By Q. Yespas. Monmouth University, West Long Branch New Jersey.

This process is inhibited by carbonic In the collecting duct (D) cheap fluticasone 500 mcg with visa, sodium enters the principal cells anhydrase inhibitors such as acetazolamide buy fluticasone from india. Sodium is then transferred into In the thick ascending limb of the loop of Henle (B) purchase online fluticasone, the the interstitial fuid by the sodium pump discount fluticasone 250 mcg visa, while potassium is Na+,K+,2Cl− symporter transports sodium, potassium, and pumped in the opposite direction and then moves through chloride ions into the tubular cells, and then sodium is trans- potassium channels into the tubular fuid. By inhibiting the symporter, the their effects via two mechanisms: amiloride and triam- loop diuretics reduce the back-diffusion of potassium and terene inhibit the entrance of sodium into the principal increase the excretion of calcium and magnesium. Osmotic Diuretics Glycerol Heart failure; nausea and vomiting; and pulmonary Potentiates effects of other diuretics. In cases of hypokalemic metabolic alkalosis, potas- be used to treat edema associated with heart failure, cir- sium chloride is administered intravenously and orally. Cor- rhosis, corticosteroid therapy, estrogen therapy and renal rection of the serum potassium level then leads to correction disorders such as nephrotic syndrome. Because thiazides of the acid-base disturbance as potassium displaces hydrogen reduce calcium excretion and decrease urinary calcium levels, ions from body cells and fewer hydrogen ions are secreted they are helpful in treating patients with nephrolithiasis by the collecting duct. In addition to causing electrolyte and acid-base distur- Thiazides are also used to treat nephrogenic diabetes bances, the thiazides can cause several metabolic abnormali- insipidus. In this disorder, the kidneys are not responsive ties, including elevated blood glucose, uric acid, and lipid to circulating antidiuretic hormone, and patients may levels. Thiazides appear to decrease insulin sensitivity and excrete from 10 to 20 L of urine per day. Thiazides exert thereby contribute to the development of diabetes in some a paradoxical antidiuretic effect in these patients and patients. In addition, thiazide-induced hypokalemia can reduce the excessive urine volume dramatically. Hyperuricemia, of diabetes insipidus, the effectiveness of thiazides is which is caused by inhibition of uric acid secretion from the believed to stem from a reduction in plasma volume proximal tubule, can lead to the development of gout. The reduced plasma volume serves effects of thiazide diuretics on serum lipid levels are dis- to increase sodium and water reabsorption from the pro- cussed in greater detail in Chapter 10. As a result, the urine output management of cardiovascular and renal diseases (see Table falls. Chapter 13 y Diuretics 125 Nephron Blood Hyperuricemia Uric acid Thiazides inhibit Blood Na+ K+ Thiazides H+ increase K+ Kaliuresis Metabolic alkalosis Hypokalemia Body cells H+ K+ H+ Increased K+ H+ excretion A Pancreas Blood Pancreas Insulin Thiazides decrease Hyperglycemia B Figure 13-1. A, Inhibition of uric acid secretion in the proximal tubule can lead to hyperuricemia and gout. Hypokalemia can lead to metabolic alkalosis by promoting the exchange of intracellular potassium for hydrogen ions and by increasing the excretion of hydrogen ions. The increased excretion is caused by lack of availability of potassium for exchange with sodium in the collecting duct. B, In the presence of hypokalemia, the amount of insulin secreted by the pancreas can be reduced, thereby leading to hyperglycemia. These drugs include chlorthalidone, indapamide, The several thiazide compounds that are available have and metolazone. Indapamide has both diuretic and vasodi- almost identical actions but differ in their potency and phar- lator actions and is indicated for the treatment of hyperten- macokinetic properties. Loop Diuretics Thiazide-like Diuretics Drug Properties Thiazide-like diuretics have a different chemical structure, Chemistry and Pharmacokinetics. They are the preferred diuretics in the treatment of persons with renal 100 impairment, because (unlike thiazide and other diuretics) Loop diuretics they are effective in patients whose creatinine clearance drops below 30 mL/min. Loop diuretics are often the drugs of choice for patients with edema caused by heart failure, cirrhosis, and other disorders. Although they are prescribed 50 for patients with hypertension, the thiazide diuretics are usually preferred for this condition. Loop diuretics can be Thiazide diuretics used to treat hypercalcemia, whereas the thiazide diuretics can increase serum calcium levels slightly. Loop comparison with other loop diuretics, torsemide has a diuretics produce dose-dependent diuresis throughout their therapeutic dosage range, whereas thiazide diuretics have a relatively fat dose-response somewhat longer half-life and a signifcantly longer duration curve and a limited maximal response. All three of the drugs are partly metabolized before they are excreted in the urine. Loop diuretics Ethacrynic acid is the only loop diuretic that is not a sul- inhibit the Na+,K+,2Cl− symporter in the ascending limb of fonamide derivative, and it is occasionally used when patients the loop of Henle and thereby exert a powerful natriuretic are allergic or intolerant to the sulfonamide drugs in this effect. Otherwise, it is seldom used because it tends to inhibit the reabsorption of a greater percentage of fltered produce more ototoxicity than do other loop diuretics. Loop diuretics are sometimes called high-ceiling diuretics because they produce a dose-dependent diuresis Potassium-Sparing Diuretics throughout their clinical dosage range. This property can be Two types of potassium-sparing diuretics exist: the epithelial contrasted with the rather fat dose-response curve and sodium channel blockers and the aldosterone receptor limited diuretic capability of thiazides and other diuretic antagonists. In addition to their natriuretic effect, the loop diuretics Amiloride and Triamterene produce kaliuresis by increasing the exchange of sodium and Amiloride and triamterene are epithelial sodium channel potassium in the late distal tubule and collecting duct via the blockers. By blocking the entry of sodium into the principal same mechanisms as those described for the thiazide diuret- tubular cells of the late distal tubule and collecting duct (see ics. Loop diuretics also increase magnesium and calcium Box 13-1), these drugs prevent sodium reabsorption at this excretion by reducing the reabsorption of these ions in the site and indirectly reduce the secretion of potassium into ascending limb (see Box 13-1). Through these actions, the inhibition of the Na+,K+,2Cl− symporter, which reduces the potassium-sparing diuretics produce a modest amount of back-diffusion of potassium into the nephron lumen. Amiloride and triamterene reduction of potassium back-diffusion decreases the tran- are primarily used to prevent and treat hypokalemia induced sepithelial electrical potential that normally drives the para- by thiazide and loop diuretics. Inhibition uses of amiloride, triamterene, and other potassium-sparing of this process thereby increases magnesium and calcium diuretics are outlined in Tables 13-1 to 13-4. The most characteristic adverse effect of the potassium- Adverse Effects and Interactions. Loop diuretics can sparing diuretics is hyperkalemia, but this is unlikely to produce a variety of electrolyte abnormalities, including occur unless the patient also ingests potassium supplements hypokalemia, hypocalcemia, hypomagnesemia, and meta- or other drugs that increase serum potassium levels (e. These diuretics can also increase blood angiotensin antagonists) or unless the patient has a renal glucose and uric acid levels in the same manner as the thia- disorder that predisposes to hyperkalemia. In some patients, use of loop diuretics causes ototoxicity with manifestations such as tinnitus, ear pain, Spironolactone vertigo, and hearing defcits. In most cases the hearing loss Spironolactone is a structural analog of aldosterone that is reversible. Other adverse effects and drug interactions are competitively blocks aldosterone binding to the miner- listed in Table 13-4. Loop diuretics are highly effective in the treatment expression of genes for sodium channels and the sodium of pulmonary edema, partly because of the vasodilation that pump that enable sodium reabsorption and potassium Chapter 13 y Diuretics 127 secretion. By blocking these actions, spironolactone Carbonic Anhydrase Inhibitors reduces sodium reabsorption and the accompanying secre- Drug Properties tion of potassium. Clinical trials have shown that spironolactone reduces mortality in persons with heart failure, as described in Specifc Drugs Chapter 12. Acetazolamide is one of several associated with an increased incidence of hyperkalemia. Dorzol- used in the treatment of polycystic ovary disease and hir- amide is partly absorbed from the eye into the circulation sutism in women. The drug is eliminated in a biphasic mastia and impotence in men (caused by the drug’s antian- manner, with a rapid decline in serum levels followed by a drogenic effects) and hyperkalemia. Eplerenone is a newer much slower release from erythrocytes, and it has a half-life aldosterone antagonist that produces fewer endocrine side of 4 months. This enzyme catalyzes the conversion of carbon dioxide and water to carbonic acid, which spon- Osmotic Diuretics taneously decomposes to bicarbonate and hydrogen ions. Because of this action, mannitol is used to treat cere- water and other substances that make up the aqueous humor. Glycerol the chronic form of glaucoma, although they must be com- is administered orally for this purpose, whereas mannitol is bined with other drugs to treat the acute form. Now some of these drugs, including dorzol- administration, it is fltered at the glomerulus but is not amide, are available for topical ocular administration. It osmotically attracts and zolamide is administered every 8 hours in the treatment of retains water as it moves through the nephron and into the chronic ocular hypertension and open-angle glaucoma. In the reabsorption of Hence, mannitol has both direct and indirect actions that sodium bicarbonate, bicarbonate must be converted to promote diuresis.

Disease processes such as hepatic failure may lead to decreased levels of vitamin K–dependent coagulation factors fluticasone 500 mcg without a prescription. The majority of the external nose is cartilaginous and is formed by the paired alar and lateral nasal cartilages and the unpaired septal cartilage discount fluticasone 500mcg overnight delivery. The nasal cavity is a somewhat pyramidal space within the skull located between the two orbits generic 250mcg fluticasone with mastercard. It is subdivided into right and left nasal cavities by the nasal septum cheap fluticasone 100 mcg with visa, which is formed by the vomer bone, perpendicular plate of the ethmoid bone, nasal crests of the maxilla and palatine bones, and the septal cartilage. The roof of each cavity is formed by the frontal, ethmoid, and sphenoid bones, and its floor is formed by the palatine portion of the maxilla and the horizontal plate of the palatine bone. The posterior openings of each nasal cav- ity into the nasopharynx are the posterior choanae. The complex lateral walls are formed by portions of the nasal, maxilla, ethmoid, and palatine bones. The superior and middle conchae are features of the ethmoid bone, whereas the inferior nasal concha is an individual bone. The posterosuperior por- tion of the nasal cavity, superior to the superior conchae, is the sphenoethmoid recess. Inferior to each of the conchae is a space named for the concha immediately superior to it. Thus, the superior, middle, and inferior nasal meatuses lie inferiorly to the superior, middle, and inferior nasal conchae, respectively. Each nasal cav- ity is lined with a highly vascular mucosa whose function is to warm and humidify inspired air (Figure 51-1). Anterior ethmoidal artery Posterior ethmoidal artery Septal branches of sphenopalatine artery Kiesselbach’s area Septal branch of superior labial artery Greater palatine artery figure 51-1. Each nasal cavity is supplied by nasal branches of the sphenopalatine artery, anterior and posterior ethmoidal arteries, greater palatine artery, and superior labial and lateral nasal branches of the facial artery (Figure 51-2). These arter- ies anastomose at Kiesselbach area on the anterior portion of the nasal septum (opposite the anterior end of the inferior concha). She has lost consciousness but cur- rently is alert and has equally reactive pupils. She is asymptomatic except for clear nasal leakage from the right nostril that has not abated over 24 h. The major blood supply to the anterior septum is the sphenopalatine artery, a branch of which supplies the nasal septum. The sphenopalatine artery arises from the maxillary artery, which is a terminal branch of the external carotid artery. The most common location of epistaxis is the region of the anterior septum known as Kiesselbach plexus, which has a rich anastomosis of arteries. However, over the past 24 h, she has had fever and difficulty opening her mouth while talking or swallowing. On exami- nation, the patient has a fever of 101°F, with redness of the left submandibular region extending to the left side of her throat. The physician states that the infection in the mouth has spread to the neck and may ultimately enter the chest. There is a left submandibular inflammation extend- ing to the left side of the throat. Occasionally, an infection involv- ing the molar teeth may extend into the submandibular space (Ludwig angina) and affect the trachea or carotid sheath contents. Fever, painful edema, limited neck mobility, drooling, and difficulty opening the mouth are clinical findings. In such cases, laryngoscopy may lead to laryngospasm and complete airway obstruction. The best treatment is intravenous antibiotics, airway protection (intubation if needed), and operative drainage of the abscess. Be able to describe the structures in the floor of the mouth and submandibular space and its communications with the spaces of the neck 3. Superiorly, it attaches to the hyoid bone, mandible, and base of the skull; inferiorly, it attaches to the acromion, clavicle, and manubrium of the sternum. The prevertebral fascia surrounds the cervical vertebral column, the spi- nal cord, and the pre- and paravertebral musculatures. It attaches to the base of the skull superiorly and the ligamentum nuchae posteriorly, and blends with the anterior longitudinal ligament of the vertebral column in the thorax. The pretracheal fascia surrounds the larynx, trachea, esophagus, thyroid, and parathyroid glands and splits to enclose the infrahyoid (strap) muscles of the neck. It is attached superiorly to the hyoid bone and inferiorly blends with the fibrous pericardium in the thorax. The carotid sheath is usually described as having originated in the investing, prevertebral, and pretracheal layers. Between the prevertebral and buccopharyngeal fasciae lies the retropharyn- geal space (“danger space”). This space is a pathway for spread of infection to the thorax, possibly resulting in cardiac tamponade. Within the pretracheal fascia is a potential space filled with loose areolar connective tissue called the visceral space (Figure 52-1). The submandibular space lies between the mucosa of the floor of the mouth and the mylohyoid and hyoglossus muscles. The root of the tongue lies medially, and the inner surface of the mandible lies laterally. The space contains the sublin- gual gland and ducts, a portion of the submandibular gland and its duct, and the lingual and hypoglossal nerves. A cleft exists between the mylohyoid and hyoglos- sus muscles, through which the submandibular gland wraps around the posterior border of the mylohyoid muscle. The roots of the posterior molar teeth are close to the inner surface of the mandible, thus increasing the risk for dental abscesses spreading into the submandibular space. Infectious material can thus spread inferiorly into the visceral space through the cleft between the mylohyoid and hyoglossus muscles. Compartments of the neck: 1 = investing fascia, 2 = sternocleidomastoid muscle, 3 = infrahyoid muscle, 4 = trapezius muscle, 5 = visceral (pretracheal) fascia, 6 = thyroid gland, 7 = trachea, 8 = recurrent laryngeal nerve, 9 = esophagus, 10 = buccopharyngeal fascia, 11 = alar fascia (present only in upper pharynx), 12 = retropharyngeal (retroesophageal) space, 13 = neurovascular (carotid) sheath, 14 = common carotid artery, 15 = internal jugular vein, 16 = vagus nerve, 17 = prevertebral fascia, 18 = phrenic nerve, 19 = sympathetic trunk, 20 = roots of the brachial plexus, 21 = vertebral artery. At that time, he developed severe chest pain due to infection of the medi- astinum. He appeared in the emergency department with a 2-cm laceration in the anterolateral neck. The wound was superficial, but the physician observed muscle fibers just deep to the superficial fascia. The major pathway between the infections of the neck and the chest is through the retropharyngeal space, which is a potential space between the prevertebral layer of fascia and the buccopharyngeal fascia surrounding the pharynx. Dental anesthesia involving the lower molar teeth is called a lower man- dibular block. The nerve affected is the inferior alveolar nerve branch of the mandibular nerve, which is a branch of V3. The platysma muscle is a wide flat muscle that covers the anterolateral region of the neck. The mass is not inflamed, and the infant is otherwise in good health and feeding well. The puncta open into lacrimal canaliculi, which ter- minate at the lacrimal sac and, in turn, are drained by the nasolacrimal duct. The nasolacrimal duct develops from a solid cord of cells that recanalizes to establish the lumen of the duct and terminates in the inferior nasal meatus. Atresia of the duct (due to failure to recanalize) occurs in 1 to 3 percent of newborns. Atresia of the lacrimal canaliculi presents with excessive tearing and without a mass. Nasolacrimal duct atresia presents as a mass due to enlargement of the lacrimal sac, and the mass accompanied by excessive tearing suggests atresia of the canaliculi and the naso- lacrimal duct.

In patients with · · respiratory disease causing shunt or V/Q mismatch this value can exceed 5kPa and is the most common cause of arterial hypoxaemia order fluticasone 500 mcg line. Alveolar gas equation End-expired gas contains a variable mixture of gas from regions of alve- · · olar dead space discount 500mcg fluticasone overnight delivery, from alveoli with V/Q ratios > 1 order generic fluticasone from india, and from ‘ideal’ alveoli buy generic fluticasone from india. Oxygen carriage in the blood Oxygen is carried in the blood in two forms: in combination with haemo- globin and in solution. Haemoglobin The haemoglobin molecule consists of four subunits, each containing an iron-porphyrin group attached to a globin chain. Three normal forms of globin chain exist (α, β, and γ), with adult haemoglobin A (HbA) consisting of two α and two β chains. Weak electrostatic bonds that determine the quaternary structure of haemoglobin are responsible for the features of the binding of oxygen by haemoglobin. In oxyhaemoglobin (HbO2) the electrostatic bonds are weaker and haemoglobin assumes its relaxed (R) state. This allows an oxygen molecule better access to the haem group which lies at the bottom of a crevice in the globin chain, such that the affinity for oxygen increases by 500 times. One oxygen molecule binding to one globin chain alters the conformation, and therefore oxygen affinity, of the other three globins, an effect referred to as co-operativity that explains the well- known shape of the haemoglobin (Hb) dissociation curve. A single amino acid substitution in the globin chain profoundly alters the function of the Hb molecule. Suppression of HbA production leads to a compensatory production of HbF, which shifts the oxyhaemoglobin dissociation curve to the left. A small proportion of the iron in Hb exists as the ferric form (Fe3+), and these molecules of methaemoglobin (metHb) are unable to carry oxygen. Carbon dioxide in solution hydrates to form carbonic acid, a reaction which is catalysed by the enzyme carbonic anhydrase, before the carbonic acid dissociates into bicarbonate and hydrogen ions. Intracellular accumulation of these ions is overcome by the following: • Buffering of H+ ions by Hb, the capacity of which increases as oxygen is dissociated from the Hb • Hamburger or chloride shift—excess bicarbonate ions are actively transported out of the cell in exchange for chloride ions to maintain electrical neutrality. This classification is in widespread use, but most diseases that traditionally cause Type 1 respiratory failure can also result in hypercapnia. The pathophysiological concepts responsible for the failure of gas exchange are fully dealt with in b Respiratory physiology and pathophysi- ology, p 2, but for the purposes of diagnosis, the causes of hypoxia and hypercapnia can be simplified as follows. Causes of hypoxia · · • Regional mismatching of ventilation and perfusion (V/Q) in the lung. The history may be obtainable from the patient, but may have to be sought from the relatives, the notes, or other healthcare professionals. Some types of severe hypoventilatory failure can develop with minimal breathlessness (particularly some chest bellows syndromes and muscular dystrophies). In these cases, worsening respiratory function is more likely to present as increasing lethargy and stupor. Nevertheless, certain patterns of dyspnoea are helpful: • Abrupt commanding dyspnoea suggests large airway narrowing (inhaled foreign body, anaphylactic laryngeal oedema), major pulmonary embolism (associated anterior chest tightness), or tension pneumothorax (often recall initial pleuritic pain when questioned). Although always a worrying symptom for both patient and doctor, in many cases no underlying diagnosis is found. Past medical history A past history of respiratory disease is clearly relevant but non-respiratory disease may also carry significance. Recurrent sickling results in pulmonary hypertension and a restrictive pattern of lung function. Pets The presence of pets can often give an indication to the potential underlying respiratory problem. This is partly explained by an increase in aspira- tion risk and impaired innate immunity (reduced macrophage phagocytic function and neutrophil chemotaxis). This condition is now being described as ‘alcoholic lung’ and consists of: • Reduced pulmonary glutathione levels. The mortality of pneumonia in this group is much higher than the mor- tality predicted using physiological scoring systems. Non-respiratory symptoms • Loss of appetite, poor motivation, and fatigue are associated with gradually advancing hypoventilation in neuromuscular disorders. Examination Physical examination in the intensive care setting has constraints due to limited patient accessibility (intubation, invasive lines, monitoring equip- ment etc. Nevertheless regular clinical examination should be conducted rather than relying solely on monitored physiological parameters, imaging, or laboratory results. Initial observation Skin colour • Central cyanosis due to deoxyhaemoglobin is readily detected in polycythaemia and easily missed in anaemia. Skin perfusion • Warm vasodilated extremities and bounding pulse associated with chronic hypercapnia, sepsis, or anaphylaxis. Nutritional state • Pickwickian habitus of chronic hypoventilation syndrome or obstructive sleep apnoea. Respiratory system assessment The respiratory examination is well described elsewhere, and a detailed discussion is beyond the scope of this book. May be inspiratory or expiratory depending on whether the obstruction is extrathoracic or intrathoracic, respectively. Consolidation is also caused by fluid (pulmonary oedema), blood (pulmonary haemorrhage), and tumours. Review of progress Respiratory failure is a dynamic process that may alter during the course of the illness, and whilst therapy is directed where possible at restoring normal function, the underlying aetiology or the associated treatment (e. Vigilance for alter- ations in the pattern of respiratory failure and low threshold for diagnostic review is appropriate throughout but essential for patients in the critical care environment. If progress is unexpectedly slow, or deterioration takes place, consider: • Is the diagnosis correct? Consider all sources (brain, meninges, sinuses, pleura, lung, heart, biliary tree and liver, abdomen, bone, joints, vascular devices, drains, skin, urine, blood). Whenever clinical concern is raised regarding worsening of respiratory failure, a complete reappraisal should be undertaken: reassess the history, examination, and investigations, and update the current examination and investigations. Investigation of respiratory disease Pulse oximetry The amounts of red (660nm wavelength) and infra-red (940nm wave- length) light absorbed by blood varies with the proportion of oxygen- ated to deoxygenated haemoglobin. Pulse-oximetry uses this principle to measure the percentage oxygen saturation in arterial blood. It only meas- ures pulsatile flow, so it is not affected by static signals (such as those from venous or capillary blood). Readings are not affected by jaundice or anaemia, but there are some reports of inaccuracy in pigmented patients. Accuracy is also affected by: • Haemodynamic instability • Carboxyhaemoglobin (registers as SaO2 90%) • Methaemoglobinaemia (registers as SaO2 85%) • Low oxygen saturations (<80%) • Pulsatile venous flow (e. Capillary blood gas sampling offers an excellent but underutilized alternative to serial arte- rial puncture outside the high-dependency setting (allowing for an under- read of 0. PaO2 PaO2 alone is insufficient to fully evaluate the defect in oxygenation and a number of methods have been described to analyse it further: • The PaO2/FiO2 ratio • The A-aO2 gradient. PaO2/FiO2 ratio PaO2/FiO2 attempts to quantify the severity of hypoxaemia, although gas exchange and ventilation are not analysed individually. The American European Consensus Conference set the following PaO2/FiO2 ratio diagnostic criteria in 1994: • Acute lung injury <40kPa (approx. The PaO2/FiO2 ratio is simple to calculate and in widespread use, but both mathematical analyses and clinical studies have highlighted important shortcomings. These are most commonly due to V/Q· · mismatch and shunt • Allows assessment of the severity of the gas exchange defect • Is a particularly useful tool in hypercarbic patients where hypoxaemia may occur in the absence of any gas exchange abnormality. This may be sufficient to ‘normalize’ PaO2 in the face of a gas exchange abnormality. Even though the PaO2 is within the normal range, the A-a gradient is elevated at 4. Three important assumptions are made and should be kept in mind when using this analysis: • Gas exchange is at a steady state. While this reliably · · happens in healthy lungs, in areas of high V/Q there may not be full equilibration, and the A-a gradient will be underestimated. There are only two causes: • Reduced minute ventilation • Increased dead space: • Anatomical as a result of equipment deadspace and rebreathing • Physiological as a result of alveolar dead space from V·/Q· mismatch. These compensatory mechanisms take days to weeks to occur, so the extent of compensation can be used as a measure of chronicity of the respiratory dysfunction. Base excess represents the theoretical quantity of acid or alkali that needs to be added to the blood to return it to a normal pH (7. It is not a substitution for understanding of blood gas analysis, but it can be useful in detecting mixed respiratory and metabolic acidoses. This reduces the haemoglobin buffering component and is thought to more closely represent whole body acid–base status.

All other anticoagulants inhibit the activity of clotting factors: either factor Xa buy generic fluticasone 250 mcg on line, thrombin fluticasone 500mcg sale, or both 250 mcg fluticasone for sale. Anticoagulants are in three pharmacologic classes—vitamin K antagonists buy fluticasone 250mcg free shipping, direct factor Xa inhibitors, and direct thrombin inhibitors (see Table 44. Heparin and Its Derivatives: Drugs That Activate Antithrombin All drugs in this group share the same mechanism of action. Specifically, they greatly enhance the activity of antithrombin, a protein that inactivates two major clotting factors: thrombin and factor Xa. In the absence of thrombin and factor Xa, production of fibrin is reduced, and hence clotting is suppressed. Although all three activate antithrombin, they do not have equal effects on thrombin and factor Xa. Heparin (Unfractionated) Heparin is a rapid-acting anticoagulant administered only by injection. Heparin differs from warfarin (an oral anticoagulant) in several respects, including mechanism, time course, indications, and management of overdose. Chemistry Heparin is not a single molecule, but rather a mixture of long polysaccharide chains, with molecular weights that range from 3000 to 30,000. The active region is a unique pentasaccharide (five-sugar) sequence found randomly along the chain. Because of these negative charges, heparin is highly polar and hence cannot readily cross membranes. Mechanism of Anticoagulant Action Heparin suppresses coagulation by helping antithrombin inactivate clotting factors, primarily thrombin and factor Xa. To inactivate thrombin, heparin must simultaneously bind with both thrombin and antithrombin, thereby forming a ternary complex. In contrast, to inactivate factor Xa, heparin binds only with antithrombin; heparin itself does not bind with factor Xa. All three drugs share a pentasaccharide sequence that allows them to bind with—and activate—antithrombin, a protein that inactivates two major clotting factors: thrombin and factor Xa. All three drugs enable antithrombin to inactivate factor Xa, but only heparin also facilitates inactivation of thrombin. Upper panel: Unfractionated heparin binds with antithrombin, causing a conformational change in antithrombin that greatly increases its ability to interact with factor Xa and thrombin. When the heparin-antithrombin complex binds with thrombin, heparin changes its conformation so that both heparin and antithrombin come in contact with thrombin. Inactivation of factor Xa is different: it only requires contact between activated antithrombin and factor Xa; contact between heparin and factor Xa is unnecessary. By activating antithrombin, and thereby promoting the inactivation of thrombin and factor Xa, heparin ultimately suppresses formation of fibrin. Because fibrin forms the framework of thrombi in veins, heparin is especially useful for prophylaxis of venous thrombosis. Because it cannot cross membranes, heparin does not traverse the placenta and does not enter breast milk. Heparin binds nonspecifically to plasma proteins, mononuclear cells, and endothelial cells. However, in patients with hepatic or renal impairment, the half-life is increased. In addition, heparin is used for patients undergoing open heart surgery and renal dialysis; during these procedures, heparin serves to prevent coagulation in devices of extracorporeal circulation (heart-lung machines, dialyzers). Heparin may also be useful for treating disseminated intravascular coagulation, a complex disorder in which fibrin clots form throughout the vascular system and in which bleeding tendencies may be present; bleeding can occur because massive fibrin production consumes available supplies of clotting factors. Bleeding develops in about 10% of patients and is the principal complication of treatment. These include reduced blood pressure, increased heart rate, bruises, petechiae, hematomas, red or black stools, cloudy or discolored urine, pelvic pain (suggesting ovarian hemorrhage), headache or faintness (suggesting cerebral hemorrhage), and lumbar pain (suggesting adrenal hemorrhage). First, dosage should be carefully controlled so that the activated partial thromboplastin time (see later) does not exceed 2 times the control value. In addition, candidates for heparin therapy should be screened for risk factors (see “Warnings and Contraindications”). B l a c k B o x Wa r n i n g : S p i n a l o r E p i d u r a l H e m a t o m a Heparin and all other anticoagulants pose a risk for spinal or epidural hematoma in patients undergoing spinal puncture or spinal or epidural anesthesia. Pressure on the spinal cord caused by the bleed can result in prolonged or permanent paralysis. Risk for hematoma is increased by the following: • Use of an indwelling epidural catheter • Use of other anticoagulants (e. This is a potentially fatal immune-mediated disorder characterized by reduced platelet counts (thrombocytopenia) and a seemingly paradoxical increase in thrombotic events. The underlying cause is development of antibodies against heparin–platelet protein complexes. These antibodies activate platelets and damage the vascular endothelium, thereby promoting both thrombosis and a rapid loss of circulating platelets. Ischemic injury secondary to thrombosis in the limbs may require amputation of an arm or leg. Platelet counts should be determined frequently (2–3 times a week) during the first 3 weeks of heparin use and monthly thereafter. If 3 severe thrombocytopenia develops (platelet count below 100,000/mm ), heparin should be discontinued. Because commercial heparin is extracted from animal tissues, these preparations may be contaminated with antigens that can promote allergy. Vasospastic reactions that persist for several hours may develop after 1 or more weeks of treatment. Heparin must be used with extreme caution in all patients who have a high likelihood of bleeding. Among these are individuals with hemophilia, increased capillary permeability, dissecting aneurysm, peptic ulcer disease, severe hypertension, or threatened abortion. Heparin must also be used cautiously in patients with severe disease of the liver or kidneys. Heparin is contraindicated for patients with thrombocytopenia and uncontrollable bleeding. In addition, heparin should be avoided both during and immediately after surgery of the eye, brain, or spinal cord. Drug Interactions In heparin-treated patients, platelet aggregation is the major remaining defense against hemorrhage. Aspirin and other drugs that depress platelet function or affect coagulation will weaken this defense and hence must be employed with caution. Laboratory Monitoring The objective of anticoagulant therapy is to reduce blood coagulability to a level that is low enough to prevent thrombosis but not so low as to promote spontaneous bleeding. Because heparin levels can be highly variable, achieving this goal is difficult and requires careful control of dosage based on frequent tests of coagulation. Heparin dosage is titrated on the basis of laboratory monitoring, and hence dosage can be adjusted as needed based on test results. Heparin sodium is supplied in single-dose vials; multidose vials; and unit-dose, preloaded syringes that have their own needles. Two routes are employed: intravenous (either intermittent or continuous) and subcutaneous. Heparin is not administered orally because heparin is too large and too polar to permit intestinal absorption. Postoperative prophylaxis of thrombosis, for example, requires relatively small doses. Because heparin is formulated in widely varying concentrations, you must read the label carefully to ensure that dosing is correct. Children/adolescents Many anticoagulants can be used safely in children, just in smaller doses. Breastfeeding Data are lacking regarding safety of these medications in breastfeeding.

A: Microaneurysms are the out pouching of capillary walls due to pericyte loss discount fluticasone 100mcg fast delivery, appears as small red dots order fluticasone with mastercard. Microaneurysm is always along the vessel wall order cheap fluticasone online, it may be confused with haemorrhage generic 100 mcg fluticasone free shipping. A: These are lipid and protein residues of serous leakage from the vessels, yellowish in colour and irregular in outline with sharply defned margin. A: As follows: • Control of diabetes mellitus, stop smoking and control of hypertension (if any). Diabetic maculopathy is one of the common causes of loss of vision in patient with non-proliferative retinopathy. Maculopathy Preproliferative Proliferative retinopathy Proliferative retinopathy retinopathy (Severe vitreous haemorrhage) Q:How to treat such a case? Plus • There are multiple photocoagulation scars (appears like exudate, with areas of small brown or yellowish spot of variable size and shape). My diagnosis is Proliferative diabetic retinopathy, treated with photocoagulation. A: Unknown, probably there is production of angiogenic factors from the area of ischaemic retina. These new vessels are very fragile and leaking, liable to rupture causing haemorrhage (intraret- inal, preretinal or vitreous). Serous protein leakage from these vessels stimulates connective tissue reaction called retinitis proliferans. Q:What are the indications of laser photocoagulation therapy in diabetic retinopathy? Presentation of a Case: • There are multiple areas of black pigmentation like bone spicules with variable size and shape, some in criss-cross pattern, at the periphery of fundus. A: It is a progressive degenerative disease of retina with pigmentary epithelium in a bone spicule pattern. A: As follows: • Isolated or congenital: Bardet–Biedl syndrome (previously called Laurence–Moon–Biedl syndrome). A: As follows: raise the upper eye lid, see the following— • Divergent squint (eyeball is fxed in downward and outward position). Nuclear lesion (causes are: infarction, haemorrhage, neoplasm and multiple sclerosis). Unruptured aneurysm of posterior communicating artery (there is painful ophthalmoplegia). Bilateral ptosis Bilateral ptosis Bilateral ptosis (senile) Bilateral ptosis (congenital) (myasthenia gravis) (ocular myopathy) Q:How to differentiate between ptosis of myopathy and ptosis due to other cause? A: It is a hereditary disorder, inherited as autosomal dominant or sporadic, common in young, charac- terized by bilateral ptosis with complete ophthalmoplegia. A: As follows: • Neck: Lymph nodes, scar, thyromegaly, aneurysm (carotid and aortic). Horner’s syndrome (left) Horner’s syndrome (bilateral) Q:What is Horner’s syndrome? A: It is a syndrome due to lesion in the sympathetic pathway characterized by: • Partial ptosis. A: Upper eye lead is controlled by Levator palpebrae superioris which is supplied by 3rd nerve. A: It originates from the sympathetic nucleus in hypothalamus and passes through the brain stem to the lateral horn of C8 and T1 segment of spinal cord. From there, pre-ganglionic fbres emerge and pass to sympathetic ganglia (usually superior cervical ganglia). Then the post-ganglionic fbres pass in the carotid sheath with internal carotid artery, enter into the skull along with it and in the cavern- ous sinus, then joins with the ophthalmic division of Vth nerve. Then it enters into the orbit via short ciliary nerve and supply the dilator pupillae, Muller’s muscle and sweat glands on the side of face. A: I want to see the features of tabes dorsalis, such as— • Wrinkling of forehead with bilateral ptosis (due to compensatory overaction of frontalis). Loss of light refex, but persistence of accommodation refex Slow reaction to light and accommodation 4. Presentation of a Case • The pupil of right (or left) eye is dilated than other, regular (or circular). A: It is an abnormality characterized by absent or delayed pupillary constriction to light or accommo- dation. During accommodation, after some delay, abnormal pupil constricts slowly, may be smaller than normal. It is also called myotonic pupil, which is a benign condition, common in young women, usually unilateral (80%), rarely bilateral. Miosis (Right eye) Mydriasis (Left eye) Anisocoria Q:What are the causes of dilated pupil (mydriasis)? It is found in encephalitis lethargica due to epidemic of von Economo’s encephalitis that causes parkinsonism. However, when light is alternately fo- cused from one eye to other, the pupil on the affected side dilates slowly, when exposed to light. The mechanism is as follows: • When light is focused on healthy eye, a rapid pupillary constriction occurs in both eyes. When light is focused again on the affected eye, the eye fails to transmit the message to continue the constriction as quickly as normal. As a result, pupils have time to recover and dilate, despite the light shining on abnormal eye. Look at the eyes from front, comment about sclera that is visible between upper eyelid and upper limbus of cornea. Look any swelling of eyelids, congestion of sclera, chemosis (oedema of conjunctiva), corneal ulcer, thyroid stare (a frightened expression). Look at the eyes from behind to confrm proptosis (eyeball may be visible above the supraorbital ridge). Place a paper between the supraorbital ridge and maxillary prominence (note the space between this). If obvious exophthalmos, note the following points: • Lid retraction (by inspection, ask the patient to look straight): The upper eyelid is retracted and sclera above the upper margin of corneal limbus is visible (normally 1/3rd of cornea is covered by upper eyelid). Now examine the following points: • Signs of thyrotoxicosis (warm sweaty hands, tremor of out-stretched hands and tachycardia). Presentation of a Case (Bilateral or Unilateral Exophthalmos): • There is bilateral (or unilateral) exophthalmos (as evidenced by sclera above the upper limbus is visible, more marked on right or left). A: It is synonymous, it means protrusion of eyeball (according to some authority: If unilat- eral, it is called proptosis and if bilateral it is called exophthalmos). Unilateral exophthalmos (right) Bilateral exophthalmos Bilateral exophthalmos (Graves’ disease) Q:What are the eponyms of signs of Graves exophthalmos? A: As follows: • Thyroid function tests (for Graves disease, see chapter on Endocrinology). Read the following topics carefully: • Cavernous sinus thrombosis: Usually follows infection of nose, orbit or face. A bruit is heard over the orbit, the intensity of which may be reduced by pressing over the carotid artery. Carotico-cavernous fstula is due to rupture of infraclinoid part of internal carotid artery to the cavernous sinus, usually due to trauma or spontaneous. Ask the patient to sit, look straight in front and see whether nystagmus is present or not: • If present in central gaze: likely to be ocular nystagmus (fxation nystagmus). Now see any nystagmus during movement of eyeball (horizontal or vertical): • Keep your fnger straight in front of the eye (not below), 2 to 3 feet from the patient. At the same time, observe any failure of adduction of other eye (called internuclear ophthalmoplegia, which is also called ataxic nystagmus). A: May be cerebellar lesion (on affected side) or vestibular lesion (on contralateral side). My diagnosis is Internuclear ophthalmoplegia (also called ataxic or dissociated nystagmus). A: It is the involuntary, rhythmical and oscillatory movement of the eyes due to inability to maintain the posture of eyes, owing to lack of balance of opposing ocular muscles.