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Myelin basic protein (MBP) is an intracellular protein that has a role in myelin compaction treatment vertigo cheap dramamine 50mg online. Mutant forms of myelin protein zero (MPZ) medicine you can give cats buy cheap dramamine 50mg line, peripheral myelin protein 22 (PMP22) medications available in mexico buy on line dramamine, gap junction protein alternative medicine order 50 mg dramamine mastercard, beta 1 (GJB1), and periaxin (PRX) cause some forms of Charcot-Marie-Tooth disease, a hereditary demyelinating neuropathy. In the case of myelinated axons, individual Schwann cells make exactly one myelin sheath that wraps around a single axon to create a myelinated segment called an internode. Internodes are separated by unmyelinated gaps referred to as nodes of Ranvier, which are uniformly spaced along the length of the axon. A number of specialized proteins are essential for normal assembly and function of myelin within internodes. Unmyelinated axons are also intimately associated with Schwann cells but in a different arrangement in which one cell surrounds segments of multiple axons. Most peripheral nerves carry out both motor and sensory functions and thus contain axons of varying diameter and myelin thickness. The axons are bundled together by three major connective tissue components: the epineurium, which encloses the entire nerve; the perineurium, a multilayered concentric connective tissue sheath that groups subsets of axons into fascicles; and the endoneurium, which surrounds individual nerve fibers. General Types of Peripheral Nerve Injury Axonal Neuropathies Axons are the primary target of the damage in this large group of peripheral neuropathies. The morphologic hallmarks of axonal neuropathies can be produced experimentally by cutting a peripheral nerve, which results in a prototypical pattern of injury described as Wallerian degeneration. Portions of axons that are distal to the point of transection are disconnected from the cell bodies (perikarya) and degenerate. Within a day of injury, the distal axons begin to fragment, and the associated myelin sheaths unravel. Macrophages are recruited and participate in the removal of axonal and myelin debris. Regeneration starts at the site of transection with the formation of a growth cone and the outgrowth of new branches from the stump of the proximal axon. Schwann cells and their associated basement membranes guide the sprouting axons, which grow at about 1 mm per day, toward their distal target. The Schwann cells create new myelin sheaths around the regenerating axons, but these myelin internodes tend to be thinner and shorter than in the original ones. The regeneration is successful only if the two transected ends remain closely approximated. A failure of the outgrowing axons to find their distal target can produce a "pseudotumor" termed traumatic neuroma-a nonneoplastic haphazard proliferation of axonal processes and associated Schwann cells that results in a painful nodule. The changes observed following experimental nerve transections only partially resemble those seen in various axonal neuropathies. One key difference is that in these neuropathies (unlike nerve transection) damage occurs over an extended period of time. With time, damage tends to outpace repair, resulting in progressive loss of axons. In cases of toxic and metabolic insults, axons often degenerate in a length-dependent fashion with the longest axons being most susceptible, resulting in a "dyingback" type of pattern of progression. The electrophysiologic hallmark of axonal neuropathies is a reduction in signal amplitude owing to the dropout of axons from affected peripheral nerves, with relative preservation of conduction velocity. In contrast, acute demyelinating disease (right axon) produces random segmental degeneration of individual myelin internodes, while sparing the axons. The regenerated axon is myelinated by proliferating Schwann cells, but the new internodes are shorter and the myelin sheaths are thinner than the original ones. Remission of demyelinating disease (right axon) allows remyelination to take place, but the new internodes are shorter and have thinner myelin sheaths than flanking normal undamaged internodes. In most cases axons are affected in a length-dependent fashion leading to deficits that start in the feet and ascend with disease progression. The hands often start to show involvement by the time deficits extend to the level of the knee, resulting in a characteristic "stocking and glove" distribution of sensory deficits. An affected patient might have a right wrist drop from involvement of the right radial nerve and a left foot drop from peroneal nerve damage. Specific Peripheral Neuropathies Patients with peripheral neuropathy often complain of numbness, painful "pins and needles" sensations, and weakness, most often in the distal portions of the extremities. Many different types of disease processes can damage peripheral nerves, including inflammatory diseases, infections, metabolic changes, toxic injury, trauma, paraneoplastic disease, and inherited gene defects. Demyelinating Neuropathies In these disorders, Schwann cells with their myelin sheaths are the primary targets of damage. This definition is similar to that of demyelinating diseases that affect the CNS (Chapter 28). Individual myelin sheaths degenerate in a seemingly random pattern, resulting in discontinuous damage of myelin segments. In response to this damage, Schwann cells or Schwann cell precursors proliferate and initiate repair through the formation of new myelin sheaths, but these again tend to be shorter and thinner than the original ones. The electrophysiologic hallmark of demyelinating neuropathies is slowed nerve conduction velocity, reflective of the loss of myelin. The disease is characterized clinically by weakness beginning in the distal limbs that rapidly advances to affect proximal muscle function ("ascending paralysis"). Histologic features are inflammation and demyelination of spinal nerve roots and peripheral nerves (radiculoneuropathy). Neuronopathies Neuronopathies result from destruction of neurons, leading to secondary degeneration of axonal processes.
In most cases symptoms 5 dpo buy generic dramamine pills, however symptoms 5 days post embryo transfer dramamine 50mg on line, the anxiolytic actions of sedative-hypnotics are accompanied by some depressant effects on psychomotor and cognitive functions medicine zocor generic 50mg dramamine with amex. In experimental animal models medications routes discount 50mg dramamine overnight delivery, benzodiazepines and older sedative-hypnotic drugs are able to disinhibit punishmentsuppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects, eg, the tricyclic antidepressants and antihistamines. However, the disinhibition of previously suppressed behavior may be more related to behavioral disinhibitory effects of sedative-hypnotics, including euphoria, impaired judgment, and loss of self-control, which can occur at dosages in the range of those used for management of anxiety. Hypnosis-By definition, all of the sedative-hypnotics induce sleep if high enough doses are given. The effects of sedativehypnotics on the stages of sleep depend on several factors, including the specific drug, the dose, and the frequency of its administration. The general effects of benzodiazepines and older sedative-hypnotics on patterns of normal sleep are as follows: (1) the latency of sleep onset is decreased (time to fall asleep); (2) the duration of stage 2 NREM (nonrapid eye movement) sleep is increased; (3) the duration of REM sleep is decreased; and (4) the duration of stage 4 NREM slow-wave sleep is decreased. Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. Eszopiclone increases total sleep time, mainly via increases in stage 2 NREM sleep, and at low doses has little effect on sleep patterns. More rapid onset of sleep and prolongation of stage 2 are presumably clinically useful effects. However, the significance of sedative-hypnotic drug effects on REM and slow-wave sleep is not clear. Deliberate interruption of REM sleep causes anxiety and irritability followed by a rebound increase in REM sleep at the end of the experiment. A similar pattern of "REM rebound" can be detected following abrupt cessation of drug treatment with older sedative-hypnotics, especially when drugs with short durations of action (eg, triazolam) are used at high doses. With respect to zolpidem and the other newer hypnotics, there is little evidence of REM rebound when these drugs are discontinued after use of recommended doses. However, rebound insomnia occurs with both zolpidem and zaleplon if used at higher doses. Despite possible reductions in slow-wave sleep, there are no reports of disturbances in the secretion of pituitary or adrenal hormones when either barbiturates or benzodiazepines are used as hypnotics. However, the suitability of a particular agent as an adjunct in anesthesia depends mainly on the physicochemical properties that determine its rapidity of onset and duration of effect. Among the barbiturates, thiopental and methohexital are very lipid-soluble, penetrating brain tissue rapidly following intravenous administration, a characteristic favoring their use for the induction of anesthesia. Rapid tissue redistribution (not rapid elimination) accounts for the short duration of action of these drugs, a feature useful in recovery from anesthesia. Benzodiazepines-including diazepam, lorazepam, and midazolam-are used intravenously in anesthesia (see Chapter 25), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long halflives and the formation of active metabolites. However, if necessary, such depressant actions of the benzodiazepines are usually reversible with flumazenil. Anticonvulsant effects-Many sedative-hypnotics are capable of inhibiting the development and spread of epileptiform electrical activity in the central nervous system. Some selectivity exists in that some members of the group can exert anticonvulsant effects without marked central nervous system depression (although psychomotor function may be impaired). Several benzodiazepines-including clonazepam, nitrazepam, lorazepam, and diazepam-are sufficiently selective to be clinically useful in the management of seizures (see Chapter 24). Of the barbiturates, phenobarbital and metharbital (converted to phenobarbital in the body) are effective in the treatment of generalized tonic-clonic seizures, though not the drugs of first choice. Muscle relaxation-Some sedative-hypnotics, particularly members of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone. Effects on respiration and cardiovascular function-At hypnotic doses in healthy patients, the effects of sedative-hypnotics on respiration are comparable to changes during natural sleep. However, even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with pulmonary disease. Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics. At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedativehypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse.
Peripheral nervous system-Autonomic ganglia are important sites of nicotinic synaptic action medications 123 order dramamine toronto. Nicotine itself has a somewhat greater affinity for neuronal than for skeletal muscle nicotinic receptors symptoms 7 dpo bfp purchase dramamine paypal. The initial response therefore often resembles simultaneous discharge of both the parasympathetic and the sympathetic nervous systems medications 500 mg purchase dramamine with american express. In the case of the cardiovascular system symptoms valley fever order 50mg dramamine with visa, the effects of nicotine are chiefly sympathomimetic. Dramatic hypertension is produced by parenteral injection of nicotine; sympathetic tachycardia may alternate with a bradycardia mediated by vagal discharge. In the gastrointestinal and urinary tracts, the effects are largely parasympathomimetic: nausea, vomiting, diarrhea, and voiding of urine are commonly observed. Neuronal nicotinic receptors are present on sensory nerve endings-especially afferent nerves in coronary arteries and the carotid and aortic bodies as well as on the glomus cells of the latter. Activation of these receptors by nicotinic stimulants and of muscarinic receptors on glomus cells by muscarinic stimulants elicits complex medullary responses, including respiratory alterations and vagal discharge. The contractile response varies from disorganized fasciculations of independent motor units to a strong contraction of the entire muscle depending on the synchronization of depolarization of end plates throughout the muscle. This latter phase of block is manifested as flaccid paralysis in the case of skeletal muscle. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. The chief differences between members of the group are chemical and pharmacokinetic-their pharmacodynamic properties are almost identical. Carbaryl (carbaril) is typical of a large group of carbamate insecticides designed for very high lipid solubility, so that absorption into the insect and distribution to its central nervous system are very rapid. Many of the organophosphates (echothiophate is an exception) are highly lipid-soluble liquids. Echothiophate, a thiocholine derivative, is of clinical value because it retains the very long duration of action of other organophosphates but is more stable in aqueous solution. Absorption, Distribution, and Metabolism Absorption of the quaternary carbamates from the conjunctiva, skin, gut and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. The organophosphate cholinesterase inhibitors (except for echothiophate) are well absorbed from the skin, lung, gut, and Chemistry & Pharmacokinetics A. Structure There are three chemical groups of cholinesterase inhibitors: (1) simple alcohols bearing a quaternary ammonium group, eg, edrophonium; (2) carbamic acid esters of alcohols having quaternary or tertiary ammonium groups (carbamates, eg, neostigmine); and (3) organic derivatives of phosphoric acid (organophosphates, eg, echothiophate). Edrophonium, neostigmine, and pyridostigmine are synthetic quaternary ammonium agents used in medicine. Neostigmine exemplifies the typical ester composed of carbamic acid ([1]) and a phenol bearing a quaternary ammonium group ([2]). The shaded ester bonds in malathion represent the points of detoxification of the molecule in mammals and birds. They are relatively less stable than the carbamates when dissolved in water and thus have a limited half-life in the environment (compared with another major class of insecticides, the halogenated hydrocarbons, eg, DDT). When prepared in aqueous solution for ophthalmic use, it retains activity for weeks. The thiophosphate insecticides (parathion, malathion, and related compounds) are quite lipid-soluble and are rapidly absorbed by all routes. Malathion and a few other organophosphate insecticides are also rapidly metabolized by other pathways to inactive products in birds and mammals but not in insects; these agents are therefore considered safe enough for sale to the general public. Unfortunately, fish cannot detoxify malathion, and significant numbers of fish have died from the heavy use of this agent on and near waterways. Parathion is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is not available for general public use in the USA. All the organophosphates except echothiophate are distributed to all parts of the body, including the central nervous system. Therefore, central nervous system toxicity is an important component of poisoning with these agents. In the second step, the covalent acetyl-enzyme bond is split, with the addition of water (hydration).
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