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Power 113 Approach the general principles of assessing power in the upper limbs (Chapter 4) apply here too generic fluconazole 200 mg mastercard antifungal while breastfeeding. Sequence the sequence tests the muscles in turn in a logical order to assess a number of muscles from each major peripheral nerve and nerve root purchase genuine fluconazole on-line fungus gnats plants. Radicular pain is weak ness in muscles inner- usually the frst symptom of nerve root vated by several peripheral compression purchase discount fluconazole online fungi gills definition. Typically safe fluconazole 150 mg fungus gnats miracle gro, distal is usually indicates the level of origin: worse than proximal and it Nerve Pain radiation is usually symmetrical root • sacral plexopathies are afected C5 Shoulder essentially unilateral C6 Lateral forearm and thumb polyneuropathies with C7 Dorsum of hand and muscles affected from middle fnger multiple nerves C8 Medial forearm, medial two fngers • a root lesionis most readily L1 Groin identifed by the distribution L2 Medial thigh of pain; however, if there is L3 Knee L4 Inner calf involvement of the ventral L5 Outer calf and great toe or spinal root, weakness will S1 Lateral foot and sole also be seen. This will be in S2 Posterior thigh muscles not restricted to a single peripheral nerve but to a recognisable spinal Clinical insight level Getting above the lesion: when signs of weakness (or sensory disturbance) are What happens next? The following features suggest a cerebellar lesion: • dysmetria: overshooting the target • intention tremor: tremor beginning as the heel approaches the target • dysdiodochokinesia: disorganised movements Proprioceptive loss can also cause tremor or dysmetria but this tends to be less dramatic. Tell them that you are going to ask them whether the pin-prick is sharp or dull and to compare it between sides. The principles of the sensory examination are to: • start distally and work proximally • test each major peripheral nerve • test each major dermatome • test both lateral and dorsal columns of the spinal cord • map out any area of sensory change encountered Equipment This requires a Neurotip, tuning fork and universal containers with hot and cold water. However, if cauda equina syndrome is suspected, also ensure to check perianal and perineal sensation: 122 Lower limbs • buttocks (inferior lateral clunical nerve; S3) • perianal (pudendal nerve; S4/5) 4. For this, test: • hips (L1) • level of the umbilicus (T10) • halfway between the umbilicus and nipples (T7) • level of the nipples (T4) • lower border of the clavicle (T2) 5. For this, test: • rib at the level of the umbilicus (T10) • rib halfway between the umbilicus and nipples (T7) • rib at the level of the nipples (T4) • clavicle (T2) 6. The distribution may look like multiple peripheral nerves or nerve roots • radiculopathy:usually multiple modalities. Lesions localising to the muscles or peripheral nerves should be investigated with nerve conduction studies. Inspection Syndromes, posture, fasciculations, wasting, feet Tone Spastic, faccid Power Gluteus maximus, adductors, iliacus, quadriceps, gluteus medius/gluteus minimis, hamstrings, gastrocnemius, tibialis posterior, small muscles of the foot, tibialis anterior, extensor hallucis longus, peroneus longus and brevis Refexes Knee, crossed adductor, ankle, plantars, clonus Co-ordination Heel–shin, tap rhythm Sensation Pin-prick: (1) outer foot, great toe, medial tibia, knee, lateral thigh, popliteal fossa, buttocks, perianal, perineum; (2) thoracic region if indicated Vibration: (1) lateral malleolus, great toe, mid-tibia, tibial plateau, hip; (2) ribs and sternum if indicated Table 5. Nonetheless, a systematic approach to examining cerebellar function is needed when the history or initial examination indicates cerebellar disease. Its role in the fne control of movements is the most clinically relevant; however, it is also involved in a wide range of higher functions, including emotion and cognition. It has a unique and uniform arrangement of cells that constitute basic circuits repeated many millions of times. It can be divided into diferent regions based on gross anatomy, which also corresponds to the origin of the major inputs and outputs. The cerebellum forms the feed-forward control over movements, smoothing out movements initiated elsewhere and ensuring the intended movement is accurately performed. There are three anatomically distinct areas: the anterior lobe, the posterior lobe and the focculonodular lobe (ure 6. The cerebellum has three functionallydistinct areas, each with distinct inputs and outputs: 126 Cerebellum Spinal and trigeminal inputs Corticopontine inputs Vestibular inputs Intermediate part of hemisphere Vermis Lateral part of Anterior lobe hemisphere Fastigial nucleus Interposed nucleus Dentate nucleus Flocculondular lobe Vestibular inputs and outputs ure 6. The anatomical focculonodular lobe receives mainly vestibular inputs and projects back to the vestibular nuclei and is closely involved in eye movements. Vertigo This is the sensation of the environment spinning while stationary – like ‘stepping of a roundabout’. Patients may not be familiar with this meaning of the word, and so care should be taken to fully determine the nature of any dizziness, faintness or unsteadiness that they report. Ataxia may be evident on walking, when a patient will tend to fall to the afected side of a unilateral lesion. Similar symptoms such as dysmetria (overshooting or undershooting a target) and impaired check (failure to stop a limb movement appropriately) also commonly occur in cerebellar lesions. As with many of the clinical abnormalities of cerebellar disease, it is thought to be due to poor co-ordination of agonist and antagonist muscles. There are distinct ‘cerebellar syndromes’ comprising a constellation of these symptoms that point to a particular anatomical location of the lesion. Syndrome Location of lesion Predominant clinical features Rostral vermis Anterior lobe/rostral Broad-based gait syndrome vermis Truncal ataxia Caudal vermis Posterior or Vertigo syndrome focculonodular lobe Staggering gait Truncal ataxia Nystagmus Hemispheric Cerebellar hemisphere Limb ataxia syndrome Intention tremor Dysmetria Dysarthria Dysdiodokokinesia Table 6. Lesions of the vermis tend to cause more truncal ataxia than limb ataxia, and fewer obvious limb signs. Lesions in the hemispheres cause a greater range of symptoms and include prominent limb signs ipsilateral to the lesion 132 Cerebellum Cerebellar disease has many underlying causes, both de- velopmental/hereditary and acquired. Developmental or hereditary Key causes include Arnold–Chiari and Dandy–Walker malforma- tions and the hereditary ataxias. The hereditary ataxias These include a large number of rare autosomal dominant and recessive conditions: • the most common autosomal dominant conditions are the spinocerebellar ataxias, which are chronic, progressive conditions. There is often arefexia of the ankles, cardiomyopathy and diabetes in up to one-quarter of cases Acquired There are a wide range of acquired causes of cerebellar disease, including vascular, toxic, neoplastic, infective and autoimmune pathologies. This causes headache in addition to cerebellar symptoms and commonly causes decreased consciousness and may lead to life-threateninghydrocephalus Toxins Alcohol is the most common toxic cause. Chronic overuse can lead to Wernicke’s (ataxia, acute confusion, eye movement disorder) or Korsakoff’s syndromes (a chronic amnesic state). Benzodiazepines, phenytoin, carbamazepine, chemo- therapeutic drugs and lithium are the more common drugs associated with dysarthria and ataxia. Tumours In children medulloblastomas, astrocytomas and ependy momasare relatively common primary tumours found in the cerebellum. Paraneoplastic syndromescausing cerebellar syn- dromes are well described and are usually the result of small cell lung carcinoma or breast cancer. Infective or immune There are many infective or immune causes, including: • encephalitis from any cause can result in an initial cerebellar syndrome but usually progresses to a more forid encephalitic picture • autoimmune diseases such as multiple sclerosisare a common cause in young people and are typically of a subacute nature • up to 10% of patients with coeliac diseasehave neurological involvement and this can include a slowly progressive cerebellar syndrome What happens next? Patients with cerebellar disease not readily explained by vascular causes or alcohol usually require careful and extensive investigation. Revisiting the family history is an ideal place to start and it may be helpful to actually see and examine family members. General observation Inspect body and feet Palpate pulse, auscultate carotids Palpate abdomen Vertigo Ataxia Sitting Standing Walking Nystagmus Primary gaze Gaze evoked Intention tremor Reassess with fnger–nose test Test for impaired check Speech Note any dysarthria or scanning speech Hypotonia Assess tone in limbs Dysdiodochokinesia Test alternating clapping Test heel–shin. Although it is less useful for fne localisation, it is very helpful in determining the impact of a disease process on a patient’s cognitive processes and for assessing its progression over time. This is often all that is needed in patients without significant cognitive impairment and provides an assessment of: • orientation Clinical insight • registration (immediate memory) Patients vary greatly in their background education and cultures. It is also more reliable at distinguishing between diferent subtypes or dementia, such as Alzheimer’s disease, frontotemporal dementia and supranuclear palsy. Bedside cognitive examinations are not designed to tease out precise anatomical regions; language function is the exception, and is discussed below. Language Language is such a defning feature of our human nature that the complexity of neural computations that it requires is easily overlooked.

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Evidence of underactivity of the sympathetic nervous system includes presence of marked postural hypotension and heightened sensitivity to dehydration and sedative–hypnotic agents buy cheap fluconazole 50mg on-line antifungal lamisil. Excessive parasympathetic nervous system activity is reflected in facial flushing associated with a feeling of generalized warmth and bradycardia purchase 150 mg fluconazole with visa diabet-x antifungal. Hypertension may be managed with short-acting α-adrenergic blocking agents order fluconazole cheap online antifungal yeast cream, hypotension with fluids buy fluconazole canada fungus behind ear, and bradyarrhythmias with atropine [19]. Paralyzed limbs require the attention of the physiotherapist so that passive limb movements can be carried out and contractures prevented. Pain may be treated with standard doses of analgesic agents, but they do not often provide adequate relief. Gabapentin or carbamazepine is particularly helpful in treating the pain in the acute phase [48] and, when disabling, epidural morphine may be necessary [49]. Deep venous thrombosis and pulmonary embolism are ever-present dangers in the bedridden patient with immobilized limbs; for these patients, in addition to physical therapy, subcutaneous heparin (5,000 U twice per day) and support stockings are recommended [48]. A number of multicenter studies [45,50,51] showed that plasmapheresis has a beneficial effect on the course of the illness, even in those patients with several poor prognostic signs [52]. Patients treated with plasmapheresis are able to walk, on average, 1 month earlier than untreated patients; respirator-dependent patients so treated walk 3 months sooner than those who do not receive plasma exchange [45]. It is important to keep in mind, however, that there are also risks with albumin, including bleeding, thrombosis, and infection (owing to loss of coagulating factors and γ- globulins during plasma exchange, which are not present in the albumin replacement fluid). Because of its potential for inducing hypotension, patients who have compromise of their cardiovascular system or autonomic dysfunction may not tolerate this procedure. For those patients who are still ambulatory, plasmapheresis may also be considered if given within 2 weeks of onset. Although retreatment with the same therapy is commonly practiced [59], evidence-based literature is lacking regarding the efficacy of repeat treatment [58]. Retreatment with the same therapy has also been suggested in those patients who are severely affected and unresponsive to treatment. Recovery is not always complete; only 60% of patients recover full motor strength at 1 year, whereas 14% have severe motor problems. Although patients who are restored to nearly normal function can resume work and leisure activities, some degree of ankle dorsiflexor weakness or numbness of the feet is commonly encountered. About 5% to 10% have a protracted course, are ventilator dependent for several months, and do not fully recover [61]. Causes of fatal outcomes include dysautonomia, sepsis, acute respiratory distress syndrome, and pulmonary emboli [4]. Poor prognostic factors include older age (≥50 years); severe disease at nadir (bedbound or requiring mechanical ventilation); rapid onset of disease; preceding diarrheal illness; and evidence of axonal loss (reflected on electrodiagnostic studies) [27,37,60,62]. A clinical prognostic scoring system has been developed to help predict the risk of respiratory failure during the first week along with the risk of being unable to walk at 6 months using several of the above prognostic factors [64,65]; it is available online at https://gbstools. The mainstay of treatment is excellent nursing and medical care, with close attention to respiratory and autonomic function. Hiraga A, Mori M, Ogawara K, et al: Recovery patterns and long term prognosis for axonal Guillain–Barré syndrome. Senanayake N, Karalliedde L: Neurotoxic effects of organophosphorus insecticides: an intermediate syndrome. Koga M, Takahashi M, Masuda M, et al: Campylobacter gene polymorphism as a determinant of clinical features of Guillain–Barré syndrome. The French Cooperative Group on Plasma Exchange in Guillain–Barré Syndrome: Efficiency of plasma exchange in Guillain–Barré syndrome: role of replacement fluids. The French Cooperative Group on Plasma Exchange in Guillain–Barré Syndrome: Appropriate number of plasma exchanges in Guillain– Barré Syndrome. Plasma Exchange/Sandoglobulin Guillain–Barré Syndrome Trial Group: Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain–Barré syndrome. Chió A, Cocito D, Leone M, et al: Guillain–Barré syndrome: a prospective, population-based incidence and outcome survey. The key to handling the emergent problems associated with myasthenia is simply the management of airway and ventilatory support with the same care as in any other instance of respiratory failure (see Chapters 8, 65, and 166). With respiration under control, the treatment of the underlying disease can be unhurried and orderly, and it is successful in most patients. This chapter reviews briefly the pathogenesis, clinical spectrum, and diagnosis of myasthenia gravis and focuses on the intensive care setting, including management of the patient in crisis or in the perioperative period. The result is fewer receptors that can be activated at affected neuromuscular junctions, causing weaker muscular contraction. Electrophysiologic study of myasthenic neuromuscular junctions discloses end-plate potentials that are diminished in amplitude [3]. These observations have been clearly linked to the receptor alterations and an altered postsynaptic response to normal quantal transmitter release from the presynaptic nerve terminals. Understanding of this underlying pathophysiology has, in turn, enabled rational approaches to treatment. Various immunosuppressive therapies and acetylcholinesterase inhibitors are primary therapeutic options in managing myasthenia gravis (see later). The overall female to male ratio is approximately 3:2, although there are two distinct sex-specific incidence peaks, with the incidence among women peaking in the third decade and that among men in the fifth to sixth decades. It may range from a mild and relatively inconsequential disease over a normal lifetime to a fulminant incapacitating disorder. The specific muscles involved and the severity of weakness are highly variable, between individuals and within the same individual over time. Ocular muscles are most frequently involved; diplopia is common, and various patterns of ophthalmoparesis are seen. Bulbar muscles are also frequently affected, leading to varying combinations of facial paresis, dysarthria, and dysphagia. Limb muscle involvement may vary from very isolated weakness to generalized (usually proximal) weakness and fatigability. Respiratory muscle weakness is unfortunately not rare, and respiratory insufficiency and the inability to handle oral and upper airway secretions are the critical problems that bring myasthenics to the intensive care setting. Myasthenia should also be considered in any patient who cannot be weaned from ventilator support after an otherwise uncomplicated surgical procedure. Longitudinal studies indicate that if an individual manifests only oculomotor weakness for more than 2 years, there is little chance of later limb or respiratory weakness. Although several clinical classification schemes have been devised for categorizing myasthenics according to the distribution and severity of their disease, it is preferable to emphasize the fact that myasthenics often fluctuate over time, with variability rather than constancy being the norm. Some factors contributing to fluctuations of strength are recognizable (see later); many fluctuations appear to occur at random. Myasthenia gravis should always be considered in the differential diagnosis of isolated ocular or bulbar weakness.

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It is preferable to graft the right posterior descending artery rather than the distal main right coronary artery purchase 50mg fluconazole otc fungus gnats larvae killer. If the right coronary artery itself must be grafted buy line fluconazole antifungal treatment for dogs, a shunt may be required to avoid ischemia and hemodynamic instability cheap 50 mg fluconazole with visa fungus garden. Right Ventricular Distention and Bradycardia It is not uncommon for bradycardia and right ventricular distension to occur with proximal occlusion of the right coronary artery buy fluconazole in india zarin anti fungal cream. Therefore, alligator clips should be applied to the epicardium and attached to a pacemaker before coronary occlusion. Conduct of the Surgery As in on-pump coronary artery surgery, the heart is exposed through a median sternotomy and all conduits are harvested in the usual manner. The operative technique for grafting vessels during an off-pump case is similar to that used with on-pump surgery. After an arteriotomy is made, an intravascular shunt is inserted and the proximal silastic tape is released. Injury to the Artery Distal to the Anastomosis Distal vessel occlusion should be avoided because it may cause intimal injury and subsequent stenosis. After each distal anastomosis, the graft is deaired by gently flushing with warm blood (or removing the internal thoracic artery occluder) before tightening and securely tying the suture. With a relatively disease-free aorta, proximal vein graft anastomoses are performed using a partial occlusion clamp. The systemic arterial blood pressure is lowered to a systolic level of approximately 100 mm Hg before the clamp is applied. Aortic Dissection Applying the clamp too tightly or during hypertension can cause aortic dissection, especially in the elderly with a fragile aorta. In patients with atherosclerotic or calcific aortic disease in whom the side-biting clamp cannot be placed safely, alternative sites for proximal anastomoses such as the innominate artery may be considered. Another strategy in this clinical situation is the use of the Heartstring System if a soft spot on the ascending aorta can be identified. However, it is typically performed after bypass grafting is completed, while the patient is still on cardiopulmonary bypass. The laser is fired to create between 15 and 20 channels 1 cm apart, covering the ischemic but not directly the revascularized area. Bubbles are seen by transesophageal echocardiography when the laser beam reaches the ventricular cavity, confirming a completed channel. After cardiopulmonary bypass is discontinued and protamine is administered, most channels readily seal at the epicardial surface with gentle digital pressure. If a patent in situ right internal thoracic graft is present and crossing the midline, or if a redundant left internal thoracic pedicle lies directly beneath the sternum, great care must be exercised to prevent injury to these grafts. If a patent in situ internal thoracic graft is present, the pedicle must be identified and mobilized if the redo procedure is to be done on cardiopulmonary bypass with cardioplegic arrest of the heart. The safest technique for identifying the left internal thoracic pedicle is to begin the dissection from the diaphragm and proceed superiorly. The anastomotic site is therefore encountered first, and the pedicle can then be gently encircled for later clamping. If repair and reestablishment of flow is not feasible, urgent initiation of cardiopulmonary bypass is advisable. Alternatively, the injured graft may be cannulated with an olive-tipped catheter and perfused with a line connected to an aortic or femoral artery catheter. It is important to evaluate the patient preoperatively for the availability and quality of remaining conduits. This may entail Doppler studies to identify residual greater saphenous vein segments or usable lesser saphenous vein. At the time of angiography, it is useful to inject any internal thoracic vessel not previously used to demonstrate its patency. Occasionally, the internal thoracic vessels are injured or occluded during chest closure, and therefore would not be available as conduits for the reoperation. This strategy also reduces the number of proximal anastomotic sites on an already overcrowded and scarred ascending aorta. The ascending aorta is often quite thickened and diseased in patients undergoing redo coronary artery procedures. Therefore, it is generally safer to perform all distal and proximal anastomoses under a single aortic cross-clamp period. The hood of the old vein graft is usually free of disease and provides a good location for a proximal anastomosis. The patent arterial grafts often provide satisfactory sites for the proximal anastomosis of short arterial grafts. Patent but diseased saphenous vein grafts should not be manipulated to prevent embolization of debris into the distal coronary artery bed. Some controversy exists as to whether antegrade cardioplegia should be administered down diseased vein grafts. Some surgeons divide all old, patent vein grafts once on cardiopulmonary bypass and flush debris out of them with retrograde cardioplegia. Inadequate Flow through Internal Thoracic Artery An internal thoracic artery may not provide sufficient flow to a previously grafted coronary artery with a diseased but patent vein graft. This is especially true if the surgeon elects to divide and oversew the old graft to prevent embolization of debris. How to deal with a patent or stenotic vein graft when an internal thoracic artery is to be used is somewhat controversial. In our practice, we tend to leave the old vein graft intact and anastomose the internal thoracic artery to the coronary just distal to the old graft. If there is not an anastomotic stenosis, a 1-mm rim of the old vein graft is left at the distal anastomotic site and the new vein graft is sewn to it. Alternatively, another vein graft and the internal thoracic artery may be connected to this coronary artery, with the risk of competitive flow causing a string sign of the arterial conduit. Often the coronary artery disease has progressed and given rise to new stenotic lesions distal to the occluded graft. In such situations, the occluded graft must be replaced to provide perfusion to the proximal coronary bed. If dissection is carried out superiorly to locate the pedicle, the lung tissue is frequently injured in multiple locations. If the internal thoracic pedicle cannot be safely found, the surgery may be performed as an off-pump procedure or on cardiopulmonary bypass with deep hypothermic arrest. The onset of ischemia is usually heralded by pain that may be followed by shock and ventricular failure owing to significant myocardial injury. The severity of symptoms and clinical manifestations are intimately related to the magnitude of myocardial necrosis and loss of contractile strength. Necrosis of the ventricular septum may result in an acute septal defect and sudden left-to-right shunt, leading to hemodynamic instability. Necrosis of papillary muscles will result in papillary muscle dysfunction or rupture, causing severe mitral valve insufficiency. Patients are initially stabilized with medical management and intraaortic balloon counterpulsation before undergoing cardiac catheterization and coronary angiography. Concomitant coronary artery bypass grafting should always be contemplated, whenever possible, to achieve complete myocardial revascularization.

It does not require energy purchase fluconazole 50mg free shipping antifungal bath mat, can be saturated order fluconazole no prescription antifungal lozenges otc, and may be inhibited by compounds that compete for the carrier buy fluconazole 50mg antifungal agents mechanisms of action. Active transport This mode of drug entry also involves specific carrier proteins that span the membrane order fluconazole on line fungi classification definition. It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher concentration. Active transport systems are selective and may be competitively inhibited by other cotransported substances. Endocytosis and exocytosis This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. Vitamin B12 is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and released by exocytosis. However, the protonated form of basic drugs is usually charged, and loss+ of a proton produces the uncharged base (B): A drug passes through membranes more readily if it is uncharged. Therefore, the effective concentration of the+ permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pK (a ure 1. Blood flow to the absorption site the intestines receive much more blood flow than does the stomach, so absorption from the intestine is favored over the stomach. Total surface area available for absorption With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption. Expression of P-glycoprotein P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved in transportation of drugs from tissues to blood. In addition to transporting many drugs out of cells, it is also associated with multidrug resistance. Bioavailability Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0. Determining bioavailability is important for calculating drug dosages for nonintravenous routes of administration. When the drug is given orally, only part of the administered dose appears in the plasma. A schematic depiction of determination of bioavailability is provided in ure 1. This biotransformation, in addition to chemical and physical characteristics of the drug, determines the rate and extent to which the agent reaches the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased. For example, more than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is primarily administered via the sublingual, transdermal, or intravenous route. Solubility of the drug Very hydrophilic drugs are poorly absorbed because of the inability to cross lipid-rich cell membranes. Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. Chemical instability Some drugs, such as penicillin G, are unstable in the pH of gastric contents. Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. Bioequivalence and other types of equivalence Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two drug formulations are therapeutically equivalent if they are pharmaceutically equivalent (that is, they have the same dosage form, contain the same active ingredient at the same strength, and use the same route of administration) with similar clinical and safety profiles. Thus, therapeutic equivalence requires that drug products are bioequivalent and pharmaceutically equivalent. Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and tissues. The distribution of a drug from the plasma to the interstitium depends on cardiac output and local blood flow, capillary permeability, tissue volume, degree of binding of the drug to plasma and tissue proteins, and relative lipophilicity of the drug. For instance, blood flow to “vessel-rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. Capillary permeability Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between endothelial cells. In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. In the brain, the capillary structure is continuous, and there are no slit junctions. These closely juxtaposed cells form tight junctions that constitute the blood–brain barrier. Binding to plasma proteins Reversible binding to plasma proteins sequesters drugs in a nondiffusible form and slows transfer out of the vascular compartment. As the concentration of free drug decreases due to elimination, the bound drug dissociates from albumin. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma. Binding to tissue proteins Many drugs accumulate in tissues, leading to higher concentrations in tissues than in interstitial fluid and blood. Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity.