Congestive cardiac failure • Supplemental oxygen impairs cardiac relaxation and increases left ventricular ﬁlling pressures purchase 200 mg plaquenil amex arthritis in dogs ankles. Bleomycin and paraquat poisining • Bleomycin-injured lung tissue is less able to scavenge free oxygen radicals and may be further harmed by supplemental oxygen order plaquenil without a prescription arthritis pain relief pills. Inspiratory muscle function Muscle weakness may be caused by increased lung volumes together with shortening and ﬂattening of the diaphragm buy plaquenil 200 mg lowest price gelatin for arthritis in dogs. Supplemental oxygen may attenuate this response with a subsequent decrease in minute ventilation. Ventilation-perfusion misdistribution • Areas of local alveolar hypoxia result in hypoxic pulmonary vasoconstriction in breathing room air even in healthy patients. Spotting individuals who may be at risk of severe hypercapnia This is a subset of individuals who have advanced disease. The development of hypercapnia in patients at risk may not be accompanied by changes in the respiratory pattern or conscious level. The Standards of Care Committee of the British Thoracic Society have published a comprehensive set of guidelines4 on the emergency use of oxygen in adults based on the best evidence available (see box). This second group is encountered in three main situations: • Post operative: a mixture of hypoventilation from fatigue, opiates, · · diaphragmatic splinting, and pleural effusions, with V/Q mismatch from infection, oedema, or atelectasis. British Thoracic Society guidelines for the use of emergency oxygen • Before blood gas results are available use a 28% Venturi mask at 4L/min and aim for a saturation of 88–92% for patients with risk factors for hypercapnia but no prior history of respiratory acidosis. Maintain saturation at 88–92% and recheck blood gases at 30–60min, looking for hypercapnia or acidosis. Oxygen delivery devices In the patient with respiratory failure the FiO2 administered by the car- egiver is often not that which reaches the distal airways or alveoli. Factors such as respiratory rate and pattern, expiratory pause, mask ﬁt and posi- tion, and the presence or absence of a reservoir bag all have an inﬂuence on the ﬁnal concentration of oxygen delivered to a patient’s lungs. This additional gas will be air round the mask or may be oxygen from a reservoir bag, if present. In order to deliver a ﬁxed or high concentration of oxygen, the delivery ﬂow rate is as important as the set FiO2. Most oxygen ﬂow meters are calibrated up to 15L/min, but in an emergency situation they can deliver up to 100L/min if the spindle valve is fully opened. This entrainment ratio varies according to the mask and determines both the ﬁnal oxygen concentration and gas delivery rates. The variability in performance should be borne in mind when interpreting blood gas results. High ﬂow oxygen delivery Devices with an oxygen reservoir Often called trauma masks or non-rebreathing masks, these devices increase the ﬁnal delivered oxygen concentration by incorporating a res- ervoir bag ﬁlled with oxygen. True non-rebreathing masks are ﬁtted with both an inhalation valve and an exhalation valve so that all exhaled gas is vented to the atmosphere and inhaled gas comes only from a reservoir connected to the mask. Most ‘non’-rebreathing masks are really partial rebreathing masks where intake of some exhaled and outside air is inevitable. In a correctly ﬁtting mask, the oxygen reservoir should be seen to collapse with inspiration. Combination of devices Devices can be combined to increase the ﬁnal gas delivery rate. This may increase the ﬁnal inspired O2 concentration by reducing the entrainment of room air. Examples include: • Nasal cannulae and face mask • ‘Double jet’—oxygen from two ﬂow meters can be combined via a Y-connector. This should only be performed by someone who has full understanding of the principles of the circuits. Failure to do so results in a rapid drying of secretions, which become tenacious and difﬁcult to expectorate. There are commercially available devices that combine high ﬂow oxygen with humidiﬁcation (e. FiO2 delivered from different oxygen delivery devices It is not possible to accurately predict the precise FiO2 that will be deliv- ered by a particular oxygen delivery device. A Whisperﬂow® valve uses a surprising 140L/min and will exhaust a size E cylinder in less than 5min. In this situation the normally small proportion of oxygen dissolved in blood becomes more important and increasing supplemental oxygen is reasonable. Entrainment of air, because of the unpredictable peak inspiratory ﬂow rate seen in critical illness, can be highly variable. At the ward level it is almost impossible to say with any degree of accuracy what the actual FiO2 is. Summary There are many ﬁrmly held, opposing views amongst the medical profession regarding oxygen administration. In the absence of oximetry, continue to use a mask with a reservoir bag until deﬁnitive treatment is available. Volume can be estimated by integrating the ﬂow delivered by the ventilator, making adjustments for the intentional and unintentional leaks. In comparison, patients with neuromuscular problems, obesity-hypoventila- tion, or scoliosis may be more comfortable with a longer rise time (0. This usually indicates that there is a lot of leakage around the mask, with a ventilator that does not have the ﬂow capacity to compensate. Failure to activate the ﬂow trigger may be due to lack of patient effort, ineffective triggering, or exces- sive leaks. This is used as a backup to prevent failure of cycling because of excess leaks and is useful in neuromuscular conditions (see below). Expiratory time should be sufﬁcient to allow complete emptying and avoid breath stacking and dynamic hyperinﬂation (Fig. Watch the patient’s respiratory pattern or look at the ventilator ﬂow/time trace to ensure that the ventilator settings allow the patient to spend adequate time in each phase of the respiratory cycle. Expiratory trigger point at 50% of peak inspiratory flow Peak inspiratory flow Expiratory trigger point with high leak flow Time Fig. During nocturnal ventilation, this may lead to better quality sleep and falling bicarbonate levels (with improved daytime respiratory drive). This is perfectly reasonable when intervening earlier in the natural history of respiratory failure, in an attempt to help prevent further deterioration to a stage where invasive ventilation will be needed. The ventilators are designed to generate sufﬁcient ﬂow to compen- sate for these leaks. Adjusting the mask straps may be sufﬁcient, but often it will be necessary to try a different style of mask (see below). Rhinitis Cooling and drying of the nasal mucosa causes rhinitis resulting in sneezing or rhinorrhoea. There will almost always be a back-up rate, for which you may need to set the timings, but the patient will dictate the respiratory pattern most of the time. Troubleshooting Look at the patient ﬁrst before you look at the numbers on the ventilator.
Judicious elevation of the periosteum of strong structural cartilaginous support of the ala and it physically the nasal bones is essential buy 200mg plaquenil arthritis in fingers australia. As the lateral crura the periosteum to the midline and no higher than the medial are repositioned into a more caudal orientation best plaquenil 200mg rheumatoid arthritis recipes, they are pivoted canthi to preserve this tight pocket cheap plaquenil online visa rheumatoid arthritis in hips. The graft is thereby fixed in caudally bringing the ala into a more favorable position. By creating these three fixation points, the graft is ular skin underlying the alar cartilage with the local anesthetic thus maximally stabilized, fixated onto the dorsum to minimize agent; this provides a means of hydrodissection, facilitating any movement. Additionally, further refinements of the dorsal subsequent elevation of the thin vestibular mucosa. Dissection graft can be undertaken to prevent graft movement and warp- is carried medial to the natural domes onto the medial crura, ing. The rapid integration of the graft onto the native dorsum thereby allowing for domal repositioning if needed. The grafts used are ideally either that of septal or costal car- ing the bone on the dorsal aspect of the nasal bones with a tilage. These autologous grafting materials allow for thin yet 2mm osteotome to expose a rough bone surface and the place- sturdy cartilaginous support. The inherent properties of costal ment of perichondrium on the undersurface of the graft cartilage permit thinning while still maintaining durable,. It is imperative that the lateral crural strut fixated to the undersurface of the dorsal graft will adhere to the grafts be curved so that concave surface of the lateral crura is roughened nasal bone to create a rigidly fixed dorsal graft that facing the internal airway. Additionally, this technique also allows for com- Once the central compartment has been lengthened, the alae plete control of dome positioning. Placement of the grafts lat- need to be brought down to complement the central compart- eral to the existing domes and the subsequent recreation of a ments new position. In addition, the inherent weakness in the new dome increases tip projection by means of lateral crural overresected lower lateral cartilage from previous rhinoplasty steal. The placement of the graft medial to the existing dome 478 Revision of the Surgically Overshortened Nose Fig. Caudally positioned pockets are then dissected at the lateral extent of the marginal incision caudal to the supra-alar groove. These pockets can then be dissected according to the extent of caudal repositioning needed. The technique also permits for “fine-tuning” of nostril positioning where preexisting nostril asymmetry can be cor- rected with proper placement of the pockets. If one ala needs to be moved more caudal than the other, the pocket is made more caudal to allow correction of such asymmetries. The new cau- dally oriented alar cartilage provides a strong structural base for the overlying soft tissue skin envelope. However, if it is noted that vestibular skin is now deficient with these newly positioned alae, auricular composite skin/cartilage grafts are then needed to fill this tissue void. The area just medial and inferior to the inferior crus on the anterolateral surface of the auricle is generally used as the donor site. This area is well camouflaged and poses little risk for auricular distortion under primary closure. If large grafts are needed precluding primary closure, a full- thickness skin graft harvested from the postauricular region is used for closure. When harvesting large grafts, it is important to leave a circumferential area of auricular cartilage that pro- trudes a few millimeters beyond the overlying skin island. The harvested graft is immediately transferred to the tissue gap internally and sutured in place using 5–0 chromic sutures. How- ever, the combination of lower lateral cartilage repositioning In patients who require further tip projection and refinement, with lateral crural strut grafts, stabilization of the pivot point dome suturing and tip grafts may provide potential benefit. In with an extension graft and extended spreader grafts, and com- some cases, tip grafts can be sutured in place along the superior posite grafts for internal lining address both deficiencies found aspect of the newly formed domes. Thick-skinned patients who need further tip refinement may benefit from a shield graft placed Alar rim grafts provide further refinements to the alar rim and on the caudal aspect of the medial crura. Most ect no more than 2mm from the superior aspect of the domes patients who have undergone repositioning of the lateral crura to prevent future visibility. The cartilage used should be and before the placement of the composite graft, minor refine- flexible to allow for a slight degree of cephalic rotation and a ments for persistent nostril asymmetry may be addressed with favorable double break. Softer, more pliable He or she is started on 14 days of oral antibiotics and nasal anti- septal or auricular cartilage is preferred. Nasal antibiotic soaks are composed of broad graft, a pocket is carefully made caudal to the marginal incision. Nasal packing is removed on the ish the chance of graft visibility, the medial edge of the graft is first postoperative day. The patient is closely observed especially during the early postoper- ative period. Alar base reduction or alar flare reduction can be used to oﬀset any excessive alar flaring or width. Often, it may be encoun- tered after lower lateral cartilage repositioning, where the cau- 61. Caution must be used prior to undertaking alar base reduc- the rhinoplasty surgeon. Eﬀective lengthening requires use of tions because it may result in an unsightly scar. Careful place- strong cartilage, which in most patients requires using costal ment of the incisions and meticulous closure are paramount in cartilage. Use of costal cartilage requires much experience to preventing an aesthetically displeasing scar. The primary steps in correcting along the vestibular side of the alar rim will serve to reduce the the short nose require lengthening the central compartment internal circumference of the naris, and wedge excision along followed by bringing down the ala to complement the position the outer perimeter of the ala will diminish outer alar circum- of the central compartment. When planning the external excision for alar flaring, ing the lateral crura using longer lateral crural strut grafts in the senior author consciously leaves a millimeter of alar skin at caudally placed pockets. These limita- excisions, particularly the external alar flare excisions, it is tions must be considered prior to embarking on this complex important to avoid the use of cautery. Arch Otolaryngol Head Neck position on the vestibular and external aspect of the sidewall Surg 1998; 124: 809–813 with 3–0 nylon. Lateral crural strut graft: technique and clinical create a seamless contour between the ala and nasal sidewall. Plast Reconstr Surg 1997; 99: 943–952, discus- The patient is typically discharged home on the day of surgery. Perkins Poor rhinoplasty results are multifaceted and have characteris- “double break” and retraction of the alae with alar/columellar tics that vary considerably in patients. Revision rhinoplasty patients may also have revision surgery either generally have problems related to the findings that do not fit well into these ideal nasofacial relation- failure to correct or identify a specific preoperative attribute or ships. For example, patients with only a low radix or poor the aggressive resection of certain nasal structures. This can upper-third support may appear to have a short nasal dorsum present a variety of problems for the revision surgeon, one of but in fact have normal nasofacial relationships. Overrotation of the tip is one of the the dorsum may leave a short dorsal appearance with normal more common components of the short nose.
The most common dose-limiting effects are psychological reactions (confusion buy generic plaquenil 200mg online arthritis treatment homeopathy, nightmares generic plaquenil 200 mg amex reactive arthritis in neck, agitation buy plaquenil 200 mg low cost rheumatoid arthritis in back and neck, hallucinations, paranoid delusions). Rarely, bromocriptine causes retroperitoneal fibrosis, pulmonary infiltrates, a Raynaud-like phenomenon, and erythromelalgia (vasodilation in the feet, and sometimes hands, resulting in swelling, redness, warmth, and burning pain). In addition, the ergot derivatives have been associated with valvular heart disease. Consequently, cabergoline is rarely used unless other management attempts have failed. A more concerning adverse effect is the development of cardiac valve regurgitation and subsequent development of heart failure. With both drugs, benefits derive from inhibiting metabolism of levodopa in the periphery; these drugs have no direct therapeutic effects of their own. Like carbidopa, entacapone inhibits metabolism of levodopa in the intestine and peripheral tissues. In clinical trials, entacapone increased the half-life of levodopa by 50% to 75% and thereby caused levodopa blood levels to be more stable and sustained. Pharmacokinetics Entacapone is rapidly absorbed and reaches peak levels in 2 hours. Elimination is by hepatic metabolism followed by excretion in the feces and urine. Adverse Effects Most adverse effects result from increasing levodopa levels, although some are caused by entacapone itself. By increasing levodopa levels, entacapone can cause dyskinesias, orthostatic hypotension, nausea, hallucinations, sleep disturbances, and impulse control disorders (see “Pramipexole”). The most common are vomiting, diarrhea, constipation, and yellow-orange discoloration of the urine. In addition to levodopa, these include methyldopa (an antihypertensive agent), dobutamine (an adrenergic agonist), and isoproterenol (a beta-adrenergic agonist). If entacapone is combined with these drugs, a reduction in their dosages may be needed. As with entacapone, benefits derive from inhibiting levodopa metabolism in the periphery, which prolongs levodopa availability. When given to patients taking levodopa, tolcapone improves motor function and may allow a reduction in levodopa dosage. For many patients, the drug reduces the “wearing-off” effect that can occur with levodopa, thereby extending levodopa “on” times by as much as 2. Unfortunately, although tolcapone is effective, it is also potentially dangerous: deaths from liver failure have occurred. Because it carries a serious risk, tolcapone should be reserved for patients who cannot be treated, or treated adequately, with safer drugs. When tolcapone is used, treatment should be limited to 3 weeks in the absence of a beneficial response. They also should be informed about signs of emergent liver dysfunction (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine) and instructed to report these immediately. If liver injury is diagnosed, tolcapone should be discontinued and never used again. B l a c k B o x Wa r n i n g : To l c a p o n e [ Ta s m a r ] Tolcapone increase the risk for hepatotoxicity. Monitoring may not prevent liver injury, but early detection and immediate drug withdrawal can minimize harm. By increasing the availability of levodopa, tolcapone can intensify levodopa- related effects, especially dyskinesias, orthostatic hypotension, nausea, hallucinations, sleep disturbances, and impulse control disorders (see “Pramipexole”); a reduction in levodopa dosage may be required. Tolcapone itself can cause diarrhea, hematuria, and yellow-orange discoloration of the urine. Abrupt withdrawal of tolcapone can produce symptoms that resemble neuroleptic malignant syndrome (fever, muscular rigidity, altered consciousness). In rats, large doses have caused renal tubular necrosis and tumors of the kidneys and uterus. Levodopa/Carbidopa/Entacapone Levodopa, carbidopa, and entacapone are now available in fixed-dose combinations sold as Stalevo. As discussed earlier, both carbidopa and entacapone inhibit the enzymatic degradation of levodopa and thereby enhance therapeutic effects. The triple combination is more convenient than taking levodopa/carbidopa and entacapone separately, and it costs a little less, too. Unfortunately, Stalevo is available only in immediate-release tablets and only in specific strengths (see Table 17. Patients who need more flexibility in their regimen cannot be treated with Stalevo, nor can patients who require a sustained-release formulation. There is some evidence suggesting that selegiline may delay neurodegeneration and hence may delay disease progression. Nonetheless, current guidelines suggest trying selegiline in newly diagnosed patients, just in case the drug does confer some protection. First, when used as an adjunct to levodopa, selegiline can suppress destruction of dopamine derived from levodopa. By helping preserve dopamine, selegiline can prolong the effects of levodopa and can thereby decrease fluctuations in motor control. This may reflect a delay in the progression of the disease, or it may simply reflect direct symptomatic relief from selegiline itself. These metabolites, which do not appear to have therapeutic effects, can be harmful. As a result, bioavailability is higher than with tablets and capsules, and hence doses can be lower. Insomnia can be minimized by administering the last daily dose no later than noon. Accordingly, patients should be instructed to avoid these foods and drugs, both while taking selegiline and for 2 weeks after stopping it. B l a c k B o x Wa r n i n g : S e l e g i l i n e [ E l d e p r y l, E m s a m, Z e l a p a r ] Antidepressants are associated with an increased risk for suicide in patients younger than 24 years. Selegiline carries an increased risk for hypertensive crisis in younger patients and is contraindicated for children younger than 12 years. When used with levodopa, selegiline can intensify adverse responses to levodopa-derived dopamine. These reactions—orthostatic hypotension, dyskinesias, and psychological disturbances (hallucinations, confusion)—can be reduced by decreasing the dosage of levodopa. The drugs differ primarily in that rasagiline is not converted to amphetamine or methamphetamine. In contrast to selegiline, rasagiline is not metabolized to amphetamine derivatives. The most common side effects are headache, arthralgia, dyspepsia, depression, and flu-like symptoms. The most common additional reactions are dyskinesias, accidental injury, nausea, orthostatic hypotension, constipation, weight loss, and hallucinations. Rasagiline may increase the risk for malignant melanoma, a potentially deadly cancer of the skin.
Co n s i d e r a t i o n s This is a 23-year-old healthy and asymptomatic woman with a 3-cm nontender mass of the thyroid plaquenil 200 mg line rheumatoid arthritis knuckles. The patient should be questioned carefully about symptoms such as possible compression on t he t rachea or esophagus order plaquenil 200 mg overnight delivery arthritis in dogs ankles, or possible sympt oms of hyperthyroidism or pheochromocytoma best purchase for plaquenil arthritis pain medication side effects. A prior history of head or neck radia- tion is very important since the risk of thyroid cancer is much higher with this history. O n physical exam, the mass should be palpated for location, tenderness, texture, and movement with the thyroid gland during swallowing. The benefits of routine pro- phylactic central lymph node dissection in patients with papillary and follicular thyroid cancers are controversial. T hy- roid nodules larger than 1 cm are considered clinically significant and require fu r t h er evalu at ion. A patient wit h a t h yr oid n odu le sh ou ld be qu est ion ed ab out sympt oms of hyper- or hypot hyroidism, compressive sympt oms such as dyspnea, cou gh in g, or ch okin g sp ells, dysph agia or h oar sen ess, an d a pr ior h ist or y of h ead or neck irradiation. Patients should also be asked about a family history of thyroid can cer, h yp er par at h yr oid ism, or ph eoch r omocyt oma. Symptoms of hyper- or hypothyroidism may be present in patient s with thy- roiditis. Symptoms of hyperthyroidism are also seen in patient s with benign func- tioning follicular adenomas. Compressive symptoms, which occur from thyroid enlarge- ment and impingement on adjacent structures (trachea, esophagus, and recurrent lar yngeal ner ve) are indicat ions for surger y. A patient with a solitary thyroid nodule and a prior history of low-dose head or neck irradiation has a 40%risk of carcinoma. A family history of thyroid cancer should increase the physician’s suspicion of car- cin oma in a pat ient wit h a t h yr oid n odule. Twent y-five percent of medullary thyroid cancers are familial cancers wit h the remainder being sporadic. The thyroid gland should be examined for other nodules, and the neck evaluated for associated cervical lymphadenopat hy. The primary challenge in the management of a thyroid nodule is selecting patients with a high risk of cancer for surgery while avoiding operations in patients with benign disease who would not benefit from surgery. Ultrasound is an impor- tant adjunct in the workup and management of thyroid nodules. H istor- ically, nuclear scint igraphy (t hyroid upt ake scan) was a st andard part of the workup of thyroid nodules looking for “cold” versus “hot” nodules to assess malignancy risk. With the increased access and improved resolution of thyroid ultrasound, thyroid uptake scans are reserved for patients with thyroid nodules and hyperthyroidism to differentiate a hyperfunctioning nodule from diffuse toxic goiter. A cytologic diagnosis of malignancy is very reliable with only a 1% to 2% incidence of false-pos- itive results. A follicular or H ürthle cell car- cinoma can n ot be dist in guish ed from a follicu lar or H ür t h le cell aden oma usin g cyt ologic crit eria alone. D iagnosis of carcinoma is based on the presence of capsular or vascular invasion as observed in a tissue sample. If pat hology returns as invasive carcinoma, complet ion thyroidectomy should be performed. Re fin e d u se o f scin t ig rap hy in the e valu at io n o f nodular thyroid disease. The prognosis of anaplastic thyroid carcinoma is dismal and involves multimodality palliative treatment with a mean survival of less than 6 months. In which of the following situations would the results of thyroid scintigraphy most likely impact t reat ment? W hich of the following sit uat ion s would be associat ed wit h the h igh est risk of malign an cy? H yp er fu n ct io n of the n o d u le seen o n t h yr o id scin t igr ap h y C. For wh ich of the followin g sit uat ion s is t h yroidect omy the best t reat ment option? M easu r em en t of r ad io io d in e u p t ak e an d t h yr o id scin t iscan n in g C. Ultrasound examination of the thyroid gland to distinguish a solid from a cyst ic nodule E. Ultrasound has shown a solid thyroid nodule wit hout ot her abnormalit ies, and iodine-123 scint ig- raphy has revealed a nonfunctioning nodule. Place patient on suppressive dose of levothyroxine and repeat ultrasound in 3 months D. Which of the following is the most appropriat e man agement for this pat ient? With a fine-needle aspirat e showing a follicular pattern, a “cold” hypofunct ioning pattern is associated with a significant risk of cancer (20%-35%), whereas a “warm or hot ” funct ioning patt ern is associat ed wit h a low (1%) risk of can cer. A history of head and neck irradiat ion greatly increases the risk of a t hy- roid nodule being malignant. A cold nonfunctioning nodule increases the risk of cancer, but not as significantly as the history of irradiation. Dominant nodules arising from a goiter do not have an increased risk of being cancer- ous; however, a clinical diagnosis based on the physical examination can be difficult because of the background abnormality. Compressive symptoms can become life threatening; therefore, urgent surgical int ervent ion is considered t he best t herapy. Right thyroidectomy is an appropriate option for this patient because an overall cancer rate of 9% has been reported for this population. T hyroxine suppression would not change t he fact t hat this is a nonfunct ioning nodule. Ethanol injection is a reasonable opt ion for the ablation of recurrent, benign thyroid cysts. However, this is not an appropriate treatment for a nodule of unknown significance. Thyroid nodules less than 1 cm in diameter are common findings in women, and most of t h ese are of no clinical consequences, do not progress, and have low probabilit y of being malignant. The probabilit y of cancer in this patient is further reduced because there are multiple nodules seen. O bserva- tion with repeat ultrasound is generally appropriate for these patients. Revised American Thyroid Association management guidelines for pat ient s wit h t hyroid nodules and different iat ed t hyroid cancer. The results of her physical examination were unremarkable, and no cardiac abnormalities were identified.
The pharmacokinetic analyses provide a basis for esti- perties purchase 200 mg plaquenil with mastercard arthritis cervical headache, thereby providing some indication of how the drug mating doses to be employed in the next phase of trials discount plaquenil online visa arthritis pain in spine, and would be handled by the human body discount 200mg plaquenil amex arthritis pain management specialist. Although a few the other examinations seek to determine if the drug is safe people object to using animals, there are even fewer willing for use in humans. These studies use a small number of patients to Discovery and • Isolate or synthesize a new drug. Placebo-control design includes a group receiving an identi- • Propose clinical studies (sites, cal formulation but with no active ingredients. With some investigators, protocols, and diseases, it is unethical to administer a placebo because of methods of data analysis). In such cases the new drug is compared with the standard drug for treat- Clinical studies • Phase 1: Gather data on drug safety and pharmacokinetics in ment of that disease. Steps in the process of drug development in the United clinical indications for the drug. Subacute toxicity Administer the drug for 90 days in two species via a Behavioral and physiologic changes, blood chemistry levels, route intended for humans. Chronic toxicity Administer the drug for 6-24 months, depending on the Behavioral and physiologic changes, blood chemistry levels, type of drug. Teratogenesis Administer the drug to pregnant rats and rabbits during Anatomic defects and behavioral changes in offspring. Examine cultured Evidence of chromosome breaks, gene mutations, mammalian cells for chromosomal defects. Carcinogenesis Administer the drug to rats and mice for their entire Higher than normal rate of malignant neoplasms. Some drugs is composed of representatives of medical and pharmacy are found to have other clinical uses after the drug has been colleges and societies from each state. These indications are known as information on the chemical analysis of drugs and indicates unlabeled or “off-label” uses. In some cases, manufacturers will 110% of the labeled amount of acetylsalicylic acid (aspirin). This was done for tion and many other aspects of drug product composition the antidepressant bupropion, the exact same drug mar- and analysis. Postmarketing surveillance is particularly Amendments to the Food, Drug, and Cosmetic Act. One type concerns drug safety and effcacy determined to be unsafe for use without the supervision of and regulates the processes by which drugs are evaluated, a designated health care professional. The other type focuses on the pre been marketed for a period of time or if it is found to be vention of drug abuse. The Act was passed in response to the The KefauverHarris Amendments were passed in 1962, sale of patent medicines, often by so-called “snake-oil sales- largely in response to reports of severe malformations in men,” which contained toxic or habit-forming ingredients. Nevertheless, the shocking pictures regulate fraudulent advertising, the legislation was only par- from Europe of deformed babies spurred Congress to tially successful in eliminating unsafe drug products. Examples are drugs Chapter 4 y Drug Development and Safety 37 used for the treatment of urea cycle enzyme defciencies, synthesis of this potent and rapid-acting derivative of mor- Gaucher disease, homocystinuria, and other rare metabolic phine. The Har- Drug Price Competition and Patent Term rison Narcotics Act had a profound and controversial effect Restoration Act on the treatment of substance abuse in that it prohibited The Drug Price Competition and Patent Term Restora physicians from administering opioid drugs to drug- tion Act of 1984 extended the patent life of drug products dependent patients as part of their treatment program. Believing that the drug abuse problem required a new range (usually ±20%), the generic drug may be approved for approach, members of Congress passed the Comprehensive marketing. The cost of such a study is relatively small com- Drug Abuse Prevention and Control Act of 1970. Note that many states have legalized the medical use of marijuana, although federally it is still illegal to use marijuana for medicinal purposes. Examples are hemolytic anemia, thrombocytope- Adverse effects, or side effects, can be classifed with respect nia, and drug-induced lupus erythematosus. The deposition caused by excessive pharmacologic activity are the most of antigen-antibody complexes in vascular endothelium predictable and are often the easiest to prevent or counteract. An example is the severe skin rash seen in patients unpredictable, because its occurrence depends on the drug with a life-threatening form of drug-induced immune vas- susceptibility of the individual patient, the drug dosage, culitis that is known as Stevens-Johnson syndrome. Hypersensitivity reactions are reactions are delayed hypersensitivity reactions that are responsible for a large number of adverse organ system mediated by sensitized lymphocytes. These reactions occur frequently with some drugs ampicillin-induced skin rash that occurs in patients with but only rarely with others. Excessive Pharmacologic Effects Adverse Effects on Organs Drugs often produce adverse effects by the same mechanism In some cases the adverse effects and therapeutic effects of that is responsible for their therapeutic effect on the target a drug are caused by different mechanisms. For example, atropine may cause dry mouth and patients taking aspirin, the adverse reaction such as hyper- urinary retention by the same mechanism that reduces ventilation that leads to respiratory alkalosis is caused by gastric acid secretion in the treatment of peptic ulcer, namely, adverse effects that do not appear to be mediated by the by muscarinic receptor antagonism. This type of adverse drug’s primary mechanism of action, which is inhibition of effect may be managed by reducing the drug dosage or by prostaglandin synthesis. A variety of drugs (Table 4-2) substituting a drug that is more selective for the target organ. Patients receiving these Hypersensitivity reactions, or drug allergies, are respon- drugs should be monitored with appropriate laboratory sible for a large number of organ toxicities that range in tests. For example, hepatotoxicity may be detected by severity from a mild skin rash to major organ system failure. The antigen and antibody subsequently interact with body tissues to produce a wide Hematopoietic Toxicity variety of adverse effects. Bone marrow toxicity, one of the most frequent types of In the Gell and Coombs classifcation system, allergic drug-induced toxicity, may manifest as agranulocytosis, reactions are divided into four general types, each of which anemia, thrombocytopenia, or a combination of these (pan- can be produced by drugs. The effects are often reversible when the drug is hypersensitivity reactions that are mediated by immuno- withdrawn, but they may have serious consequences before globulin E antibodies. Chapter 4 y Drug Development and Safety 39 agranulocytosis may succumb to a fatal infection before the Other Organ Toxicities problem is recognized. Many drugs, such as chloramphenicol, are believed to Some drugs, such as opioid analgesics, cause respiratory cause hematopoietic toxicity by triggering hypersensitivity depression via their effects on the brain stem respiratory reactions directed against the stem cells in bone marrow or centers. Chloramphenicol also produces a reversible monary fbrosis, so patients who are being treated with these form of anemia by blocking the action of the enzyme fer- agents should have periodic chest radiographs and blood gas rochelatase and thereby preventing the incorporation of iron measurements to detect early signs of fbrosis. Anthracy- The most serious form of hematopoietic toxicity is aplas cline anticancer drugs, such as doxorubicin (Adriamycin), tic anemia, which may be associated with several types of produce adverse cardiac effects that resemble congestive blood cell defciencies and lead to pancytopenia. This can result in muscle pain and by administration of hematopoietic growth factors (see sometimes leads to rhabdomyolysis and renal failure. Skin rashes of all varieties, including macular, papular, maculopapular, and urticarial rashes, may be produced by Hepatotoxicity drug hypersensitivity reactions. A mild skin rash may dis- A large number of drugs produce liver toxicity, either via an appear with continued drug administration. Nevertheless, immunologic mechanism or via their direct effect on the because rashes may lead to more serious skin or organ toxic- hepatocytes. Liver toxicity can be classifed as cholestatic or ity, they should be monitored carefully.