By T. Ortega. Monmouth College, Monmouth Illinois.
THERAPY Parkinsonism is unique among diseases of the CNS levitra plus 400mg visa, in that it results from the known loss of a particular NT 400 mg levitra plus visa, i discount levitra plus 400 mg overnight delivery. DA purchase 400mg levitra plus amex, resulting from the degeneration of a particular path- way purchase levitra plus 400mg without prescription, the nigrostriatal. Dopamine also has a relatively limited distribution in the brain and few peripheral effects. It should therefore be amenable to therapy based on augmenting its function. Also since the role of DA appears to be to maintain a tonic inhibitory control on GABA output pathways from the striatum, possibly in part by an extra synaptic action (Chapter 6), it may not be necessary for it to be released physiologically from nerve terminals. Nevertheless it must also be expected that anything which increases DA function not only controls extrapyramidal function but also reproduces the other central effects of DA; i. Despite these problems, the therapy of PD is one of the success stories of neurology. It is generally assumed that DA itself cannot be used because it does not cross the blood±brain barrier although some recent mocrodialysis studies following intravenous DA indicates that this may not be so, in rats anyway. Thus PD may be treated by 304 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION DISEASES OF THE BASAL GANGLIA 305 (A) Augmenting the action of DA (Fig. The DA neuronal uptake transporter can be distinguished from that for NA and is blocked preferentially by nomifensine. Also unlike NA, which is a substrate for MAOA, dopamine is a substrate for MAOB for which selegiline (deprenyl) is an effective inhibitor. The efficacy of both nomifensine and selegiline might be augmented initially by supersensitivity to the remaining DA (increased receptor number) but this decreases with time and augmenting synaptic DA increases the likelihood of stimulating terminal autoreceptors and inhibiting DA release. In view of these problems and the progressive degeneration of DA neurons it is not surprising that nomifensine has little effect but selegiline does produce some improvements in the early stages of the disease and there has been much interest in the possibility that it can prevent, or at least reduce, further degeneration (see section on Aetiology). O-methylation of DA is a secondary line of metabolism and its inhibition has little effect on the removal of DA but drugs that block this enzyme are gaining a place in prolonging the action of levodopa. Levodopa, by contrast, is not a good substrate for MAO, although metabolised by COMT (Fig. Early attempts to treat PD with dopa failed because the doses used were too small. This arose partly from the fear that it would be converted to NA as well as DA and so 306 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 15. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD. The deamination of DA to DOPAC can be prevented by MAOB inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD Ð dopa decarboxylase; MAO Ð monoamine oxidase; COMT Ð catechol-o- methyl transferase raise BP. In fact DA synthesis is favoured, since dopa decarboxylase is widely distri- buted and never saturated, but further synthesis to NA is limited by the restriction of dopamine B-hydroxylase to vesicles in NA nerve terminals. Fortunately Cotzias and his colleagues (1967), after finding that large doses of levodopa (in excess of 3 g) were effective in South American miners suffering from manganese poisoning and showing symptoms akin to PD, tried them successfully in Parkinsonism patients. It is generally accepted that the improvement is very good in 35% of patients, good in 30% and moderate in 30% with some (55%) not really responding. Indeed its effect is so dramatic that the validity of PD diagnosis in the non- responders is questioned. DISEASES OF THE BASAL GANGLIA 307 It is not the object of this text to cover the detailed pharmacology and use of drugs but levodopa must be an exception. Its use in PD illustrates the problems that still have to be overcome even after the cause of a disease of the CNS has been established and a treatment devised. Mode of action Levodopa itself has virtually no affinity for DA receptors and if its conversion to DA is stopped by inhibiting its decarboxylation in the brain then it has no behavioural (DA-like) effects in animals. More importantly, it loses its efficacy in primates with experimental (MPTP) Parkinsonism. Unfortunately most of the DA nerves that would normally do that in the striatum have degenerated and the remainder are already working overtime. Nevertheless it is known from experimental studies, after virtually complete destruction of the nigrostriatal tract, that systemic dopa can still increase striatal DA.
The en- zymes that catalyze the various deiodination reactions are Binding of T4 and T3 to Plasma Proteins generic levitra plus 400mg otc. Most of the T4 regulated discount 400 mg levitra plus visa, resulting in different thyroid hormone concen- and T3 molecules that enter the bloodstream become trations in various tissues in different physiological and bound to plasma proteins purchase levitra plus 400 mg on line. Each molecule of TBG has a sin- cretory product of the thyroid gland and is the predominant gle binding site for a thyroid hormone molecule buy levitra plus 400 mg on-line. However generic 400 mg levitra plus with mastercard, about 40% of the maining T4 and T3 in the blood are bound to transthyretin T4 secreted by the thyroid gland is converted to T3 by enzy- or to albumin. Less than 1% of the T4 and T3 in blood is in matic removal of the iodine atom at position 5 of the thyro- the free form, and it is in equilibrium with the large protein- nine ring structure (Fig. It is this small amount of free thyroid hor- 5 -deiodinase (type 1) located in the liver, kidneys, and thy- mone that interacts with target cells. The T3 formed by this deiodination and that se- The protein-bound form of T4 and T3 represents a creted by the thyroid react with thyroid hormone receptors large reservoir of preformed hormone that can replenish in target cells; therefore, T3is the physiologically active form the small amount of circulating free hormone as it is of the thyroid hormones. A second 5 -deiodinase (type 2) is 600 PART IX ENDOCRINE PHYSIOLOGY NH 2 DIT free Regulation of 5 -Deiodination. The 5 -deiodination reac- CH2 CH radicals tion is a regulated process influenced by certain physiolog- O CO ical and pathological factors. The result is a change in the relative amounts of T3 and reverse T3 produced from T4. O NH CH CH For example, a human fetus produces less T3 from T4 than 2 CO a child or adult because the 5 -deiodination reaction is less active in the fetus. Also, 5 -deiodination is inhibited during fasting, particularly in response to carbohydrate restriction, Radical addition but it can be restored to normal when the individual is fed again. Trauma, as well as most acute and chronic illnesses, NH Quinoid also suppresses the 5 -deiodination reaction. Under all of CH2 CH intermediate these circumstances, the amount of T3 produced from T4 is O CO reduced and its blood concentration falls. However, the O amount of reverse T rises in the circulation, mainly be- NH 3 CH2 CH cause its conversion to 3,3 -diiodothyronine by 5 -deiodi- CO nation is reduced. A rise in reverse T3 in the blood may sig- nal that the 5 -deiodination reaction is suppressed. Electronic rearrangement Note that during fasting or in the disease states mentioned above, the secretion of T4 is usually not increased, despite the Thyroxine decrease of T3in the circulation. This response indicates that, residue under these circumstances, a T decrease in the blood does 3 NH not stimulate the hypothalamic-pituitary-thyroid axis. T4 and, to a lesser extent, T3 are also metabolized by conjugation with glucuronic + acid in the liver. The conjugated hormones are secreted NH Dehydroalanine into the bile and eliminated in the feces. Many tissues also CH2 CH residue metabolize thyroid hormones by modifying the three-car- CO bon side chain of the iodothyronine structure. These mod- Theoretical model for the coupling reaction ifications include decarboxylation and deamination. This model is based on free radical (tetrac), may also undergo deiodinations before being ex- formation catalyzed by thyroid peroxidase. Philadelphia: Lippincott TSH Regulates Thyroid Hormone Synthesis Williams & Wilkins, 2000;61–85. Type 2 deiodinase is believed to function pri- tration of TSH in the blood. This action results in increased marily to maintain intracellular T3in target tissues, but it may interactions between TSH and its receptors on thyroid fol- also contribute to the generation of circulating T3. This rare amino acid has properties that make it ideal to catalyze TSH Receptors and Second Messengers. TSH is a transmembrane glycoprotein thought to be located on the basal plasma membrane of the follicular cell. Whereas the ceptors are coupled by Gsproteins, mainly to the adenylyl cy- 5 -deiodination of T4 to produce T3 can be viewed as a clase-cAMP-protein kinase A pathway, however, there is also metabolic activation process, both T4 and T3 undergo en- evidence for effects via phospholipase C (PLC), inositol zymatic deiodinations, particularly in the liver and kidneys, trisphosphate, and diacylglycerol (see Chapter 1). For example, about 40% of the T4 iological importance of TSH-stimulated phospholipid me- secreted by the human thyroid gland is deiodinated at the tabolism in human follicular cells is unclear, since very high 5 position on the thyronine ring structure by a 5-deiodi- concentrations of TSH are needed to activate PLC. Since reverse T3 has little or no thyroid hormone activity, this deiodina- TSH and Thyroid Hormone Formation and Secretion.
A feedforward controller generates The structure and activity of cellular proteins are also af- commands without directly sensing the regulated variable purchase levitra plus 400 mg mastercard, al- fected by ionic strength generic levitra plus 400 mg visa. Feedforward controllers often on the total number and charge of ions per unit volume of operate through feedback controllers best 400mg levitra plus. One explanation for this remarkable behavior is that is sensed levitra plus 400 mg sale, information is fed back to the controller purchase levitra plus 400 mg with mastercard, and the exercise simultaneously produces a centrally generated feed- effector acts to oppose change (hence, the term negative). Room tem- feedback information generated as a consequence of in- perature (regulated variable) is subjected to disturbances. For creased movement and muscle activity, adjusts the heart, example, on a cold day, room temperature falls. In addition, control mometer (sensor) in the thermostat (controller) detects the system function can adapt over a period of time. The thermostat is set for a certain tem- ence and learning can change the control system’s output so perature (set point). The controller compares the actual tem- that it behaves more efficiently or appropriately. The resulting change in room temperature is diabetes, and hypertension, develop because of a defective monitored, and when the temperature rises sufficiently, the control mechanism. Such a negative-feedback system allows sult in inappropriate actions, such as autoimmune diseases, some fluctuation in room temperature, but the components in which the immune system attacks the body’s own tissue. Effective com- Scar formation is one of the most effective homeostatic munication between the sensor and effector is important in mechanisms of healing, but it is excessive in many chronic keeping these oscillations to a minimum. One example is the system that regulates arte- rial blood pressure (see Chapter 18). This system’s sensors Positive Feedback Promotes a (arterial baroreceptors) are located in the carotid sinuses Change in One Direction and aortic arch. Changes in stretch of the walls of the carotid sinus and aorta, which follow from changes in With positive feedback, a variable is sensed and action is blood pressure, stimulate these sensors. Positive feed- fibers transmit impulses to control centers in the medulla back does not lead to stability or regulation, but to the oblongata. Efferent nerve fibers send impulses from the opposite—a progressive change in one direction. One medullary centers to the system’s effectors, the heart and example of positive feedback in a physiological process is blood vessels. The output of blood by the heart and the re- the upstroke of the action potential in nerve and muscle sistance to blood flow are altered in an appropriate direc- (Fig. Depolarization of the cell membrane to a value tion to maintain blood pressure, as measured at the sensors, greater than threshold leads to an increase in sodium within a given range of values. Positively charged Na ions rush trol system compensates for any disturbance that affects into the cell through membrane Na channels and cause blood pressure, such as changing body position, exercise, further membrane depolarization; this leads to a further anxiety, or hemorrhage. Nerves accomplish continuous increase in Na permeability and more Na entry. Var- snowballing event, which occurs in a fraction of a mil- ious hormones are also involved in regulating blood pres- sure, but their effects are generally slower and last longer. Feedforward control is another strategy for regulating systems in the body, particularly when a change with time Depolarization of nerve or muscle is desired. In this case, a command signal is generated, membrane which specifies the target or goal. The moment-to-moment operation of the controller is “open loop”; that is, the regu- lated variable itself is not sensed. Feedforward control mechanisms often sense a disturbance and can, therefore, take corrective action that anticipates change. For example, heart rate and breathing increase even before a person has begun to exercise. Feedforward control usually acts in combination with negative-feedback systems. One example is picking up a Entry of Increase in Na Na into cell permeability pencil. The movements of the arm, hand, and fingers are di- rected by the cerebral cortex (feedforward controller); the movements are smooth, and forces are appropriate only in part because of the feedback of visual information and sen- sory information from receptors in the joints and muscles.
A third way of adding an image to a course is to embed it into any web page within the course generic 400mg levitra plus overnight delivery. HTML pages may be edited within the Manage Files area of the course; there is also an Edit File option for files contained within a Content Module generic levitra plus 400mg otc. However you choose to edit the page best 400 mg levitra plus, once you are in the HTML discount levitra plus 400mg otc, you will link to the graphic with some HTML code effective levitra plus 400 mg, an example of which is shown below. If the graphic is in the root directory of the Manage Files area of the course, the code would be: Levitra Plus
8 of 10 - Review by T. Ortega
Votes: 304 votes
Total customer reviews: 304