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By B. Karmok. New College of Florida.

Silicone implants can be largely divided varial bone grafts and costal cartilage grafts can provide an into two groups: (1) L-shaped ones that augment both the nasal ample supply of autogenous material for dorsal augmentation; tip and the dorsum and (2) straight ones for dorsal augmenta- nevertheless purchase 160mg kamagra super amex, many patients often shy away from these options tion only buy 160mg kamagra super fast delivery. Silicone implants are inexpensive purchase kamagra super with a visa, easy to carve quality 160mg kamagra super, and implants for the nasal dorsum and autogenous grafts at the easily removed during revision surgeries. They are also well tol- nasal tip, where thinning of the skin and extrusion most often erated by most Asian patients with typically thicker subcutane- occur. In one surgeon’s 10-year experience,9 with monly employed for dorsal augmentation, and either septal car- 98% of the study population being Southeast Asian, only 0. On the other hand, not all Asian patients have thick skin and weak cartilaginous support. Therefore, it is important for the surgeon to carefully examine the patient and determine the cat- egory the patient belongs in: (1) thin skin+strong cartilage, (2) thick skin+strong cartilage, or (3) thick skin+weak cartilage. The strength of the nasal tip cartilage can be tested by applying digital pressure as shown in ▶Fig. If the patient has (1) thin skin and strong cartilaginous framework, as in typical northern European noses, then the surgeon can use the maneuvers often employed in Western noses to increase projection (e. If the patient has (2) strong cartilage but thick skin and subcutaneous tissue, then the best course of action is the use of autogenous cartilage onlay grafts for the tip in combination with alloplastic implants for the dor- sum. The trial of trimming the lower lateral cartilages or thin- ning the subcutaneous tissue of the tip to improve definition almost invariably will result in disappointment, for these patients tend to form excessive scar tissue in the area postoper- atively. On the other hand, if the patient has (3) thick skin and weak cartilage, the author recommends combining the techni- ques for both categories (1) and (2). The surgeon may also con- sider the use of premaxillary grafts to achieve the maximum possible projection (see the box Various Types of Asian Noses and the Suggested Methods of Nasal Augmentation (p. Thick skin+weak cartilages=2+interdomal suturing/ carti- lage columella strut/premaxillary grafts Commonly used autogenous cartilages for the Asian augmenta- tion rhinoplasty are septal cartilages. A systematic approach to augmentation Asian rhinoplasty has been discussed in this chapter; the following is a brief sum- mary of the discussion. First, it is crucial for the surgeon to rec- ognize the unique anatomical features of the Asian face and plan surgery accordingly. He or she would be naive to expect that typical rhinoplastic maneuvers used in Western noses will work well in Asians with thick skin and weak cartilaginous framework. Moreover, not all Asians have similar anatomical features; therefore, the author believes that the surgeon should first be able to classify the nose of the Asian patient into the Fig. Various surgical options including the choice of allo- plastic implants and different types of autogenous cartilage tip projection without altering the dorsal height. Currently, the combined technique patients are often concerned about excessive tip rotation that that employs alloplastic implants for nasal dorsal augmentation results in increased nostril showing, because it is considered (silicone versus Gore-Tex) and autogenous cartilage grafts (sep- aesthetically unpleasing in most Asian cultures. Finally, the surgeon should overly rotated nasal tip with excessive nostril showing. This make sure that the nose resulting from the rhinoplasty blends result was corrected by replacing the silicone implant with a well with the rest of the patient’s facial features, for these dorsal Gore-Tex implant for the nasal dorsum and adding a sep- patients are seeking aesthetic enhancement rather than com- arate auricular cartilage graft for the tip that allowed increased plete alteration of their ethnic identity. The use of augmentation rhinoplasty tech- References niques for the correction of the non-Caucasian nose. Arch Facial Plast Surg 1999; 1: 118–121, discussion 122 Reconstr Surg 1986; 77: 239–252 [11] Ahn J, Honrado C, Horn C. Arch Facial Plast Surg 2004; 6: 120–123 Arch Otolaryngol 1977; 103: 461–467 158 Sonic Rhinoplasty: Innovative Applications 20 Sonic Rhinoplasty: Innovative Applications Edmund Pribitkin and Jewel Greywoode approved by the United States Food and Drug Administration 20. Unfortunately, each of the recontouring of nasal bones,5 turbinate reduction (senior instruments traditionally used by rhinoplasty surgeons to author’s experience), endoscopic transorbital decompression reshape nasal bones exhibits shortcomings, which potentially (senior author’s experience), and dacryocystorhinostomy. Three-dimensional bone sought to replace these instruments with new ultrasonic tech- sculpting permits deepening of the glabellar angle, removal of nologies to enable safe, precise recontouring of the nasal bones. This may eliminate hump through a high-impact, blunt-force osteotomy typically the need for multiple or more aggressive osteotomies. The osteotome cuts lowing osteotomies, mobile bone fragments may be contoured through both cartilage and bone and tends to follow pathways without the risk of bony or cartilaginous avulsion. Improper use of the osteotome can result in palpable contour irregularities that can 20. The skin and soft tissue envelope overlying bony edges and asymmetric treatment of bones can be per- the upper and lower lateral cartilages is elevated in the subper- formed when necessary. Nonetheless, the rasp’s shearing forces ichondrial/superficial musculoaponeurotic system plane. The can injure underlying cartilage, avulse the upper lateral carti- upper lateral cartilages are submucosally separated from the lages from the nasal bones, or weaken the osseocartilaginous septum. The rasp also generates fragments of bone that can result pletely dissected free using a Cottle elevator. The shape of the rasp limits its use in deepening the glabellar angle and reducing the nasal 20. It is difficult to address irregularities with the rasp once the osteotomies have been made and the nasal bones are To address the bony and cartilaginous dorsum, an Aufricht mobile. Finally, if the rasp is improperly used, underlying carti- retractor is inserted underneath the soft tissue envelope to lage injury and overlying skin injury may occur. The incision through the septum is usu- ally carried beneath the nasal bones and the septal cartilage removed from the field. The handpiece allows for dorsal height and contour of the dorsum are achieved, any neces- concurrent irrigation and suction. Three-dimensional bone sculpting, In more than 150 cases to date, no skin injuries, inverted V therefore, can occur under direct visualization. Note that upper lateral cartilages and any residual cartilaginous septum are not reduced with the ultrasonic bone aspirator and need to be taken down separately. The capability to smooth rough edges Traditionally, glabellar deepening has been difficult to achieve and prevent palpable and/ or visible irregularities following even with specialized carbide rasps, power-assisted rasps, or osteotomies is especially helpful in thin-skinned patients. Although intermediate osteotomies may of the prominent glabella under direct visualization address these deformities, they may become visible/palpable or. Irregularities or asymmetries in reduction of the nasal spine with avoidance of bony irregular- the mobile nasal bones following osteotomies are difficult to ities. Bottom three photographs: after bony dorsum reduction with the ultrasonic bone aspirator. Rather than exposed conchal bone is then emulsified without injury to the elevation of a mucoperichondrial flap through a hemitransfixion overlying mucosal lining. Simultaneous irrigation or Killian incision, the elevation is performed above and below an and suction preserves a clean surgical field. The carti- binate heals, there is no intervening bone to prevent scarring lage overlying the bony spur or maxillary crest is first removed. In an mucoperichondrium, the elevated ipsilateral flaps may generally ongoing prospective study, 35 patients have experienced a stat- be placed without the need for suture closure or packing. Bottom three photographs: after bony dorsum reduction, deepening of the glabella, and recontouring of curved nasal bones with the ultrasonic bone aspirator. Cost savings may be realized by using the device for ancillary procedures otherwise requiring instrumentation such as 20. The Sonic rhinoplasty allows graded bony refinements without main unit console may also be used for applications in neu- damaging surrounding structures and affords excellent visual- rosurgery, orthopedic surgery, and ophthalmology and, ization for achieving superior functional and cosmetic out- therefore, would be a cost-effective purchase for a hospital comes. There is a three-dimensional sculpting of the nasal dorsum and spine, potential increase in operative time, which is difficult to deepening of the glabellar angle, turbinoplasty, and contouring quantify. Perhaps 10- to 15-minute instrument setup time of mobile bone fragments without the risk of bony or cartilagi- and increased time spent more precisely sculpting the nasal nous avulsion. Sonic rhinoplasty: sculpt- ing the nasal dorsum with the ultrasonic bone aspirator. Sonic rhinoplasty: sculpting nical refinements using the ultrasonic bone aspirator. Ultrasonic bone removal with the Sono- pet Omni: a new instrument for orbital and lacrimal surgery. Otolaryngol Head Neck Surg 2004; 130: 157–163 164 Endoscopic-Guided Rhinoplasty 21 Endoscopic-Guided Rhinoplasty Hans Behrbohm and Johanna May adopt endoscopic surgical procedures in septorhinoplasty and 21. Initial The question of the best approach for septorhinoplasty is a success was achieved using endonasal endoscopic access to the long-standing controversy in rhinosurgery and even today is nose to endoscopically correct circumscribed disorders of the often a topic at international congresses and workshops. In 1904 The nasal septum as part of the medial wall of the nose has he first reported simultaneous intranasal correction of the many bony and cartilaginous structures: the lamina perpendi- anterior septum and a nasal hump. Several of the building blocks are always involved in Rethi and Padovan long remained outsiders. The septal cartilage is vir- the closed technique was primarily used for resections of the tually only the crumple zone of tension.

Accordingly generic 160 mg kamagra super, you should assess the ability to swallow before prescribing oral medications buy discount kamagra super 160 mg on line. If the patient is unable to swallow the water buy kamagra super pills in toronto, parenteral medication must be substituted for oral medication discount kamagra super online mastercard. However, atropine should not be employed routinely because the drug can mask the early signs (e. Dosage determination is accomplished by administering a small initial dose followed by additional small doses until an optimal level of muscle function has been achieved. Important signs of improvement include increased ease of swallowing and increased ability to raise the eyelids. You can help establish a correct dosage by having the patient or family keep records of (1) times of drug administration, (2) times at which fatigue occurs, (3) the state of muscle strength before and after drug administration, and (4) signs of excessive muscarinic stimulation. To maintain optimal responses, patients must occasionally modify dosage themselves. To do this, they must be taught to recognize signs of undermedication (ptosis, difficulty in swallowing) and signs of overmedication (excessive salivation and other muscarinic responses). For example, they may find it necessary to take supplementary medication 30 to 60 minutes before activities such as eating or shopping. Left untreated, myasthenic crisis can result in death from paralysis of the muscles of respiration. As noted previously, overdose with a cholinesterase inhibitor can produce cholinergic crisis. Like myasthenic crisis, cholinergic crisis is characterized by extreme muscle weakness or frank paralysis. In addition, cholinergic crisis is accompanied by signs of excessive muscarinic stimulation. The offending cholinesterase inhibitor should be withheld until muscle strength has returned. Because myasthenic crisis and cholinergic crisis share similar symptoms (muscle weakness or paralysis), but are treated very differently, it is essential to distinguish between them. A history of medication use or signs of excessive muscarinic stimulation are usually sufficient to permit a differential diagnosis. If these clues are inadequate, the provider may elect to administer a challenging dose of edrophonium, an ultrashort-acting cholinesterase inhibitor. If edrophonium-induced elevation of acetylcholine levels alleviates symptoms, the crisis is myasthenic. Because the symptoms of cholinergic crisis will be made even worse by edrophonium and could be life-threatening, atropine and oxygen should be immediately available whenever edrophonium is used for this test. Toxicology of Muscarinic Agonists Sources of Muscarinic Poisoning Muscarinic poisoning can result from ingestion of certain mushrooms (e. Symptoms Manifestations of muscarinic poisoning result from excessive activation of muscarinic receptors. Prominent symptoms are (1) respiratory (bronchospasm and excessive bronchial secretions); (2) cardiovascular (bradycardia and hypotension); (3) gastrointestinal (profuse salivation, nausea and vomiting, abdominal pain, diarrhea, and fecal incontinence); (4) genitourinary (excessive urination and urinary incontinence); integumentary (diaphoresis); and visual (lacrimation and miosis). Some common mnemonics can help you to identify this potentially dangerous condition. Mnemonic 1: Dumbels Diaphoresis/Diarrhea Urination Miosis Bradycardia/Bronchospasm/Bronchorrhea Emesis Lacrimation Salivation Mnemonic 2: Sludge and the Killer Bs Salivation Lacrimation Urination Diaphoresis/Diarrhea Gastrointestinal cramping Emesis Bradycardia Bronchospasm Bronchorrhea Treatment Management is direct and specific: administer atropine (a selective muscarinic blocking agent) and provide supportive therapy. By blocking access of muscarinic agonists to their receptors, atropine can reverse most signs of toxicity. Muscarinic Antagonists (Anticholinergic Drugs) Muscarinic antagonists competitively block the actions of acetylcholine at muscarinic receptors. Because most muscarinic receptors are located on structures innervated by parasympathetic nerves, the muscarinic antagonists are also known as parasympatholytic drugs. Additional names for these agents are antimuscarinic drugs, muscarinic blockers, and anticholinergic drugs. This term is unfortunate in that it implies blockade at all cholinergic receptors. However, as normally used, the term anticholinergic only denotes blockade of muscarinic receptors. Therefore, when a drug is characterized as being anticholinergic, you can take this to mean that it produces selective muscarinic blockade—and not blockade of all cholinergic receptors. In this chapter, the terms muscarinic antagonist and anticholinergic agent are used interchangeably. Atropine Atropine [AtroPen, others] is the best-known muscarinic antagonist and will serve as our prototype for the group. Mechanism of Action Atropine produces its effects through competitive blockade at muscarinic receptors. Rather, all responses to atropine result from preventing receptor activation by endogenous acetylcholine (or by drugs that act as muscarinic agonists). At therapeutic doses, atropine produces selective blockade of muscarinic cholinergic receptors. However, if the dosage is sufficiently high, the drug will produce some blockade of nicotinic receptors, too. Pharmacologic Effects Because atropine acts by causing muscarinic receptor blockade, its effects are opposite to those caused by muscarinic activation. Accordingly, we can readily predict the effects of atropine by knowing the normal responses to muscarinic receptor activation (see Table 11. Like the muscarinic agonists, the muscarinic antagonists exert their influence primarily on the heart, exocrine glands, smooth muscles, and eyes. Because activation of cardiac muscarinic receptors decreases heart rate, blockade of these receptors will cause heart rate to increase. Atropine decreases secretion from salivary glands, bronchial glands, sweat glands, and the acid-secreting cells of the stomach. Note that these effects are opposite to those of muscarinic agonists, which increase secretion from exocrine glands. Blockade of muscarinic receptors on the iris sphincter causes mydriasis (dilation of the pupil). Blockade of muscarinic receptors on the ciliary muscle produces cycloplegia (relaxation of the ciliary muscle), thereby focusing the lens for far vision. It is important to note that not all muscarinic receptors are equally sensitive to blockade by atropine and most other anticholinergic drugs: at some sites, muscarinic receptors can be blocked with relatively low doses; whereas at other sites, much higher doses are needed. As a result, atropine and most other muscarinic antagonists are not very desirable for treating peptic ulcer disease or asthma. Differences in receptor sensitivity to muscarinic blockers are of clinical significance. Accordingly, if we want to use atropine to treat peptic ulcer disease (by suppressing gastric acid secretion) or asthma (by dilating the bronchi), we cannot do so without also affecting the heart, exocrine glands, many smooth muscles, and the eyes. Because of these obligatory side effects, atropine and most other muscarinic antagonists are not preferred drugs for treating peptic ulcers or asthma. Procedures that stimulate baroreceptors of the carotid body can initiate reflex slowing of the heart, resulting in profound bradycardia. Because this reflex is mediated by muscarinic receptors on the heart, pretreatment with atropine can prevent a dangerous reduction in heart rate. Certain anesthetics irritate the respiratory tract and thereby stimulate secretion from salivary, nasal, pharyngeal, and bronchial glands. If these secretions are sufficiently profuse, they can interfere with respiration. By blocking muscarinic receptors on secretory glands, atropine can help prevent excessive secretions. The availability of these new anesthetics has greatly reduced the use of atropine for this purpose during anesthesia. By blocking muscarinic receptors in the eyes, atropine can cause mydriasis and paralysis of the ciliary muscle. The ophthalmic uses of atropine and other muscarinic antagonists are discussed in Chapter 84. Heart rate is increased because blockade of cardiac muscarinic receptors reverses parasympathetic slowing of the heart. By blocking muscarinic receptors in the intestine, atropine can decrease both the tone and motility of intestinal smooth muscle. This can be beneficial in conditions characterized by excessive intestinal motility, such as mild dysentery and diverticulitis. When taken for these disorders, atropine can reduce both the frequency of bowel movements and associated abdominal cramps.

The same factors that determine the movement of drugs across other membranes determine the movement of drugs across the placenta purchase kamagra super. Accordingly discount kamagra super 160mg without prescription, lipid-soluble proven 160mg kamagra super, nonionized compounds readily pass from the maternal bloodstream into the blood of the fetus buy kamagra super with visa. To enter the fetal circulation, drugs must cross membranes of the maternal and fetal vascular systems. Lipid-soluble drugs can readily cross these membranes and enter the fetal blood, whereas ions and polar molecules are prevented from reaching the fetal blood. Protein Binding Drugs can form reversible bonds with various proteins in the body. Of all the proteins with which drugs can bind, plasma albumin is the most important. As indicated by the two-way arrows, binding between albumin and drugs is reversible. A, Albumin is the most prevalent protein in plasma and the most important of the proteins to which drugs bind. Even though a drug can bind albumin, only some molecules will be bound at any moment. The percentage of drug molecules that are bound is determined by the strength of the attraction between albumin and the drug. For example, the attraction between albumin and the anticoagulant warfarin is strong, causing nearly all (99%) of the warfarin molecules in plasma to be bound, leaving only 1% free. On the other hand, the attraction between the antibiotic gentamicin and albumin is relatively weak; less than 10% of the gentamicin molecules in plasma are bound, leaving more than 90% free. Because albumin is too large to leave the bloodstream, drug molecules that are bound to albumin cannot leave either (see Fig. As a result, bound molecules cannot reach their sites of action or undergo metabolism or excretion until the drug-protein bond is broken so that the drug is free to leave the circulation. In addition to restricting drug distribution, protein binding can be a source of drug interactions. Because the number of binding sites is limited, drugs with the ability to bind albumin will compete with one another for those sites. As a result, one drug can displace another from albumin, causing the free concentration of the displaced drug to rise, thus increasing the intensity of drug responses. Entering Cells Many drugs produce their effects by binding with receptors located on the external surface of the cell membrane; however, some drugs must enter cells to reach their sites of action, and practically all drugs must enter cells to undergo metabolism and excretion. The factors that determine the ability of a drug to cross cell membranes are the same factors that determine the passage of drugs across all other membranes, namely, lipid solubility, the presence of a transport system, or both. Metabolism Drug metabolism, also known as biotransformation, is defined as the enzymatic alteration of drug structure. Hepatic Drug-Metabolizing Enzymes Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, also known as the P450 system. It is important to appreciate that cytochrome P450 is not a single molecular entity, but rather a group of 12 closely related enzyme families. Each of the three P450 families that metabolize drugs is composed of multiple forms, each of which metabolizes only certain drugs. Therapeutic Consequences of Drug Metabolism Drug metabolism has six possible consequences of therapeutic significance: • Accelerated renal excretion of drugs • Drug inactivation • Increased therapeutic action • Activation of prodrugs • Increased toxicity • Decreased toxicity Accelerated Renal Drug Excretion The most important consequence of drug metabolism is promotion of renal drug excretion. The kidneys, which are the major organs of drug excretion, are unable to excrete drugs that are highly lipid soluble. Hence, by converting lipid-soluble drugs into more hydrophilic (water-soluble) forms, metabolic conversion can accelerate renal excretion of many agents. Drug Inactivation Drug metabolism can convert pharmacologically active compounds to inactive forms. Increased Therapeutic Action Metabolism can increase the effectiveness of some drugs. The analgesic activity of morphine is so much greater than that of codeine that formation of morphine may account for virtually all the pain relief that occurs after codeine administration. Activation of Prodrugs A prodrug is a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form through metabolism. Increased or Decreased Toxicity By converting drugs into inactive forms, metabolism can decrease toxicity. Conversely, metabolism can increase the potential for harm by converting relatively safe compounds into forms that are toxic. Increased toxicity is illustrated by the conversion of acetaminophen into a hepatotoxic metabolite. It is this product of metabolism, and not acetaminophen itself, that causes injury when acetaminophen is taken in overdose. Special Considerations in Drug Metabolism Several factors can influence the rate at which drugs are metabolized. The liver does not develop its full capacity to metabolize drugs until about 1 year after birth. During the time before hepatic maturation, infants are especially sensitive to drugs, and care must be taken to avoid injury. Induction and Inhibition of Drug-Metabolizing Enzymes Drugs may be P450 substrates, P450 enzyme inducers, and P450 enzyme inhibitors. By increasing the rate of drug metabolism, the amount of active drug is decreased and plasma drug levels fall. If dosage adjustments are not made to accommodate for this, a drug may not achieve therapeutic levels. By slowing the rate of metabolism, inhibition can cause an increase in active drug accumulation. First-Pass Effect The term first-pass effect refers to the rapid hepatic inactivation of certain oral drugs. When drugs are absorbed from the gastrointestinal tract, they are carried directly to the liver through the hepatic portal vein before they enter the systemic circulation. If the capacity of the liver to metabolize a drug is extremely high, that drug can be completely inactivated on its first pass through the liver. To circumvent the first-pass effect, a drug that undergoes rapid hepatic metabolism is often administered parenterally. This permits the drug to temporarily bypass the liver, thereby allowing it to reach therapeutic levels in the systemic circulation before being metabolized. Nutritional Status Hepatic drug-metabolizing enzymes require a number of cofactors to function. In the malnourished patient, these cofactors may be deficient, causing drug metabolism to be compromised. Competition Between Drugs When two drugs are metabolized by the same metabolic pathway, they may compete with each other for metabolism and may thereby decrease the rate at which one or both agents are metabolized. Specifically, the process is limited to drugs that have undergone glucuronidation, a process that converts lipid-soluble drugs to water-soluble drugs by binding them to glucuronic acid. After glucuronidation, these drugs can enter the bile and then pass to the duodenum. In the intestine, some drugs can be hydrolyzed by intestinal beta-glucuronidase, an enzyme that breaks the bond between the original drug and the glucuronide moiety, thereby releasing the free drug. Because the free drug is more lipid soluble than the glucuronidated form, the free drug can undergo reabsorption across the intestinal wall, followed by transport back to the liver, where the cycle can start again. Because of enterohepatic recycling, drugs can remain in the body much longer than they otherwise would. And still others undergo enterohepatic recirculation, a repeating cycle in which a drug moves from the liver into the duodenum (through the bile duct) and then back to the liver (through the portal blood). As discussed in the text under Enterohepatic Recirculation, the process is limited to drugs that have first undergone hepatic glucuronidation. Drugs and their metabolites can exit the body in urine, bile, sweat, saliva, breast milk, and expired air. When the kidneys are healthy, they serve to limit the duration of action of many drugs.

Main differences are: • Anaemia is more marked in iron defciency and relatively less in thalassaemia minor kamagra super 160mg for sale. A: As follows: • Bleeding from any site (haemorrhoid buy kamagra super overnight delivery, haematemesis generic 160 mg kamagra super visa, melaena purchase kamagra super online from canada, gum bleeding, any bleeding disorder, injury). It means eating of unusual items such as earth, coal, ice or some foods in excess like tomato, sour foods. A: As follows: • Bleeding due to any cause: Commonest from gastrointestinal tract (haemorrhoid, colorectal carcinoma, carcinoma stomach, diverticulitis, angiodysplasia), menorrhagia in female. Test to fnd out the causes (according to the history and suspicion of cause): • Stool for ova or cyst of hookworm, occult blood test. Bone marrow to see stainable iron (by Prussian blue shows empty stain): not a routine, may be done in some cases. A: Common symptoms of anaemia with brittle nails, spoon shaped nails (koilonychia), atrophy of the papillae of the tongue, angular stomatitis, brittle hair, a syndrome of dysphagia and glossitis (Plummer Vinson or Paterson Brown Kelly syndrome). A: As follows: • If severe anaemia or haemoglobin is low: blood transfusion (packed cell). To be given for 3 to 6 months after haemoglobin is normal to replenish the iron store. A: Anaemia may be defned as a clinical condition, characterized by reduced level of haemoglobin according to the age and sex of the individual. Causes are: • Acute: Trauma, postpartum bleeding, haematemesis, melaena, epistaxis. A: When both microcytes and macrocytes are found, this is called dimorphic anaemia. Malaria, chronic haemolytic anaemia, acute infection, leukaemia, lymphoma, portal hypertension 5. Acute leukaemia, multiple myeloma, lymphoma, myelofbrosis Q:How to investigate a patient with anaemia? A: Detailed history, physical examination and relevant laboratory investigations are done to diagnose anaemia. Bone marrow examination: To diagnose megaloblastic anaemia, aplastic anaemia, bone marrow infltration (secondary deposit), ring sideroblasts (in sideroblastic anaemia). If normoblast is found, further investigation should be done according to history (see above). A: It is an autoimmune disease, in which, there is atrophy of gastric mucosa with loss of parietal cells causing intrinsic factor defciency. There is anti-intrinsic factor (50%) and anti-parietal cell antibodies (90%) in the blood. In the absence of intrinsic factor, less than 1% of dietary vitamin B12 is absorbed. It is more common in individuals with other autoimmune disease (Hashimoto’s thyroiditis, Graves’ disease, vitiligo, hypoparathyroidism or Addison’s disease) or a family history of these or pernicious anaemia. A: When plasma volume is increased and haemoglobin is relatively low, it is called spurious anaemia. A: Sideroblastic anaemias are inherited or acquired disorders characterized by refractory anaemia, a variable number of hypochromic cells in the peripheral blood with excess iron and ring sideroblasts. A: It is characterized by accumulation of iron in mitochondria of erythroblast around the nucleus, giving a ring shaped appearance in the bone marrow. Polychromatia Young red cells, reticulocytes (bluish tinge) Haemolysis, acute haemorrhage, increased red cell turnover mebooksfree. Presentation of a Case: (Patient is usually Young, Face is Plethoric) • Spleen is enlarged,. A: Face is plethoric, deep dusky, cyanosed, redness of conjunctiva (bloodshot eyes). I would like to ask whether any history of itching, especially after hot bath or warm body. Features are: Symptoms: • Features of hyperviscosity syndrome: headache, dizziness, giddiness, blackout, lack of concentration, blurring of vision. Signs: • Face—plethoric, deep dusky, cyanosed, redness of conjunctiva (bloodshot eyes). Pathological erythropoietin production • Tumours—renal cell cancer, cerebellar haemangioblastoma, hepatoma, phaeochromocytoma, uterine fbroid. Causes are—dehydration, diuretic, smoking, alcohol excess, obesity, Gaisbock’s syndrome. A: Polycythaemia rubra vera is a stem cell disorder in which there is excess proliferation of erythroid, myeloid and megakaryocyte progenitor cells. But in secondary polycy- thaemia, red cell mass is low and erythropoietin is normal or high. Bone marrow showing hypercellularity with erythroid, granulocytic and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size) 3. A: Venesection (400 to 500 mL of blood, every 5 to 7 days) until haematocrit is,45% and platelet,400 3 109/L). A: As follows: • Myelofbrosis (15%) • Acute myeloid leukaemia • Refractory state with anaemia. A: Myelofbrosis is a disorder of unknown cause characterized by clonal proliferation of the stem cells with bone marrow fbrosis, extramedullary haemopoiesis and leucoerythroblastic blood picture. Fibrosis in the marrow is due to hyperplasia of abnormal megakaryocyte, which releases fbroblast stimulating factors such as platelet derived growth factor. Bone marrow may be dry tap, trephine biopsy should be done (which shows increased megakaryocyte, increased reticulin and fbrous tissue). Remember, the diagnosis of endocrine disease may be obvious by looking at the patient. Once you are asked to examine the patient, take few seconds to have a quick look from head to foot carefully. Diagno- sis of thyroid disorders (such as Graves’ disease, thyrotoxicosis, hypothyroidism) is obvious on the face of the patient. Also, Cushing’s syndrome and acromegaly are easily diagnosed by looking at the patient. Underlying diagnoses by looking at the face may be: • Graves’ disease (hyperthyroid, euthyroid or hypothyroid) or thyrotoxicosis (due to any cause). For example (for details, see later in this chapter): • If your diagnosis is thyroid disease: further clinical examination will be related to thyroid problems, e. After you have observed the patient, the examiner may ask, ‘What is the likely diagnosis? In such a case, you must have few readymade questions to be asked in a particular disease. For example: • If Cushing’s syndrome is suspected: ask whether the patient is taking steroid for long time, or experiencing weight gain, backache, diffculty in standing up after sitting etc. Look at the patient’s face: • Anxious, restless, fdgety and frightened face with staring looks (indicates thyrotoxicosis). If any goitre, see whether it is diffuse, single or multinodular, check if one side is larger than the other. Palpation (from back): Ask the patient to sit, ensure the neck is slightly fexed, palpate the gland with both hands and ask the patient to swallow again. If goitre is present, see if it is unilateral or bilateral, diffuse or nodular (single or multinodular), then examine following points: • Size (which one is large, right or left). Examine for retrosternal extension (prominent veins in neck and upper chest, feel the lower limit, tracheal deviation and percuss the upper part of chest for dullness. Palpate the cervical lymph nodes (if palpable, it may be suggestive of metastasis). Feel for carotid pulse (absence of pulsation indicates pressure effect or malignant infltration). Finally, ask the patient to hold breath and auscultate for thyroid bruit (also carotid bruit and venous hum, which can be obliterated by gentle pressure at the root of neck). If thyroid bruit is present, check whether it is a murmur of aortic stenosis (ejection systolic murmur) radiating from chest. For thyroid status, look for the signs of thyrotoxicosis and signs of hypothyroidism. Signs of thyrotoxicosis: • See tremor of outstretched hands with fngers spread out. Signs of hypothyroidism: Puffy face with periorbital swelling with baggy eyelids, loss of outer 1/3rd of eyebrows and • apathetic look.

This disorder often results from insuffcient folic preparations or fail to respond to oral iron therapy 160mg kamagra super with mastercard. After acid intake in the diet proven kamagra super 160 mg, but it can also result from impaired administration buy kamagra super 160mg on line, the iron dextran complex is removed from folic acid absorption effective 160mg kamagra super, such as that seen in patients with the circulation by the reticuloendothelial system, and the alcoholism and certain malabsorption syndromes. In patients iron is transferred to the plasma for distribution to the bone with megaloblastic anemia, vitamin B12 defciency must be marrow and other tissues. This is The dosage required for each patient is calculated on the because treatment with folic acid may partly correct the basis of the observed hemoglobin concentration and body anemia caused by a vitamin B12 defciency but will not weight. Irreversible neu- Intravenous administration of iron dextran can cause rologic damage can occur if a B12 defciency is incorrectly peripheral fushing and hypotensive reactions. These from the gut in the presence of intrinsic factor (a glycopro- include chemotherapeutic folate reductase inhibitors, such tein secreted by gastric parietal cells) and calcium. An inad- as trimethoprim, pyrimethamine, and methotrexate (see equate secretion of intrinsic factor leads to vitamin B12 Chapters 40, 44, and 45). Other drugs inhibit folate absorp- defciency and eventually results in pernicious anemia. Vitamin B12 Because vitamin B12 is not absorbed from the gut in the Vitamin B12 consists of a porphyrin-like ring with a central absence of intrinsic factor, the vitamin must be administered cobalt atom attached to a nucleotide (see Fig. Two intramuscularly in the treatment of pernicious anemia, and synthetic forms of vitamin B12, cyanocobalamin and treatment must be continued for life. At the start of therapy, hydroxocobalamin, are available for the treatment of B12 injections are given daily for 5 to 10 days. In the body, these forms of the vitamin are con- tenance doses are given once a month. Nasal spray formu- verted to methylcobalamin or deoxyadenosylcobalamin, lations of cyanocobalamin (CaloMist, Nascobal) are which are cofactors for biochemical reactions. Vitamin B12 available for maintenance therapy after normalization of serves as a cofactor for methylation reactions, including the serum B12 concentrations with intramuscular B12 injections. Hydroxocobalamin is also used for out-of-hospital Vitamin B12 is essential for growth, cell replication, empiric treatment of cyanide poisoning resulting from hematopoiesis, and myelin synthesis. In this setting, hydroxocobalamin (Cya- dietary meats, dairy products, and eggs, and it is absorbed nokit) is administered intravenously, and then it rapidly Chapter 17 y Hematopoietic Drugs 171 endogenous human erythropoietin. Darbepoetin alfa and epoetin beta are modifed forms of erythropoietin that have Dietary folate longer half-lives than epoetin alfa and may be given less Folate reductase frequently. Epoetin alfa and darbepoetin are also indicated for anemia resulting from chemotherapy for non- myeloid malignancies. Only epoetin alfa is approved for Pyrimidine Purine Amino acid anemia caused by zidovudine therapy for human immuno- synthesis synthesis synthesis A defciency virus infection, and for reducing the need for blood transfusions during surgery. B, The two active forms of vitamin B12 are meth- cancer chemotherapy should be minimized. These forms are cofactors for methylation reactions, including the conversion of homocysteine to Filgrastim, Pegflgrastim, and Sargramostim methionine and the conversion of methylmalonyl-CoA to succinyl-CoA. Methyl H -folate donates a methyl group to cobalamin to form Filgrastim is recombinant human granulocyte colony- 4 methylcobalamin. The endogenous forms of these growth factors are produced combines with cyanide to form harmless cyanocobalamin in by various leukocytes, fbroblasts, and endothelial cells. Several growth factors are now available for Pegflgrastim is eliminated primarily by neutrophil uptake treating anemia or leukopenia. Filgrastim, pegflgrastim, and sargramostim are used pri- Erythropoiesis-Stimulating Agents marily to treat neutropenia associated with cancer chemo- Erythropoietin is secreted primarily by the kidney in adults therapy and bone marrow transplantation. Several forms of erythropoietin have been developed of infections and shortens the period of hospitalization. Sargramostim is used to accelerate myeloid cell recovery (A) cyanocobalamin in patients who have lymphoma, acute lymphoblastic leu- (B) epoetin kemia, or Hodgkin disease and are undergoing autologous (C) ferrous gluconate bone marrow transplantation or chemotherapy. It has also (D) flgrastim been used to reduce the incidence of fever and infections in (E) folic acid patients with severe chronic neutropenia. A 47-year-old woman exhibits severe neutropenia after a neously or intravenously once a day for 2 weeks or until the course of chemotherapy for breast cancer. A 66-year-old man with progressive fatigability and of its longer half-life, pegflgrastim requires administration anorexia is found to have a low blood hemoglobin con- only once during each cycle of cancer chemotherapy in order centration, an elevated mean corpuscular volume, and an to manage chemotherapy-induced neutropenia. Iron defciency orally for several months in the treatment of iron def- anemia is a hypochromic (low mean corpuscular hemo- ciency anemia. Folic recombinant forms of human erythropoietin used acid and vitamin B12 are required for normal leukopoiesis, to treat anemia caused by chronic renal failure, but these vitamins will not by themselves accklerate leu- can cer-related anemia, and anemia caused by other copoiesis caused by drug-induced myelosuppression. They are used to because of decreased production of intrinsic factor by treat neutropenia associated with cancer chemother- gastric parietal cells. Vitamin B12 defciency causes a apy, bone marrow transplantation, and various disease megaloblastic anemia characterized by an abnormally states. Persons with pernicious anemia will also have a low serum level of vitamin B12 and a high serum concentration of methylmalonic acid, because B12 is required to convert methylmalonyl CoA to succinyl CoA. Patients with end-stage renal disease often require epoetin treatment to prevent anemia because their kidneys are unable to produce suffcient erythropoi- etin to maintain adequate erythrocyte production. A neuromodulator is a processing occurs because of the complex interplay of neu- general term for any substance that exerts an effect on neu- rotransmitters and neuromodulators acting on their recep- rotransmission among a set of neurons in the brain. Brain disorders are seen in association with a taneously interact with receptors on neurons in several dif- variety of disease processes, including degenerative, isch- ferent neuronal tracts. Although short-term drug treatment may be effective in relieving acute symptoms such Neurotransmitter Synthesis and Metabolism as pain and insomnia, drug therapy for many brain disorders Neurotransmitters are synthesized in neuronal cell bodies or is a lifelong process. A neurotransmitter’s gists believed that neurons communicated by electrical action is then terminated either by its reuptake into the signals directly passing from neuron to neuron in a hard- presynaptic neuron or by its degradation to inactive com- wired fashion much like wires in a telegraph relay. The early pounds, with degradation catalyzed by enzymes located on pharmacologists argued for chemical transmission, with sub- presynaptic and postsynaptic neuronal membranes or within stances released into the synapse between communicating the cytoplasm. Modern research shows that both were right to Neurotransmitters can also diffuse from the synapse of some degree because most neuronal communication occurs their origin to affect neurons in the surrounding vicinity. In by chemical neurotransmitters serving as messengers that this way, different neurotransmitters released from different enable neurons to communicate with one another. However, types of neurons form a chemical milieu, as described previ- there is also evidence of direct voltage signaling between ously. The net infuence of the chemical milieu on neuro- neurons at electrotonic or gap junctions. An early statement by Sir Henry Dale, known as Dale’s principle, suggested that each neuron con- Excitatory and Inhibitory Neurotransmission tained only one type of neurotransmitter. It was also thought that neurotransmitter action was excitatory postsynaptic membrane potential reaches fring limited to the single synapse where released. An inhibitory epinephrine and serotonergic fbers arising from brain stem postsynaptic membrane potential hyperpolarizes the neu- nuclei, led to the concept of the chemical soup or chemical ronal membrane and inhibits the fring of action potentials. The net effect of neuronal interactions on neurotransmission from B to C is shown in the accompanying table. Each interaction presupposes that the other neurons + + are quiescent at that time. Ethanol (ethyl alcohol), for instance, can diminish the inhibitory infuence Acetylcholine of the cerebral cortex on certain human behaviors and Acetylcholine, synthesized from acetyl coenzyme A and thereby increase drug-induced behaviors, a phenomenon choline, is degraded to acetate and choline by the enzyme called behavioral disinhibition. Acetylcholine receptors depressants, initially or at low doses, exert their effects on (also known as cholinergic receptors) consist of two main the smaller and more numerous inhibitory neurons, creating types: muscarinic receptors and nicotinic receptors. The disinhibition via excitation owing to removal of inhibitory properties and mechanisms of these receptors are compared neurotransmitters. Binding of these amino acid neurotransmitters directly sensory processing, and motor coordination, respectively. Amino Acids Examples of slow neurotransmitters are norepinephrine Several amino acids are important neurotransmitters in the and serotonin acting at G protein–coupled receptors. Others, such as glutamate and slower, multistep process with alterations in second mes- aspartate, are excitatory. A slow (long-acting) signal is the most ubiquitous inhibitory neurotransmitter in the can infuence the overall tone of a neuron because it can brain and spinal cord. Table 18-1 lists the names, receptors, mecha- receptor are used to control spasticity (Chapter 24). Glycine is a major inhibitory trans- ionotropic receptors, also called ligand-gated ion chan- mitter in the spinal cord. Its strychnine-sensitive receptors nels, which are directly associated with ion channels, and are coupled with the chloride ion channel, and activation metabotropic receptors, which are typical G protein– of these receptors leads to membrane hyperpolarization.

It undergoes considerable frst-pass and systemic approved for treating symptoms of benign prostatic hyper- metabolism before renal and biliary excretion cheap kamagra super online visa. Doxazosin and terazosin are longer-acting α1-blockers The most common adverse effects of α1-blockers include that are usually administered once a day to treat hyperten- hypotension generic kamagra super 160 mg amex, dizziness order kamagra super in india, and sedation order kamagra super from india, which are attributed sion or to relieve lower urinary tract symptoms. Their dura- to excessive vasodilation and to the central nervous system tion of action ranges from about 20 hours (terazosin) to effects of these drugs. A small percentage of men selective α1-blockers that relieve lower urinary tract symp- experience abnormal ejaculation when taking α1-blockers. These drugs are indi- cated only for treating symptoms of urinary outfow 4 obstruction in men with prostatic hyperplasia and are not used to treat hypertension. In addition to blocking β1- 1 adrenoceptors in heart tissue, they block β2-adrenoceptors Before After treatment treatment in smooth muscle, liver, and other tissues. All of 6 the nonselective β-blockers can be administered orally, and propranolol can also be administered parenterally. Mechanisms and Effects 4 The nonselective β-blockers competitively block the effects of norepinephrine and other adrenoceptor agonists at β1- and β2-adrenoceptors. In addition, some of them 2 exhibit intrinsic sympathomimetic activity and membrane- Before After stabilizing (local anesthetic) activity, as outlined in Table 9-2 treatment treatment and defned later. In the kidneys, β1-adrenoceptor blockade reduces renin secretion 130 from the juxtaglomerular cells. In the eye, adrenoceptor blockade reduces aqueous humor secretion and intraocular 120 pressure. Blockade of β2-adrenoceptors produces several effects 110 that can lead to adverse reactions in some patients receiving β-blockers, such as patients with asthma or diabetes. In the 100 lungs, antagonism of β2-adrenoceptors can cause broncho- constriction in patients with asthma. These persons depend on endogenous epinephrine to prevent bronchospasm, so 90 agents that block β2-adrenoceptors should be avoided or Before After treatment treatment used with great caution. If a β-blocker is required to treat C an asthmatic patient, a selective β1-blocker should be used. Cardiovascular effects of α1-adrenoceptor antagonists (solid stimulated glycogenolysis and can thereby reduce hepatic line) and β1-adrenoceptor antagonists (dotted line) in patients with hyper- tension. A, The α -blockers reduce peripheral vascular resistance, whereas glucose output during hypoglycemia resulting from excessive 1 β1-blockers can cause a slight increase in peripheral resistance as a result of insulin administration. B, The β1-blockers reduce cardiac output, whereas of the early signs of hypoglycemia (e. For these reasons, β-blockers should be used and β1-blockers reduce mean arterial blood pressure. A comparison of the effects of norepinephrine, phentolamine, and prazosin on heart rate. This increases the stimulation of cardiac β1-adrenoceptors (β1) and results in tachycardia. C, Prazosin, a selective α1-blocker, does not block α2-adrenoceptor–mediated inhibition of norepinephrine release. Specifc Properties This effect is observed when the patient is resting and sym- Tables 9-1 and 9-2 compare the effects, uses, and properties pathetic tone is low, and it can result in a smaller reduction of four nonselective β-blockers: nadolol, pindolol, proprano- in heart rate than that caused by β-blockers without intrinsic lol, and timolol. When sympathetic tone is high, Of these four drugs, only pindolol has intrinsic sympa- pindolol acts as a competitive receptor antagonist to inhibit thomimetic activity, or partial agonist activity, which sympathetic stimulation of the heart in the same manner as enables it to exert a weak agonist effect on β-adrenoceptors. Prostatic hyperplasia leads to obstruction of urine outfow from the bladder through the urethra. Although pindolol and propranolol exhibit membrane- reduce these symptoms until the underlying thyroid disorder stabilizing activity, or local anesthetic activity, nadolol and can be treated. Drugs with local anesthetic activity can block quently administered to patients with acute myocardial sodium channels in nerves and heart tissue and thereby slow infarction because clinical trials have shown that β-blockers conduction velocity. In patients with pheochromocytoma, propranolol trast, propranolol has many clinical applications. Proprano- is used to reduce cardiac stimulation caused by circulating lol is used, for example, to treat patients with hypertension, catecholamines released from this adrenal medullary tumor. Patients tension and angina pectoris and to prevent migraine with thyrotoxicosis often experience tachycardia and palpi- headache. The drug is absorbed through the cornea and penetrates shown in Tables 9-1 and 9-2. In glaucoma, which is discussed in greater α1-adrenoceptors and possesses antioxidant activity. Each of detail in Chapter 6, β-blockers reduce aqueous humor these actions contributes to its cardioprotective effects in secretion and intraocular pressure. The antioxidant effects ophthalmic use partly because it does not have membrane- of carvedilol include (1) inhibition of lipid peroxidation in stabilizing activity and therefore does not anesthetize the myocardial membranes, (2) scavenging of free radicals, and cornea when instilled into the eye. In addition, carve- dilol has antiapoptotic properties that can prevent myocyte death and reduce infarct size in persons with myocardial Selective β1-Blockers ischemia. For these reasons, carvedilol has been called a General Properties “third-generation β-blocker and neurohumoral antagonist,” Examples of selective β1-blockers include acebutolol, aten- and its value in treating myocardial infarction has been olol, esmolol, and metoprolol. Because β1- Carvedilol decreases blood pressure and has been used in adrenoceptors are primarily located in cardiac tissue, the the treatment of hypertension. Chapter 12, it also decreases cardiac afterload, increases In comparison with the nonselective β-blockers, the selec- cardiac output, and reduces mortality in patients with heart tive β1-blockers produce less bronchoconstriction and other failure. Their selectivity for β1- Labetalol is a nonselective β-blocker and a selective α1- adrenoceptors, however, is not absolute, and β2-receptor blocker that is primarily used in the treatment of hyperten- blockade increases with dosage. It is 5 to 10 times more potent as a β-blocker than as β1-blockers should be used with caution in patients who an α-blocker, but both actions are believed to contribute to have asthma. Labetalol decreases heart rate and cardiac output as a result of β1-adrenoceptor blockade, and it decreases peripheral vascular resistance as a result of α1- Specifc Properties adrenoceptor blockade. Tables 9-1 and 9-2 compare the effects, uses, and properties of four selective β1-blockers. It is converted to an active metabolite, N-acetyl acebutolol, which has a • The α-adrenoceptor antagonists relax smooth muscle longer half-life than the parent compound and accounts for and decrease vascular resistance, whereas the the drug’s relatively long duration of action. Acebutolol is β-adrenoceptor antagonists reduce heart rate and administered orally to treat hypertension and cardiac cardiac output. Atenolol shows less variability in its oral absorption than • The nonselective α-blockers include phenoxybenza- do other β-blockers and is excreted largely unchanged in the mine (a noncompetitive blocker) and phentolamine (a urine. These drugs block both α1- and ated with a lower incidence of central nervous system side α2-adrenoceptors and are primarily used to treat hyper- effects (e. Esmolol is rapidly metabolized to inactive com- β1- and β2-adrenoceptors, include nadolol, pindolol, pounds by plasma esterase enzymes. In comparison with other Metoprolol is used to treat hypertension, angina pecto- β-blockers, pindolol has a higher degree of intrinsic ris, and acute myocardial infarction. It can be administered sympathomimetic activity (partial agonist activity), and orally or parenterally, and it is extensively metabolized propranolol has a higher degree of membrane- by cytochrome P450 enzymes before undergoing renal stabilizing activity (local anesthetic activity). Both of these drugs are administered choconstriction than do nonselective β-blockers. Topical ocular adminis- including the prevention of migraine headache and tration of betaxolol reduces aqueous humor secretion while the treatment of hypertension, angina pectoris, cardiac producing negligible blockade of systemic β-adrenoceptors. Chapter 9 y Adrenoceptor Antagonists 85 • Carvedilol blocks α- and β-adrenoceptors and exerts Answers And explAnAtions other cardioprotective effects that make it useful in the treatment of myocardial infarction and heart 1. Phentolamine is a nonselective review Questions α-adrenoceptor antagonist that can be injected directly into affected tissues to counteract the vasoconstrictive Questions 1 to 4. Alfuzosin is a selective α1- (A) alfuzosin adrenoceptor blocker that acts to relax smooth muscle in (B) carvedilol the bladder outfow tract and thereby relieve urinary (C) betaxolol obstruction caused by prostatic hyperplasia. Alfuzosin is (D) phenoxybenzamine sometimes used in combination with fnasteride, a drug (E) phentolamine that inhibits the conversion of testosterone to dihydrotes- 1. A woman experiences pain and ischemia in her fnger tosterone and thereby reduces prostatic growth. Carvedilol is a nonselec- she carries for emergency treatment for allergic tive β-adrenoceptor antagonist and a selective α1- reactions. A man complains of urinary urgency, frequency, and noc- It acts to reduce cardiac output by blocking cardiac β1- turia and is found to have benign enlargement of the adrenoceptors, and to reduce peripheral resistance by prostate gland. This tumor secretes massive quantities of markedly elevated levels of epinephrine and norepineph- epinephrine and norepinephrine, thereby causing severe rine metabolites in his urine and requires a long-acting hypertension.