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Gain of function mutation Na+ reabsorption in collecting tubules (activity of Na+ channel). Hereditary deficiency of 11-hydroxysteroid dehydrogenase, which normally converts cortisol (can activate mineralocorticoid receptors) to cortisone (inactive on mineralocorticoid receptors) in cells containing mineralocorticoid receptors. Excess cortisol in these cells from enzyme deficiency mineralocorticoid receptor activity hypertension, hypokalemia, metabolic alkalosis. Can acquire disorder from glycyrrhetinic acid (present in licorice), which blocks activity of 11-hydroxysteroid dehydrogenase. Treatment: corticosteroids (exogenous corticosteroids endogenous cortisol production mineralocorticoid receptor activation). Affects baroreceptor function; limits reflex bradycardia, which would normally accompany its pressor effects. Hormones acting on kidney Atrial natriuretic peptide Secreted in response toatrial pressure. Binds to receptors on principal cells, causing number of aquaporins and H2O reabsorption. If measured Pco2 > predicted Pco2 concomitant respiratory acidosis; if measured Pco2 < predicted Pco2 concomitant respiratory alkalosis: Pco2 = 1. Associated with hypokalemia, risk for calcium phosphate kidney stones (due to urine pH and bone turnover). Causes: amphotericin B toxicity, analgesic nephropathy, congenital anomalies (obstruction) of urinary tract. Associated with azotemia, oliguria, hypertension (due to salt retention), proteinuria. Crescents consist of fibrin and plasma proteins (eg, C3b) with glomerular parietal cells, monocytes, macrophages. Presents with unilateral flank tenderness, colicky pain radiating to groin, hematuria. Most common kidney stone presentation: calcium oxalate stone in patient with hypercalciuria and normocalcemia. Can result from ethylene glycol (antifreeze) ingestion, vitamin C abuse, hypocitraturia, malabsorption (eg, Crohn disease). Calcium phosphate: pH Ammonium magnesium phosphate pH Radiopaque Radiopaque Radiopaque Radiopaque Also known as struvite; account for 15% of stones. Caused by infection with urease bugs (eg, Proteus mirabilis, Staphylococcus saprophyticus, Klebsiella) that hydrolyze urea to ammonia urine alkalinization. Treatment: low sodium diet, alkalinization of urine, chelating agents if refractory. Serum creatinine becomes elevated if obstruction is bilateral or if patient has only one kidney. Immunotherapy (eg, aldesleukin) or targeted therapy for metastatic disease, rarely curative. A B C Renal oncocytoma A Benign epithelial cell tumor arising from collecting ducts (arrows in A point to wellcircumscribed mass with central scar). Large eosinophilic cells with abundant mitochondria without perinuclear clearing B (vs chromophobe renal cell carcinoma). B Fibrovascular core in papillary tumor Dysplastic urothelium Squamous cell carcinoma of the bladder Chronic irritation of urinary bladder squamous metaplasia dysplasia and squamous cell carcinoma. Risk factors include Schistosoma haematobium infection (Middle East), chronic cystitis, smoking, chronic nephrolithiasis. Urinary incontinence Stress incontinence Outlet incompetence (urethral hypermobility or intrinsic sphincteric deficiency) leak with intra-abdominal pressure (eg, sneezing, lifting).

It should not be used in acute myocardial infarction, as it increases myocardial oxygen demand and may be pro-dysrhythmogenic. Nefopam causes a high incidence of minor adverse effects, especially after parenteral use. These include sweating, nausea, headache, dry mouth, insomnia, dizziness and anorexia. Nefopam is contraindicated in glaucoma, and can cause urinary retention in men with prostatic hypertrophy. It is extensively metabolized by the liver to inactive compounds excreted in the urine. These work by inhibiting prostaglandin synthesis, and are available over the counter. Some anaesthetists give synthetic high potency opioids, such as fentanyl, either intravenously or epidurally, for obstetric surgery. Several endogenous peptides with analgesic properties are widely distributed throughout the nervous system. These peptides are derived from larger precursors (proopiomelanocortin, pro-encephalin and pro-dynorphin) and act as neurotransmitters or neuromodulators (neurotransmitters convey information from an axon terminal to a related nerve cell, whereas neuromodulators influence the responsiveness of one or more neurons to other mediators, see Figure 25. A fourth category, is now not classified as an opioid receptor because they bind non-opioid psychotomimetic drugs of abuse, such as phencyclidine and the only opioids that bind appreciably to them are drugs like pentazocine that have psychotomimetic adverse effects. Blocking opioid receptors with naloxone (see below) has little effect in normal individuals, but in patients suffering from chronic pain it produces hyperalgesia. A number of notably discreditable events, including the Opium Wars, ensued from the commercial, social, moral and political interests involved in its world-wide trade and use. Opium is a complex mixture of alkaloids, the principal components being morphine, codeine and papaverine. Much work has gone into synthesizing morphine analogues in the hope of producing a drug with the therapeutic actions of morphine, but without its disadvantages. Synthetic drugs such as pethidine, dextropropoxyphene and pentazocine were originally incorrectly thought to lack potential for abuse. Pain relief by acupuncture may also be mediated by encephalin release, because it is antagonized by naloxone. The resulting pattern of pharmacological activity depends on their affinity for the various receptors and whether they are full or partial agonists. The affinity of narcotic analgesics for -receptors parallels their analgesic potency. In addition to their involvement in brain function, the opioid peptides play a neuroendocrine role. High concentrations of opioid peptides are also present in sympathetic ganglia and the adrenal medulla. Their function at these sites has not been elucidated, but they may play an inhibitory role in the sympathetic system. On withdrawal of the drug, endogenous opioids are not sufficient to stimulate the insensitive receptors, resulting in a withdrawal state characterized by autonomic disturbances. Mechanism of action Morphine relieves both the perception of pain and the emotional response to it. Adverse effects Certain patients are particularly sensitive to the pharmacological actions of morphine. These include the very young, the elderly and those with chronic lung disease, untreated hypothyroidism, chronic liver disease and chronic renal failure. Morphine depresses the sensitivity of the respiratory centre to carbon dioxide, thus causing a progressively decreased respiratory rate. Patients with decreased respiratory reserve due to asthma, bronchitis, emphysema or hypoxaemia of any cause are more sensitive to the respiratory depressant effect of opioids. Bronchoconstriction occurs via histamine release, but is usually mild and clinically important only in asthmatics, in whom morphine should be used with care and only for severe pain.

After instillation of dilute pilocarpine eyedrops (fourth row), the pupil constricts markedly. Horner syndrome is named after the Swiss ophthalmologist Johann Horner,whodescribedthesyndromein1869,but,likeothereponymous pupillaryfindings(AdiepupilandMarcusGunnpupil),earlierpublished descriptionsofthefindingexist. Horner Syndrome Versus Simple Anisocoria When evaluating a pupil that dilates abnormally (left half of. The sympathetic innervation of the eye consists of three neurons connected in series: first-order neurons, second-order neurons, and third-order neurons. The first-order neurons (central neurons) extend from the posterior hypothalamus to the C8 to T2 level of the spinal cord. The second-order neurons (preganglionic neurons) leave the spinal cord and travel over the lung apex, around the subclavian artery, and along the carotid artery to the superior cervical ganglion. The third-order neurons (postganglionic neurons) diverge and take two paths: Those to the pupil and lid muscles travel along the internal carotid artery through the cavernous sinus to reach the orbit; those to the facial sweat glands travel with the external carotid artery to the face. Lesions in any of these neurons cause Horner syndrome and distinct associated physical signs. Both pictures are of the same patient, before (top) and 45 minutes after (bottom) instillation of cocaine drops into each eye. At baseline, there is a mild right ptosis and miosis, which suggests the diagnosis of Horner syndrome of the right pupil. Cocaine eyedrops block the reuptake of norepinephrine at the myoneural junction of the iris dilator, causing the pupil to dilate unless norepinephrine is absent because of sympathetic denervation. Theoretically,therefore,Hornersyndromefromathird-order neuron lesion would preserve facial sweating, whereas Horner syndrome from first- and second-order neurons would cause asymmetrical facial sweating. Whenthecause of Horner syndrome remains unexplained despite careful bedside examination,manycliniciansnowroutinelyordermagneticresonanceimaging toinvestigatetheentiresympatheticpathwaytotheeye. Analternative and older method uses eyedrop tests to distinguish first-order or secondordernervelesionsfromthird-ordernervelesions. In one study of 317 patients with the unilaterally redeye,anisocoriaof1mmormorewiththesmallerpupilintheredeye significantlyincreasedtheprobabilityofseriouseyedisease(i. Outcome after acute traumatic subdural and epidural haematoma in Switzerland: a single-centre experience. Duration of positive urine for cocaine metabolite after ophthalmic administration: implications for testing patients with suspectedHornersyndromeusingophthalmiccocaine. Moderate, severe, and very severe nonproliferative retinopathy share the same funduscopic findings, although they differ in severity (based on standardized photographs) and the number of retinal quadrants involved. Hard exudates (deposition of lipid in the inner retina) are small, white or yellowish-white deposits with sharp margins that often have a waxy or glistening appearance. Soft exudates (or cottonwool exudates) are ischemic swellings of the superficial nerve fiber layer, which appear as white, round, or oval patches with ill-defined, feathery edges. The center figure depicting the fundus of a patient with diabetic retinopathy is surrounded by four enlarged views, each labeled with a letter (A to D) corresponding to specific locations on the center figure. The diameter of microaneurysms is less than the width of a major vein at the disc margin (reproduced in square inset). The findings that best predict subsequent proliferative retinopathy are venous beading, intraretinal microvascular abnormalities, and the extent of microaneurysms and hemorrhages. Soft exudates are less predictive, and the extent of hard exudates correlates poorly with subsequent proliferative retinopathy. In fact, the most common causes of diminished visual acuity in diabetics are cataracts (49% of diabetics with diminished acuity) and macular degeneration (29%), not diabetic retinopathy (15%). Not surprisingly, specialists using direct ophthalmoscopy perform better than general clinicians, and dilated examinations are superior to nondilated ones. Macular edema is rarely detected by general providers using direct ophthalmoscopy. Table 21-2 reviews the screening schedule recommended by the American Diabetes Association. Definition of findings: For sight-threatening retinopathy, proliferative retinopathy or macular edema, or both. Any patient with macular edema, more than moderate nonproliferative retinopathy, or proliferative retinopathy should be seen by eye care providers with experience in the management of diabetic retinopathy. In some patients with normal eye examinations, eye specialists may advise less frequent examinations (every 2 to 3 years). Visual acuity measurement and ocular co-morbidity in diabeticretinopathyscreening.

They cause blockade of repetitive discharges at a concentration that does not block normal impulse conduction. These agents are not all sedative, but selectively block repetitive discharges at concentrations below those that block normal impulse conduction. Carbamazepine and phenytoin prolong the inactivated state of the sodium channel and reduce the likelihood of repetitive action potentials. Consequently, normal cerebral activity, which is associated with relatively low action potential frequencies, is unaffected, whilst epileptic discharges are suppressed. The ideal anti-epileptic drug would completely suppress all clinical evidence of epilepsy, while producing no immediate or delayed side effects. This ideal does not exist (the British National Formulary currently lists 23 anti-epileptic drugs), and the choice of drug depends on the balance between efficacy and toxicity and the type of epilepsy being treated. Control should initially be attempted using a single drug which is chosen on the basis of the type of epilepsy. The dose is increased until either the seizures cease or the blood drug concentration (see Chapter 8) is in the toxic range and/or signs of toxicity appear. It should be emphasized that some patients have epilepsy which is controlled at drug blood concentrations below the usual therapeutic range, and others do not manifest toxicity above the therapeutic range. Thus, estimation of drug plasma concentration is to be regarded as a guide, but not an Table 22. The availability of plasma concentration monitoring of anticonvulsant drugs has allowed the more efficient use of individual drugs, and is a crude guide to compliance. If a drug proves to be ineffective, it should not be withdrawn suddenly, as this may provoke status epilepticus. Another drug should be introduced in increasing dosage while the first is gradually withdrawn. Few studies have investigated combined drug therapy, although empirically this is sometimes necessary. Combinations of three or more drugs probably do more harm than good by increasing the likelihood of adverse drug reaction without improving seizure control. Many anticonvulsant drugs are enzyme inducers, so pharmacokinetic interactions are common. They are particularly troublesome early in treatment, before induction of the enzyme responsible for carbamazepine elimination (see above). Sedation, ataxia, giddiness, nystagmus, diplopia, blurred vision and slurred speech occur in 50% of patients with plasma levels over 8. Other effects include rash and (much more rarely) blood dyscrasia, cholestatic jaundice, renal impairment and lymphadenopathy. Carbamazepine can cause hyponatraemia and water intoxication due to an antidiuretic action. Its use in pregnancy has been associated with fetal neural-tube defects and hypospadias. Generally increase the dose every two weeks until either the seizures cease or signs of toxicity appear and/or the plasma drug concentration is in the toxic range. Probably less than 10% of epileptic patients benefit from two or more concurrent anticonvulsants. Drug interactions Carbamazepine should not be combined with monoamine oxidase inhibitors. It is a potent enzyme inducer and, in particular, it accelerates the metabolism of warfarin, theophylline and the oral contraceptive.