillatory movement around a joint and is best characterized by its relation to activity. A conspicuous postural tremor is the cardinal feature of benign essential or familial tremor. In some instances, the proximal muscles of the limbs are most severely affected, and because the abnormal movements are then particularly violent, the term ballismus has been used to 472 describe them. The disease is generally progressive, leading to increasing disability unless effective treatment is provided. Staining for -synuclein has revealed that pathology is more widespread than previously recognized, developing initially in the olfactory nucleus and lower brainstem (stage 1 of Braak scale), then the higher brainstem (stage 2), the substantia nigra (stage 3), the mesocortex and thalamus (stage 4), and finally the entire neocortex (stage 5). The normally high concentration of dopamine in the basal ganglia of the brain is reduced in parkinsonism, and pharmacologic attempts to restore dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder. An alternative but complementary approach has been to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs. However, the precise function of these anatomic structures is not yet fully understood, and it is not possible to relate individual symptoms to involvement at specific sites. Various other neurotransmitters, such as norepinephrine, are also depleted in the brain in parkinsonism, but these deficiencies are of uncertain clinical relevance. The D2 receptors are located postsynaptically on striatal neurons and presynaptically on axons in the substantia nigra belonging to neurons in the basal ganglia. However, D1receptor stimulation may also be required for maximal benefit and one of the newer drugs is D3 selective. Unfortunately, only about 1­3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the blood-brain barrier. Clinical Use the best results of levodopa treatment are obtained in the first few years of treatment. Some patients become less responsive to levodopa, perhaps because of loss of dopaminergic nigrostriatal nerve terminals or some pathologic process directly involving striatal dopamine receptors. The benefits of co-administration of carbidopa include reduction of the amount of levodopa required for benefit and of the absolute amount diverted to peripheral tissues and an increase in the fraction of the dose that reaches the brain.

They may be used in various gram-positive and gram-negative bacterial infections hiv infection by age group discount 500 mg valtrex with visa, including vibrio infections hiv infection and aids-ppt order valtrex 500 mg without a prescription, provided the organism is not resistant hiv infection life expectancy generic valtrex 500 mg overnight delivery. Tetracyclines remain effective in most chlamydial infections antiviral quizlet buy valtrex 500 mg free shipping, including sexually transmitted infections hiv infection causes buy valtrex 500 mg without prescription. Doxycycline antivirus worth it discount valtrex 1000 mg without a prescription, in combination with ceftriaxone, is an alternative treatment for gonococcal disease. Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis and urinary tract infections. Minocycline, 200 mg orally daily for 5 days, can eradicate the meningococcal carrier state, but because of side effects and resistance of many meningococcal strains, ciprofloxacin or rifampin is preferred. Demeclocycline inhibits the action of antidiuretic hormone in the renal tubule and has been used in the treatment of inappropriate secretion of antidiuretic hormone or similar peptides by certain tumors (see Chapter 15). Tigecycline, the first glycylcycline to reach clinical practice, has several unique features that warrant its consideration apart from the older tetracyclines. Many tetracycline-resistant strains are susceptible to tigecycline because it is not affected by the common resistance determinants. Coagulase-negative Pharmacokinetics Tetracyclines differ in their absorption after oral administration and in their elimination. Absorption after oral administration is approximately 30% for chlortetracycline; 60­70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95­100% for doxycycline and minocycline. Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); by dairy products and antacids, which contain multivalent cations; and by alkaline pH. Oral dosages of 500 mg every 6 hours of tetracycline hydrochloride or oxytetracycline produce peak blood levels of 4­6 mcg/mL. Tetracyclines are distributed widely to tissues and body fluids except for cerebrospinal fluid, where concentrations are 10­25% of those in serum. As a result of chelation with calcium, tetracyclines are bound to- and damage-growing bones and teeth. Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline by 50% due to induction of hepatic enzymes that metabolize the drug. Tigecycline, formulated for intravenous administration only, is given as a 100 mg loading dose, then 50 mg every 12 hours. However, in a meta-analysis of clinical trials, tigecycline was associated with a small but significant increase in the risk of death compared with other antibiotics used to treat these infections. Tigecycline has in vitro activity against a wide variety of multidrug-resistant nosocomial pathogens (eg, methicillin-resistant S aureus, extendedspectrum -lactamase-producing gram-negatives, and Acinetobacter sp); however, its clinical efficacy in infections with multidrug-resistant organisms, compared with other agents, is unproven. Doxycycline is the oral tetracycline of choice because it can be given twice daily, and its absorption is not significantly affected by food. Parenteral Dosage Several tetracyclines are available for intravenous injection in doses of 0. Intramuscular injection is not recommended because of pain and inflammation at the injection site. Adverse reactions Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon. Most adverse effects are due to direct toxicity of the drug or to alteration of microbial flora. However, the risk of C difficile colitis may be lower with tetracyclines than with other antibiotics. Bony Structures and Teeth Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. Other Toxicities Tetracyclines can impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously. Renal tubular acidosis and Fanconi syndrome have been attributed to the administration of outdated tetracycline preparations. Systemically administered tetracycline, especially demeclocycline, can induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus. Three mechanisms have been identified: (1) reduced permeability of the cell membrane or active efflux; (2) production (by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3) modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase. Efflux and methylase production are the most important resistance mechanisms in gram-positive organisms. Erythromycin is active against susceptible strains of gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, Erythromycin base is destroyed by stomach acid and must be administered with enteric coating. Oral dosage of 2 g/d results in serum erythromycin base and ester concentrations of approximately 2 mcg/mL. However, only the base is microbiologically active, and its concentration tends to be similar regardless of the formulation. A 500 mg intravenous dose of erythromycin lactobionate produces serum concentrations of 10 mcg/mL 1 hour after dosing. Erythromycin had also been useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci. Emergence of erythromycin resistance in staphylococci and in strains of group A streptococci has made macrolides less attractive as first-line agents for treatment of pharyngitis and skin and soft tissue infections. Erythromycin has been recommended as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, but clindamycin, which is better tolerated, has largely replaced it. The recommended dosage is 250­500 mg twice daily or 1000 mg of the extended-release formulation once daily. Portions of active drug and this major metabolite are eliminated in the urine, and dosage reduction (eg, a 500 mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min. The advantages of clarithromycin compared with erythromycin are lower incidence of gastrointestinal intolerance and less frequent dosing. Azithromycin is slightly less active than erythromycin and clarithromycin against staphylococci and streptococci and slightly more active against H influenzae. A 500 mg dose of azithromycin produces relatively low serum concentrations of approximately 0. The drug is slowly released from tissues (tissue half-life of 2­4 days) to produce an elimination half-life approaching 3 days. Community-acquired pneumonia can be treated with azithromycin given as a 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days. Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Recent studies have suggested that azithromycin may be associated with a small increased risk of cardiac death. Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Erythromycin metabolites inhibit cytochrome P450 enzymes and, thus, increase the serum concentrations of numerous drugs, including theophylline, warfarin, cyclosporine, and methylprednisolone. Clarithromycin also has activity against Mycobacterium leprae, Toxoplasma gondii, and H influenzae. It is active in vitro against Streptococcus pyogenes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis, Mycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria gonorrhoeae, B fragilis, T gondii, and certain nontuberculosis mycobacteria. Many macrolide-resistant strains are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance, and they bind to ribosomes of some bacterial species with higher affinity than macrolides. Telithromycin is metabolized in the liver and eliminated by a combination of biliary and urinary routes of excretion. It is administered as a oncedaily dose of 800 mg, which results in peak serum concentrations of approximately 2 mcg/mL. Other respiratory tract infections were removed as indications when it was recognized that use of telithromycin can result in hepatitis and liver failure. Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane. When administered intravenously, 600 mg of clindamycin every 8 hours gives levels of 5­15 mcg/mL. Clindamycin penetrates well into most tissues, with brain and cerebrospinal fluid being important exceptions. Clinical Use Clindamycin is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci. Clindamycin is also indicated for treatment of infections caused by Bacteroides sp and other anaerobes. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung abscesses. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with specific valvular heart disease who are undergoing certain dental procedures and have significant penicillin allergies. Bacteroides sp and other anaerobes, both gram-positive and gram-negative, are usually susceptible. Quinupristin-dalfopristin is rapidly bactericidal for most susceptible organisms except Enterococcus faecium, which is killed slowly. Quinupristin-dalfopristin is active against gram-positive cocci, including multidrug-resistant strains of streptococci, penicillinresistant strains of S pneumoniae, methicillin-susceptible and resistant strains of staphylococci, and E faecium (but not Enterococcus faecalis). Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. Most gram-positive bacteria are inhibited at concentrations of 1­10 mcg/mL, and many gram-negative bacteria are inhibited by concentrations of 0. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines. Adverse reactions Adults occasionally develop gastrointestinal disturbances, including nausea, vomiting, and diarrhea. Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/ kg/d after 1­2 weeks. The anemia tends to be irreversible and can be fatal, although it may respond to bone marrow transplantation or immunosuppressive therapy. Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Pharmacokinetics Linezolid is 100% bioavailable after oral administration and has a half-life of 4­6 hours. Clinical Uses Linezolid is approved for vancomycin-resistant E faecium infections, health care-associated pneumonia, community-acquired pneumonia, and both complicated and uncomplicated skin and soft tissue infections caused by susceptible gram-positive bacteria. These side effects are thought to be related to linezolid-induced inhibition of mitochondrial protein synthesis. Tedizolid is the active moiety of the prodrug tedizolid phosphate, a next-generation oxazolidinone, with high potency against gram-positive bacteria, including methicillin-resistant S aureus. It is currently in the late stages of clinical development for the treatment of skin and soft tissue infection and health care-associated pneumonia. Potential advantages over linezolid include increased potency against staphylococci and once-daily dosing. It is active against gram-positive organisms including staphylococci, streptococci, enterococci, grampositive anaerobic cocci, and gram-positive rods such as corynebacteria, Nocardia sp, and L monocytogenes. Tasina E et al: Efficacy and safety of tigecycline for the treatment of infectious diseases: A meta-analysis. Blood cultures were obtained at the time of his fever and results the drugs described in this chapter are bactericidal inhibitors of protein synthesis that interfere with ribosomal function. Mechanism of Action the mode of action of streptomycin has been studied more closely than that of other aminoglycosides, but all aminoglycosides act similarly. Aminoglycosides are irreversible inhibitors of protein synthesis, but the precise mechanism for bactericidal activity is not known. Physical and Chemical Properties Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (in other aminoglycosides), to the authors thank Dr. This may be genotypic, resulting from mutation or deletion of a porin protein or proteins involved in transport and maintenance of the electrochemical gradient; or phenotypic, eg, resulting from growth conditions under which the oxygen-dependent transport process described above is not functional. Pharmacokinetics and Once-Daily Dosing Aminoglycosides are absorbed very poorly from the intact gastrointestinal tract, and almost the entire oral dose is excreted in feces after oral administration. After intramuscular injection, aminoglycosides are well absorbed, giving peak concentrations in blood within 30­90 minutes. After a brief distribution phase, peak serum concentrations are identical to those following intravenous injection. The normal half-life of aminoglycosides in serum is 2­3 hours, increasing to 24­48 hours in patients with significant impairment of renal function. Aminoglycosides are only partially and irregularly removed by hemodialysis-eg, 40­60% for gentamicin-and even less effectively by peritoneal dialysis. The circled numerals on the kanamycin molecule indicate points of attack of plasmidmediated bacterial transferase enzymes that can inactivate this drug. In the presence of active inflammation, however, cerebrospinal fluid levels reach 20% of plasma levels, and in neonatal meningitis, the levels may be higher. With prolonged therapy, diffusion into pleural or synovial fluid may result in concentrations 50­90% of that of plasma. Traditionally, aminoglycosides have been administered in two or three equally divided doses per day in patients with normal renal function.

The oral route of administration allows greater concentrations of hormone to reach the liver antiviral kleenex order cheap valtrex, thus increasing the synthesis of these proteins hiv-1 infection cycle purchase valtrex 500mg without prescription. In addition to having important hormonal effects antiviral eye drops valtrex 1000 mg otc, it serves as a precursor to the estrogens how hiv infection can be prevented generic 1000 mg valtrex with mastercard, androgens hiv infection rate mozambique order valtrex with american express, and adrenocortical steroids anti virus ware generic 500 mg valtrex with visa. Normal males appear to secrete 1­5 mg of progesterone daily, resulting in plasma levels of about 0. They should be avoided in patients with undiagnosed genital bleeding, liver Synthetic Progestins A variety of progestational compounds have been synthesized. It is almost completely metabolized in one passage through the liver, and for that reason it is quite ineffective when the usual formulation is administered orally. In the liver, progesterone is metabolized to pregnanediol and conjugated with glucuronic acid. This measure has been very useful despite the fact that the proportion of secreted progesterone converted to this compound varies from day to day and from individual to individual. In addition to progesterone, 20- and 20-hydroxyprogesterone (20- and 20-hydroxy-4-pregnene-3-one) are also found. These compounds have about one fifth the progestational activity of progesterone in humans and other species. The usual routes of administration and durations of action of the synthetic progestins are listed in Table 40­2. Most of these agents are extensively metabolized to inactive products that are excreted mainly in the urine. The response element for progesterone appears to be similar to the corticosteroid response element, and the specificity of the response depends upon which receptor is present in the cell as well as upon other cell-specific receptor coregulators and interacting transcription factors. Like the estrogen receptor, it can form heterodimers as well as homodimers between two isoforms, A and B. This leads to a measurable reduction in arterial and alveolar Pco2 during pregnancy and in the luteal phase of the menstrual cycle. Progesterone is responsible for the alveolobular development of the secretory apparatus in the breast. Other effects of progesterone and its analogs are noted below in the section, Hormonal Contraception. The major problem with this regimen is the prolonged time required in some patients for ovulatory function to return after cessation of therapy. Medroxyprogesterone acetate, 10­20 mg orally twice weekly- or intramuscularly in doses of 100 mg/m2 every 1­2 weeks-will prevent menstruation, but it will not arrest accelerated bone maturation in children with precocious puberty. Controlled studies have not confirmed the effectiveness of such therapy except when doses sufficient to suppress ovulation have been used. The administration of progesterone, 150 mg/d, or medroxyprogesterone, 10 mg/d, for 5­7 days, is followed by withdrawal bleeding in amenorrheic patients only when the endometrium has been stimulated by estrogens. Of these, only testosterone has a significant amount of biologic activity, although androstenedione can be converted to testosterone or estrone in peripheral tissues. Although the amino acid sequence differs from that of insulin, this hormone, like insulin, consists of two chains linked by disulfide bonds, cleaved from a prohormone. It has been shown to increase glycogen synthesis and water uptake by the myometrium and to decrease uterine contractility. Several other nonsteroidal substances such as corticotropinreleasing hormone, follistatin, and prostaglandins are produced by the ovary. Etonogestrel, also used in some oral contraceptives, is available in the subcutaneous implant form listed in Table 40­3. The combination agents also produce a change in the cervical mucus, in the uterine endometrium, and in motility and secretion in the uterine tubes, all of which decrease the likelihood of conception and implantation. The other factors mentioned, therefore, play a major role in the prevention of pregnancy when these agents are used. The great majority of patients return to normal menstrual patterns when these drugs are discontinued. About 2% of patients remain amenorrheic for periods of up to several years after administration is stopped. Effects on the Breast Stimulation of the breasts occurs in most patients receiving estrogen-containing agents. The administration of estrogens and combinations of estrogens and progestins tends to suppress lactation. Studies of the transport of the oral contraceptives into breast milk suggest that only small amounts of these compounds cross into the milk, and they have not been considered to be of importance. Estrogens tend to increase excitability in the brain, whereas progesterone tends to decrease it. Plasma renin activity has been found to increase, and there is an increase in aldosterone secretion. Effects on blood-Serious thromboembolic phenomena occurring in women taking oral contraceptives gave rise to a great many studies of the effects of these compounds on blood coagulation. Increased amounts of coumarin anticoagulants may be required to prolong prothrombin time in patients taking oral contraceptives. The effects on serum proteins result from the effects of the estrogens on the synthesis of the various 2 globulins and fibrinogen. These changes may be responsible for the observed increase in cholelithiasis associated with the use of these agents. Although the effects are marked with doses of 100 mcg of mestranol or ethinyl estradiol, doses of 50 mcg or less have minimal effects. The progestins (particularly the "19-nortestosterone" derivatives) tend to antagonize these effects of estrogen. Progesterone increases the basal insulin level and the rise in insulin induced by carbohydrate ingestion. Effects on the cardiovascular system-These agents cause small increases in cardiac output associated with higher systolic and diastolic blood pressure and heart rate. Although the magnitude of the pressure change is small in most patients, it is marked in a few. This effect seems to be enhanced in women with dark complexions and by exposure to ultraviolet light. Some of the androgen-like progestins might increase the production of sebum, causing acne in some patients. Clinical Uses the most important use of combined estrogens and progestins is for oral contraception. A large number of preparations are available for this specific purpose, some of which are listed in Table 40­3. In general, they are very effective; when these agents are taken according to directions, the risk of conception is extremely small. The pregnancy rate with combination agents is estimated to be about 5­12 per 100 woman years at risk. When severe dysmenorrhea is the major symptom, the suppression of ovulation with estrogen alone may be followed by painless periods. However, migraine is often made worse and has been reported to be associated with an increased frequency of cerebrovascular accidents. When this occurs or when migraine has its onset during therapy with these agents, treatment should be discontinued. Withdrawal bleeding sometimes fails to occur-most often with combination preparations-and may cause confusion with regard to pregnancy. The biphasic and triphasic oral contraceptives (Table 40­3) decrease breakthrough bleeding without increasing the total hormone content. It can usually be controlled by shifting to preparations with less progestin effect or by dieting. It tends to increase with time, the incidence being about 5% at the end of the first year and about 40% after 8 years. Acne may be exacerbated by agents containing androgen-like progestins (Table 40­2), whereas agents containing large amounts of estrogen usually cause marked improvement in acne. Following cessation of administration of oral contraceptives, 95% of patients with normal menstrual histories resume normal periods and all but a few resume normal cycles during the next few months. Patients who have had menstrual irregularities before taking oral contraceptives are particularly susceptible to prolonged amenorrhea when the Adverse Effects the incidence of serious known toxicities associated with the use of these drugs is low-far lower than the risks associated with pregnancy. Nausea, mastalgia, breakthrough bleeding, and edema are related to the amount of estrogen in the preparation. Vascular disorders-Thromboembolism was one of the earliest of the serious unanticipated effects to be reported and has been the most thoroughly studied. Venous thromboembolic disease-Superficial or deep thromboembolic disease in women not taking oral contraceptives occurs in about 1 patient per 1000 woman years. The incidence of these disorders is too low for cost-effective screening by current methods, but prior episodes or a family history may be helpful in identifying patients with increased risk. The incidence of venous thromboembolism appears to be related to the estrogen but not the progestin content of oral contraceptives and is not related to age, parity, mild obesity, or cigarette smoking. Decreased venous blood flow, endothelial proliferation in veins and arteries, and increased coagulability of blood resulting from changes in platelet functions and fibrinolytic systems contribute to the increased incidence of thrombosis. The risk attributable to oral contraceptives in women 30­40 years of age who do not smoke is about 4 cases per 100,000 users per year, as compared with 185 cases per 100,000 among women 40­44 who smoke heavily. Recent studies suggest that risk of infarction is not increased in past users who have discontinued oral contraceptives. The risk of thrombotic or hemorrhagic stroke attributable to oral contraceptives (based on older, higher-dose preparations) has been estimated to about 37 cases per 100,000 users per year. It is most often observed in the first three cycles and is particularly common in women with a history of cholestatic jaundice during pregnancy. Ischemic bowel disease secondary to thrombosis of the celiac and superior and inferior mesenteric arteries and veins has also been reported in women using these drugs. Depression-Depression of sufficient degree to require cessation of therapy occurs in about 6% of patients treated with some preparations. Cancer-The occurrence of malignant tumors in patients taking oral contraceptives has been studied extensively. The lifetime risk of breast cancer in the population as a whole does not seem to be affected by oral contraceptive use. Some studies have shown an increased risk in younger women, and it is possible that tumors that develop in younger women become clinically apparent sooner. It should be noted that a number of recent studies associate the use of oral contraceptives by women who are infected with human papillomavirus with an increased risk of cervical cancer. The use of progestational agents alone for contraception might be especially useful in such patients (see below). These agents are contraindicated in adolescents in whom epiphysial closure has not yet been completed. The low levels of hormone have little effect on lipoprotein and carbohydrate metabolism or blood pressure. An association of intracranial hypertension with an earlier type of implant utilizing norgestrel was observed in a small number of women. The side effects include headache, dizziness, bloating and weight gain of 1­2 kg, and a reversible reduction of glucose tolerance. Postcoital Contraceptives Pregnancy can be prevented following coitus by the administration of estrogens alone, progestin alone, or in combination ("morning after" contraception). The hormones are often administered with antiemetics, since 40% of patients have nausea or vomiting. Mifepristone, an antagonist at progesterone and glucocorticoid receptors, has a luteolytic effect and is effective as a postcoital contraceptive. They are about as effective as intrauterine devices or combination pills containing 20­30 mcg of ethinyl estradiol. Almost all users experience episodes of unpredictable spotting and bleeding, particularly during the first year of use. This preparation is not desirable for women planning a pregnancy soon after cessation of therapy because ovulation suppression can sometimes persist for as long as 18 months after the last injection. These capsules Beneficial Effects of Oral Contraceptives It has become apparent that reduction in the dose of the constituents of oral contraceptives has markedly reduced mild and severe adverse effects, providing a relatively safe and convenient method of contraception for many young women. The mechanism of its mixed agonist/antagonist relations to the estrogen receptor has been intensively studied but is still not completely understood. Tamoxifen is extensively used in the palliative treatment of breast cancer in postmenopausal women and is approved for chemoprevention of breast cancer in high-risk women (see Chapter 54). Tamoxifen has an initial half-life of 7­14 hours in the circulation and is predominantly excreted by the liver. Hot flushes and nausea and vomiting occur in 25% of patients, and many other minor adverse effects are observed. Studies of patients treated with tamoxifen as adjuvant therapy for early breast cancer have shown a 35% decrease in contralateral breast cancer. It has estrogenic effects on lipids and bone but appears not to stimulate the endometrium or breast. Although subject to a high first-pass effect, raloxifene has a very large volume of distribution and a long half-life (> 24 hours), so it can be taken once a day. However, because the compound has a long half-life, large doses may prolong the follicular phase of the subsequent cycle and so make it difficult to use continuously for this purpose. A single dose of 600 mg is an effective emergency postcoital contraceptive, though it may result in delayed ovulation in the following cycle. Doses of 400­600 mg/d for 4 days or 800 mg/d for 2 days successfully terminated pregnancy in over 85% of the women studied. The major adverse effect was prolonged bleeding that on most occasions did not require treatment. It does not bind to intracellular estrogen receptors, but it does bind to sex hormone-binding and corticosteroid-binding globulins. It inhibits P450scc (the cholesterol side chain-cleaving enzyme), 3-hydroxysteroid dehydrogenase, 17-hydroxysteroid dehydrogenase, P450c17 (17-hydroxylase), P450c11 (11-hydroxylase), and P450c21 (21-hydroxylase).

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