Antabuse

By Z. Orknarok. Central Christian College of Kansas.

The tremendous metabolic rate of the brain rotransmitter will accumulate within the synaptic cleft to makes it highly susceptible to oxygen deprivation cheap antabuse 250 mg overnight delivery symptoms vitamin d deficiency. Neurotransmitters are decomposed by enzymes present in Objective 10 Describe the general features of the brain discount antabuse 250 mg mastercard medications to treat anxiety. Synaptic transmission may be affected by various drugs or Objective 12 List the metabolic needs of the brain. Caffeine is a stimulant that increases the rate of The entire delicate CNS is protected by a fixed bony encase- transmission across the synapse. The drug strychnine profoundly re- duces synaptic transmission; it affects breathing and paralyzes brain and a flexible vertebral column surrounding the spinal respiratory structures, causing death. Nervous Tissue and the © The McGraw−Hill Anatomy, Sixth Edition Coordination Central Nervous System Companies, 2001 Chapter 11 Nervous Tissue and the Central Nervous System 359 Over 200 neuropeptides have been identified within the brain, yet most of their functions are not well understood. Two groups of neuropeptides that have received considerable attention are enkephalins and endorphins. These classes of substances numb the brain to pain, functioning in a manner similar to morphine. They are released in response to stress or pain in a traumatized person. The brain has a tremendous metabolic rate and therefore needs a continuous supply of oxygen and nutrients. Although it ac- counts for only 2% of a person’s body weight, the brain receives ap- proximately 20% of the total resting cardiac output. The volume remains relatively constant even with changes in physical or mental activity. This continuous flow is so crucial that a failure of cerebral circula- tion for as short an interval as 10 seconds causes unconsciousness. Because of its high metabolic rate, it not only re- quires continuous oxygen, but also a continuous nutrient supply and the rapid removal of wastes. The cerebrospinal fluid aids the metabolic needs of the brain by serving as a medium for exchange of nutri- ents and waste products between the blood and nervous tissue. Cerebrospinal fluid also maintains a protective homeostatic en- vironment within the brain. The blood-brain barrier and the se- cretory activities of neural tissue also help maintain homeostasis. The brain has an extensive vascular supply through the paired internal carotid and vertebral arteries that unite at the cerebral arterial circle (circle of Willis) (see chapter 16 and fig. The brain of a newborn is especially sensitive to oxygen depri- vation or to excessive oxygen. If complications arise during childbirth and the oxygen supply from the mother’s blood to the baby is interrupted while it is still in the birth canal, the infant may be still- born or suffer brain damage that can result in cerebral palsy, epilepsy, paralysis, or mental retardation. PET scans are of value in studying neurotransmitters The CNS is composed of gray and white matter. Gray matter and neuroreceptors, as well as the substrate metabolism of the brain. From each of these regions, dis- as the outer convoluted cortex layer of the cerebrum and cerebel- tinct functional structures are formed. In addition, specialized gray matter clusters of nerve cells marized in table 11. It consists of aggregations of dendrites and myelinated axons, along with associated neuroglia. What characteristics do the brain and spinal cord have in scribed in the previous section, neurons communicate with one common? Explain how the study of neuropeptides can enhance un- and dendrites within the brain. Using specific examples, describe the metabolic require- called neuropeptides. Nervous Tissue and the © The McGraw−Hill Anatomy, Sixth Edition Coordination Central Nervous System Companies, 2001 360 Unit 5 Integration and Coordination (a) (b) FIGURE 11. Nervous Tissue and the © The McGraw−Hill Anatomy, Sixth Edition Coordination Central Nervous System Companies, 2001 Chapter 11 Nervous Tissue and the Central Nervous System 361 (c) Cerebrum Corpus callosum Cerebellum Lateral ventricle Pons Medulla oblongata Spinal cord (d) FIGURE 11. Nervous Tissue and the © The McGraw−Hill Anatomy, Sixth Edition Coordination Central Nervous System Companies, 2001 362 Unit 5 Integration and Coordination (a) (b) FIGURE 11.

Its accuracy depends on the chosen ligand only binding to the receptor it is intended to study and no other receptor purchase antabuse 250mg line symptoms 0f food poisoning. It must be emphasised that binding studies only measure the ability of a drug to combine with a receptor generic antabuse 500 mg with amex treatment yeast in urine, they do not indicate whether it is an agonist or antagonist. Also compared with an antagonist the binding of an agonist may be affected in an uncertain manner by the change in state caused by the activation of the receptor. DRUG ANTAGONISM One drug can overcome the effect of another or reduce the activity of an endogenously released and active substance such as a neurotransmitter, either by competing with that substance for its receptor site (receptor antagonism) or stimulating a different receptor to induce an opposing effect (physiological or functional antagonism). The former may be regarded as true antagonism for in the latter case both drugs are actually agonists. It is epitomised by the use in asthma of beta adrenoceptor agonists like salbutamol to dilate bronchi that have been constricted by a cocktail of local mediators such as PHARMACOLOGY AND DRUG EFFECTS 109 110 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION histamine, acetylcholine and kinins. In the CNS the inhibitory NT (GABA) could be regarded as the physiological antagonist of the excitatory NT (glutamate). When the agonist and antagonist compete for the same receptor the binding of the agonist and the response it produces are both reduced. Thus to obtain the same response in the presence, as in the absence of antagonist, the concentration of agonist must be increased and over a range of agonist concentrations this results in a parallel shift to the right in the position of its DRC (Fig. The degree of this shift, the amount by which the agonist concentration has to be increased in order to produce the same response in the presence as in the absence of the antagonist, is known as the dose ratio (r). The larger this ratio, the greater the shift in the DRC and the more potent is the antagonist. In fact if the antagonism is really competitive then the degree of shift of the DRC will be proportional to the increase in concentration of the antagonist used. Also if the antagonism is competitive not only will the DRCs remain parallel but it should always be possible to restore the maximal response to the agonist by giving more of it, irrespective of the amount of antagonist present. Since both agonist and antagonist are continuously combining with and dissociating from the receptor the likelihood of either occupying it at any time will depend on their relative concentrations. The dose ratio r ˆ XB=KB†‡1 where XB is the concentration of antagonist and KB its equilibrium constant. This can be expressed logarithmically as log r À 1†ˆlog XB À log KB and a plot of log r À 1† against log XB (the Schild plot) should give a straight line with slope of 1, which intercepts the abscissa at the value À log KB (pKB) for the antagonist (Fig. This is frequently converted into a simple number by taking its negative logarithm, much as pH values represent hydrogen ion concentration, so that KBsof 10À7 or 3. This pA value was defined by Schild as 2 the negative logarithm of the molar concentration of antagonist required to give a dose ratio of 2. Thus the larger the pA2 value, the smaller the concentration of antagonist needed and the greater its affinity and effectiveness. In practice full DRCs are rarely obtainable especially in studies on the CNS, or even necessary, provided that responses to two doses of agonist can be obtained at each concentration of antagonist. This will establish the position of the DRC and allow r to be calculated. If the antagonist does not readily dissociate from the receptor, because it is bound firmly, then the agonist will not be able to displace it and restore a maximal response. An agonist can often achieve a maximal response by activating only a small percentage of its receptors, so in the presence of low concentrations of a non-dissociating antagonist there may be sufficient spare receptors available for increased concentrations of the agonist still to achieve a maximal response. As the concentration of antagonist is increased, however, fewer unoccupied receptors are left and since the agonist cannot displace the antagonist a maximal response cannot be achieved (Fig. It is still competitive because the drugs are competing for the same receptor. This is non- competitive antagonism which may, or may not, be reversible, depending on the action of the antagonist. There are a number of drugs with this action on the glutamate NMDA receptors (Chapter 10). PHARMACOKINETICS This is generally accepted as the term to describe the absorption distribution and metabolism of a drug in vivo and it is these factors which determine how quickly and how much of the administered drug can actually reach its site of action (in the CNS) and be maintained there for the required time (see Fig. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs.

Chemotaxis is initiated by the release of iron”) buy antabuse 250 mg visa medications via g-tube, but iron can also be provided by the absorption of chemotactic factors from the bacteria or by chemotactic inorganic iron by intestinal epithelial cells purchase 250mg antabuse visa symptoms before period. Chemo- iron attached to heme is released and reduced to the fer- tactic factors are generated when bacteria or their products 2 bind to circulating antibodies, by tissue cells when infected rous form (Fe ) by intracellular flavoprotein. The re- duced iron (both released from heme and absorbed as the with bacteria, and by lymphocytes and platelets after inter- inorganic ion) is transported through the cytoplasm action with bacteria. When it is released to After neutrophils migrate to the site of infection, they the plasma, it is oxidized to the ferric state and bound to engulf the invading pathogen by the process of phagocy- transferrin for use in heme synthesis. Phagocytosis is facilitated when the bacteria are coated with the host defense proteins known as opsonins. A burst of metabolic events occurs in the neutrophil af- Platelets Participate in Clotting ter phagocytosis (Fig. In the phagocytic vacuole or phagosome, the bacterium is exposed to enzymes that Platelets are irregularly shaped, disk-like fragments of the were originally positioned on the cell surface. Membrane-bound enzymes, activated when the where they function in hemostasis. Several factors stimu- phagocytic vacuole closes, work in conjunction with en- late megakaryocytes to release platelets, including the hor- zymes secreted from intracellular granules into the phago- mone thrombopoietin, which is generated and released cytic vacuole to destroy the invading pathogen efficiently. They are adenine dinucleotide phosphate (NADPH) oxidase, pro- one fourth to one third the size of erythrocytes. Superoxide is an unstable possess physiologically important proteins, stored in intra- free radical that kills bacteria directly. Superoxide also cellular granules, which are secreted when the platelets are participates in secondary free radical reactions to generate activated during coagulation. The role of platelets in blood other potent antimicrobial agents, such as hydrogen per- clotting is discussed below. Superoxide generation in the phagocytic vacuole proceeds at the expense of reducing agents oxidized in the cytoplasm. The reducing agent, NADPH, is generated Leukocytes Participate in Host Defense from glucose by the activity of the hexose monophos- Each of the three general types of leukocytes—myeloid, phate shunt. Aerobic cells generate reduced nicotinamide lymphoid, and monocytic—follows a separate line of de- adenine dinucleotide (NADH) and ATP when glucose is velopment from primitive cells (see Fig. The hexose monophosphate cells of the myeloid series are termed granulocytes, based shunt operates in neutrophils and other cells when large 198 PART IV BLOOD AND CARDIOVASCULAR PHYSIOLOGY 1. Invagination chemiluminescence) when they oxidize components in the bacterial cell wall. Other bactericidal agents and processes operate in neu- trophils to ensure efficient bacterial killing. Phagocytized bacteria encounter intracellular defensins, cationic proteins that bind to and inhibit the replication of bacteria. De- fensins and other antibacterial agents pour into the phago- cytic vacuole after phagocytosis. Agents stored in neu- trophil granules include lysozyme, a bacteriolytic enzyme, Cell-surface receptors Cell membrane sense invading pathogens surrounds microbes and myeloperoxidase, which reacts with hydrogen perox- ide to generate potent, bacteria-killing oxidants. One of the oxidants generated by the myeloperoxidase reaction is hypochlorous acid (HOCl), the killing agent found in 4. Eosinophils are rare in the circulation but are easily identified on stained blood films. As the name im- plies, the eosinophil takes on a deep eosin color during polychromatic staining; the large, refractile cytoplasmic granules of these cells stain orange-red to bright yellow. Cellular granules release contents into vacuole; membrane Like neutrophils, eosinophils migrate to sites where they NADPH oxidase is activated are needed and exhibit a metabolic burst when activated. Eosinophils participate in defense against certain parasites, FIGURE 11. Basophils are polymorphonuclear leukocytes tivation of the respiratory burst, resulting in the generation of po- with multiple pleomorphic, coarse, deep-staining tent oxidants within the phagosome, and the secretion of bacte- metachromatic granules throughout their cytoplasm. These granules contain heparin and histamine, which have anticoagulant and vasodilating properties, respectively. The release of these and other mediators by basophils in- creases regional blood flow, facilitating the transport of other leukocytes to areas of infection and allergic reactivity amounts of NADPH are needed to maintain intracellular or other forms of hypersensitivity. Oxygen reduction by the NADPH oxidase that gener- Monocytes and Lymphocytes.

Complete disruption of the tendon fibers is seen in type III posterior tibial tendon tears order antabuse 500 mg without prescription treatment dynamics. These are quite Achilles tendon injuries may be classified into non-in- rare and appear at MR imaging as tendon discontinuity cheap antabuse 500mg with amex medicine during the civil war. The former group in- The gap may be filled with fluid or granulation tissue. Insertional Achilles disease in- cludes insertional tendinosis, which may be associated Tears of the peroneal tendons are most commonly seen with a Haglund deformity of the calcaneus and insertion- along the lateral malleolus, along the lateral calcaneal al tears. At the lateral At MR imaging, partial Achilles tendon tears demon- malleolus, tears may be associated with either superior strate heterogeneous signal intensity and thickening of peroneal retinacular tear or laxity secondary to a previous the tendon without complete interruption. Signal tenosynovitis include scarring around the tendons and changes tend to be along the posterior aspect of the ten- fluid within the common tendon sheath, respectively. Partial Care should be taken to differentiate physiologic fluid ac- tears, especially when acute, often depict edema and he- cumulation within the tendon sheath and tenosynovitis morrhage within Kager’s fat pad. Complete Achilles ten- from fluid within the common peroneal sheath secondary to a tear of the calcaneofibular ligament. Care should al- don rupture manifests as discontinuity with fraying and so be taken as well to differentiate between tendinosis retraction of the torn edges of the tendon. US is comparable to MR imaging for assessing Longitudinal intrasubstance tears of the peroneus bre- Achilles tendon injuries. In addition, US demonstrates vis tendon have a distinct appearance on axial MR im- neovascularization in painful Achilles tendons. The tendon assumes a C-shaped or boomerang con- while strongly associated with pain, is not predictable of figuration that partially envelops the peroneus longus an unfavorable outcome. Ultrasound may miss Achilles tendon lesions at frequently seen at the level of the peroneal tubercle or the muscle- tendon junction, while MR imaging at this cuboid tunnel. The imaging diagnosis of a tear of the per- site is associated with muscle edema, retraction of mus- oneus longus tendon at this location is clinically impor- cle fibers and hematoma. On An abnormal position of an os peroneum on conven- most follow-up MR imaging studies, intratendinous sig- tional radiographs may be a clue for possible tear of the nal intensity will decrease as the tendon heals. Hypertrophy of the peroneal tu- the tendon may remain thickened, simulating chronic bercle has also been implicated as a cause for tear of the tendinosis, even after normal signal intensity has been re- peroneus longus tendon at the midfoot. Imaging of the Foot and Ankle 43 Ligaments the ligament will allow the talar head to collapse result- ing in an acquired flat foot deformity. There is a high as- Lateral Collateral Ligaments sociation between rupture of the spring ligament and dys- function of the posterior tibial tendon. Ankle sprains are the most common musculoskeletal The spring ligament is composed of the inferior longi- cause for hospital emergency rooms and private practice tudinal calcaneonavicular and superomedial calcaneonav- visits. The anterior tibiofibular lig- oblique) of the spring ligament has been demonstrated. The posterior tibiofibular ligament, also visible on icular in the lower layer of the spring ligament complex, axial images at the tip of the fibula, is rarely torn. Early investigations have indicated that the calcane- Each of the three components can be visualized on MR ofibular ligament runs obliquely from the fibular tip pos- images. Therefore, oblique images have been considered to be superior in the Impingement Syndromes assessment of the ligament. In our experience, however, this plane is not clearly superior to coronal images in de- The role of impingement syndromes in producing chron- lineating the calcaneofibular ligament. This may be ex- ic ankle pain has been better appreciated in recent years. This is discussed more fully under the category of Among the four most common impingement syn- osseous injuries. Intra-articular synovial hypertrophy The tibiofibular syndesmosis is an important stabilizer of and fibrosis may occur in the lateral gutter secondary to the distal tibiofibular joint. It consists of the anteroinfe- capsular or ligamentous tears associated with inversion rior tibiofibular ligament, the posteroinferior tibiofibular injuries. This condition is optimally assessed with MR ligament, the transverse tibiofibular ligament, and the in- arthrography, although positive experience with this ap- terosseous tibiofibular ligament. Disruption or irregularities of the ligaments, ankle, excluding Morton’s neuroma, is tarsal tunnel syn- degenerative changes at the distal tibiofibular joint, and drome.