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Effects on respiration and cardiovascular function—At hypnotic doses in healthy patients generic 60 ml rumalaya liniment with mastercard spasms gerd, the effects of sedative- hypnotics on respiration are comparable to changes during natural sleep buy rumalaya liniment 60 ml lowest price muscle relaxant pills over the counter. However generic rumalaya liniment 60 ml with mastercard muscle relaxant pediatrics, even at therapeutic doses buy genuine rumalaya liniment on-line spasms after bowel movement, 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 sedative-hypnotics 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, possibly via facilitation of the actions of adenosine, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously. Tolerance: Psychologic & Physiologic Dependence Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. The perceived desirable properties of relief of anxiety, euphoria, disinhibition, and promotion of sleep have led to the compulsive misuse of virtually all sedative-hypnotics. The psychologic component may initially parallel simple neurotic behavior patterns difficult to differentiate from those of the inveterate coffee drinker or cigarette smoker. When the pattern of sedative-hypnotic use becomes compulsive, more serious complications develop, including physiologic dependence and tolerance. Physiologic dependence can be described as an altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome. Most sedative-hypnotics—including benzodiazepines—are capable of causing physiologic dependence when used on a long-term basis. However, the severity of withdrawal symptoms differs among individual drugs and depends also on the magnitude of the dose used immediately before cessation of use. When higher doses of sedative-hypnotics are used, abrupt withdrawal leads to more serious withdrawal signs. Differences in the severity of withdrawal symptoms resulting from individual sedative-hypnotics relate in part to half-life, since drugs with long half-lives are eliminated slowly enough to accomplish gradual withdrawal with few physical symptoms. The use of drugs with very short half-lives for hypnotic effects may lead to signs of withdrawal even between doses. For example, triazolam, a benzodiazepine with a half-life of about 4 hours, has been reported to cause daytime anxiety when used to treat sleep disorders. The abrupt cessation of zolpidem, zaleplon, or eszopiclone may also result in withdrawal symptoms, though usually of less intensity than those seen with benzodiazepines. Although the drug reverses the sedative effects of benzodiazepines, antagonism of benzodiazepine-induced respiratory depression is less predictable. Because all benzodiazepines have a longer duration of action than flumazenil, sedation commonly recurs, requiring repeated administration of the antagonist. Orexin Receptor Antagonists: Sleep-Enabling Drugs Orexin A and B are peptides found in hypothalamic neurons that are involved in the control of wakefulness; their levels increase in the day and decrease at night. Loss of orexin neurons is associated with narcolepsy, a disorder characterized by daytime sleepiness and cataplexy. Flumazenil may cause a severe precipitated abstinence syndrome in patients who have developed physiologic benzodiazepine dependence. In patients who have ingested benzodiazepines with tricyclic antidepressants, seizures and cardiac arrhythmias may follow flumazenil administration. Typically, the psychic awareness of anxiety is accompanied by enhanced vigilance, motor tension, and autonomic hyperactivity. Anxiety is often secondary to organic disease states—acute myocardial infarction, angina pectoris, gastrointestinal ulcers, etc— which themselves require specific therapy. Another class of secondary anxiety states (situational anxiety) results from circumstances that may have to be dealt with only once or a few times, including anticipation of frightening medical or dental procedures and family illness or other stressful event. Even though situational anxiety tends to be self-limiting, the short-term use of sedative-hypnotics may be appropriate for the treatment of this and certain disease-associated anxiety states. Similarly, the use of a sedative-hypnotic as premedication prior to surgery or some unpleasant medical procedure is rational and proper (Table 22–2). The benzodiazepines continue to be widely used for the management of acute anxiety states and for rapid control of panic attacks. Anxiety symptoms may be relieved by many benzodiazepines, but it is not always easy to demonstrate the superiority of one drug over another. Alprazolam has been used in the treatment of panic disorders and agoraphobia and appears to be more selective in these conditions than other benzodiazepines. The choice of benzodiazepines for anxiety is based on several sound pharmacologic principles: (1) a rapid onset of action; (2) a relatively high therapeutic index (see drug B in Figure 22–1), plus availability of flumazenil for treatment of overdose; (3) a low risk of drug interactions based on liver enzyme induction; (4) minimal effects on cardiovascular or autonomic functions. The patient should be warned of this possibility to avoid impairment of performance of any task requiring mental alertness and motor coordination. However, these agents have a slow onset of action and thus minimal effectiveness in acute anxiety states. Some patients may tolerate the drug better if most of the daily dose is given at bedtime, with smaller doses during the day. Prescriptions should be written for short periods, since there is little justification for long-term therapy (defined as use of therapeutic doses for 2 months or longer). The physician should make an effort to assess the efficacy of therapy from the patient’s subjective responses. Combinations of antianxiety agents should be avoided, and people taking sedatives should be cautioned about the consumption of alcohol and the concurrent use of over-the-counter medications containing antihistaminic or anticholinergic drugs (see Chapter 63). Nonpharmacologic therapies that are useful for sleep problems include proper diet and exercise, avoiding stimulants before retiring, ensuring a comfortable sleeping environment, and retiring at a regular time each night. In some cases, however, the patient will need and should be given a sedative-hypnotic for a limited period. It should be noted that the abrupt discontinuance of many drugs in this class can lead to rebound insomnia. The newer hypnotics, zolpidem, zaleplon, and eszopiclone, are less likely than the benzodiazepines to change sleep patterns.
Combinations of valproic acid with other psychotropic medications likely to be used in the management of either phase of bipolar illness are generally well tolerated generic 60 ml rumalaya liniment with visa 3m muscle relaxant. Valproic acid is an appropriate first-line treatment for mania buy 60 ml rumalaya liniment with amex muscle relaxant creams over the counter, although it is not clear that it will be as effective as lithium as a maintenance treatment in all subsets of patients discount 60 ml rumalaya liniment otc spasms left abdomen. Many clinicians advocate combining valproic acid and lithium in patients who do not fully respond to either agent alone safe 60 ml rumalaya liniment spasms jerks. Adverse effects (discussed in Chapter 24) are generally no greater and sometimes less than those associated with lithium. Carbamazepine may be used alone or, in refractory patients, in combination with lithium or, rarely, valproate. The use of carbamazepine as a mood stabilizer is similar to its use as an anticonvulsant (see Chapter 24). Plasma concentrations between 3 and 14 mg/L are considered desirable, although no therapeutic range has been established. Blood dyscrasias have figured prominently in the adverse effects of carbamazepine when it is used as an anticonvulsant, but they have not been a major problem with its use as a mood stabilizer. Overdoses of carbamazepine are a major emergency and should generally be managed like overdoses of tricyclic antidepressants (see Chapter 58). Although not effective in treating acute mania, it appears effective in reducing the frequency of recurrent depressive cycles and may have some utility in the treatment of bipolar depression. Caccia S et al: A new generation of antipsychotics: Pharmacology and clinical utility of cariprazine in schizophrenia. Chue P: Glycine reuptake inhibition as a new therapeutic approach in schizophrenia: Focus on the glycine transporter 1 (GlyT1). Citrome L: Cariprazine: Chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Citrome L: A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: An evidence-based medicine approach. Grunder G, Nippius H, Carlsson A: The ‘atypicality’ of antipsychotics: A concept re-examined and re-defined. Hashimoto K et al: Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Urichuk L et al: Metabolism of atypical antipsychotics: Involvement of cytochrome p450 enzymes and relevance for drug-drug interactions. Walsh T et al: Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Symptoms commonly include auditory hallucinations, paranoid or bizarre delusions, disorganized thinking and speech, and social and occupational dysfunction. For many patients, typical (eg, haloperidol) and atypical agents (eg, risperidone) are of equal efficacy for treating positive symptoms. Atypical agents are often more effective for treating negative symptoms and cognitive dysfunction and have lower risk of tardive dyskinesia and hyperprolactinemia. Other indications for the use of selected antipsychotics include bipolar disorder, psychotic depression, Tourette’s syndrome, disturbed behavior in patients with Alzheimer’s disease and in the case of older drugs (eg, chlorpromazine), treatment of emesis and pruritus. Although her promotion was welcome and came with a sizable raise in pay, it resulted in her having to move away from an office and group of colleagues she very much enjoyed. As a consequence, she is not eating as well as she might and has dropped 7% of her body weight in the last 3 months. She also reports being so stressed that she breaks down crying in the office occasionally and has been calling in sick frequently. When she comes home, she finds she is less motivated to attend to chores around the house and has no motivation, interest, or energy to pursue recreational activities that she once enjoyed such as hiking. The patient has a history of one depressive episode after a divorce that was treated successfully with fluoxetine. Medical workup including complete blood cell count, thyroid function tests, and a chemistry panel reveals no abnormalities. She is started on fluoxetine for a presumed major depressive episode and referred for cognitive behavioral psychotherapy. In addition, depression is characterized by disturbances in sleep and appetite as well as deficits in cognition and energy. Coronary artery disease, diabetes, and stroke appear to be more common in depressed patients, and depression may considerably worsen the prognosis for patients with a variety of comorbid medical conditions. However, it is clear that American physicians have been increasingly inclined to use antidepressants to treat a host of conditions and that patients have been increasingly receptive to their use. In addition, major depression is commonly associated with a variety of medical conditions—from chronic pain to coronary artery disease. When depression coexists with other medical conditions, the patient’s disease burden increases, and the quality of life—and often the prognosis for effective treatment—decreases significantly. Some of the growth in antidepressant use may be related to the broad application of these agents for conditions other than major depression. In addition, antidepressants are commonly used to treat pain disorders such as neuropathic pain and the pain associated with fibromyalgia. Pathophysiology of Major Depression There has been a marked shift in the last decade in our understanding of the pathophysiology of major depression. In addition to the older idea that a deficit in function or amount of monoamines (the monoamine hypothesis) is central to the biology of depression, there is evidence that neurotrophic and endocrine factors play a major role (the neurotrophic hypothesis). The evidence suggests that depression is associated with the loss of neurotrophic support and that effective antidepressant therapies increase neurogenesis and synaptic connectivity in cortical areas such as the hippocampus. Likewise, the anterior cingulate plays a role in the integration of emotional stimuli and attention functions, whereas the medial orbital frontal cortex is also thought to play a role in memory, learning, and emotion. Over 30 structural imaging studies suggest that major depression is associated with a 5–10% loss of volume in the hippocampus, although some studies have not replicated this finding. Depression and chronic stress states have also been associated with a substantial loss of volume in the anterior cingulate and medial orbital frontal cortex. Loss of volume in structures such as the hippocampus also appears to increase as a function of the duration of illness and the amount of time that the depression remains untreated. Much evidence supports the neurotrophic hypothesis of depression, but not all evidence is consistent with this concept. Depression appears to be associated with changes in serotonin or norepinephrine signaling in the brain (or both) with significant downstream effects. It has been known for many years that reserpine treatment, which is known to deplete monoamines, is associated with depression in a subset of patients. Similarly, depressed patients who respond to serotonergic antidepressants such as fluoxetine often rapidly suffer relapse when given diets free of tryptophan, a precursor of serotonin synthesis. Patients who respond to noradrenergic antidepressants such as desipramine are less likely to relapse on a tryptophan-free diet. Moreover, depleting catecholamines in depressed patients who have previously responded to noradrenergic agents likewise tends to be associated with relapse. Administration of an inhibitor of norepinephrine synthesis is also associated with a rapid return of depressive symptoms in patients who respond to noradrenergic but not necessarily in patients who had responded to serotonergic antidepressants. A functional polymorphism exists for the promoter region of the serotonin transporter gene, which regulates how much of the transporter protein is available. Subjects who are homozygous for the s (short) allele may be more vulnerable to developing major depression and suicidal behavior in response to stress.
Using linear pharmacokinetics purchase generic rumalaya liniment canada spasms left side under rib cage, the new dose to attain the desired concentration should be proportional to the old dose that produced the measured concentration: Dnew = (Css buy 60 ml rumalaya liniment free shipping spasms knee,new / Css rumalaya liniment 60 ml mastercard muscle relaxant non prescription,old)Dold = (4 μg/mL / 2 safe 60 ml rumalaya liniment spasms spanish. A steady-state lidocaine serum concentration could be measured after steady state is attained in 3–5 half-lives. The patient would be expected to achieve steady-state conditions after a day (5 t1/2 = 5 ⋅ 5 h = 25 h) of therapy. Using linear pharmacokinetics, the new dose to attain the desired concentration should be proportional to the old dose that produced the measured concentration: Dnew = (Css,new / Css,old)Dold = (3 μg/mL / 6. If the patient was experiencing adverse drug effects, the infusion could be held for one estimated half- life (5 hours) until the new dose was started. A steady-state lidocaine serum concentration could be measured after steady state is attained in 3–5 half-lives. Since the patient is expected to have a half-life equal to 5 hours, the lidocaine steady-state concentration could be obtained any time after the ﬁrst day of dosing (5 half-lives = 5 ⋅ 5 h = 25 h). Lidocaine serum concentrations should also be measured if the patient experiences a return of their ventricular arrhythmia, or if the patient develops potential signs or symptoms of lidocaine toxicity. The patient would be expected to achieve steady-state conditions after 10–12 hours (5 t1/2 = 5 ⋅ 2 h = 10 h) of therapy. Using linear pharmacokinetics, the new dose to attain the desired concentration should be proportional to the old dose that produced the measured concentration: Dnew = (Css,new / Css,old)Dold = (4 μg/mL / 2. A steady-state lidocaine serum concentration could be measured after steady state is attained in 3–5 half-lives. Lidocaine serum concentrations should also be measured if the patient experiences a return of their ventricular arrhythmia, or if the patient develops potential signs or symptoms of lidocaine toxicity. Pharmacokinetic Parameter Method The pharmacokinetic parameter method of adjusting drug doses was among the ﬁrst techniques available to change doses using serum concentrations. It allows the computa- tion of an individual’s own, unique pharmacokinetic constants and uses those to calculate a dose that achieves desired lidocaine concentrations. The pharmacokinetic parameter method requires that steady state has been achieved and uses only a steady-state lidocaine concentration (Css in mg/L or μg/mL). During a continuous intravenous infusion, the fol- lowing equation is used to compute lidocaine clearance (Cl in L/min): Cl = k0/Css, where k0 is the dose of lidocaine in mg/min. The clearance measured using this technique is the patient’s own, unique lidocaine pharmacokinetic constant and can be used in the intra- venous continuous infusion equation to compute the required dose (k0 in mg/min) to achieve any desired steady-state serum concentration (Css in mg/L or μg/mL): k0 = CssCl, where Cl is lidocaine clearance in L/min. Because this method also assumes linear pharmacokinetics, lidocaine doses computed using the pharmacokinetic parameter method and the linear pharmacokinetic method should be identical. Lidocaine clearance can be computed using a steady-state lidocaine concentration Cl = k0 / Css = (2 mg/min) / (2. A steady-state lidocaine serum concentration could be measured after steady state is attained in 3–5 half-lives. Lidocaine serum concentrations should also be measured if the patient experiences a return of their ventricular arrhythmia, or if the patient develops potential signs or symptoms of lidocaine toxicity. The patient would be expected to achieve steady-state conditions after a day (5 t1/2 = 5 ⋅ 5 h = 25 h) of therapy. Lidocaine clearance can be computed using a steady-state lidocaine concentration Cl = k0 / Css = (2 mg/min) / (6. If the patient was experiencing adverse drug effects, the infusion could be held for one estimated half- life (5 hours) until the new dose was started. A steady-state lidocaine serum concentration could be measured after steady state is attained in 3–5 half-lives. Since the patient is expected to have a half-life equal to 5 hours, the lidocaine steady-state concentration could be obtained any time after the ﬁrst day of dosing (5 half-lives = 5 ⋅ 5 h = 25 h). Lidocaine serum concentrations should also be measured if the patient experiences a return of their ventricular arrhythmia, or if the patient develops potential signs or symptoms of lidocaine toxicity. The patient would be expected to achieve steady-state conditions after 10–12 hours (5 t1/2 = 5 ⋅ 2 h = 10 h) of therapy. Lidocaine clearance can be computed using a steady-state lidocaine concentration Cl = k0 / Css = (1 mg/min) / (2. Since the patient is expected to have a half-life equal to 2 hours, the lidocaine steady-state concentration could be obtained any time after the first 10–12 hours of dosing (5 half-lives = 5 ⋅ 2 h = 10 h). Lidocaine serum concentrations should also be measured if the patient experiences a return of their ventricular arrhyth- mia, or if the patient develops potential signs or symptoms of lidocaine toxicity. The most reliable computer programs use a nonlinear regression algorithm that incorporates components of Bayes’ theorem. Nonlinear regression is a statis- tical technique that uses an iterative process to compute the best pharmacokinetic parame- ters for a concentration/time data set. The computer program has a pharmacokinetic equation preprogrammed for the drug and administration method (oral, intravenous bolus, intravenous infusion, etc. Typically, a one-compartment model is used, although some pro- grams allow the user to choose among several different equations. Using population esti- mates based on demographic information for the patient (age, weight, gender, liver func- tion, cardiac status, etc. Kinetic parameters are then changed by the computer program, and a new set of estimated serum concentrations are computed. The pharmacokinetic parameters that generated the estimated serum concentrations closest to the actual values are remembered by the computer program, and the process is repeated until the set of pharmacokinetic parameters that result in esti- mated serum concentrations that are statistically closest to the actual serum concentrations are generated. Bayes’ theorem is used in the computer algorithm to balance the results of the computations between values based solely on the patient’s serum drug concentrations and those based only on patient population parameters. Results from studies that compare various methods of dosage adjustment have consistently found that these types of computer dosing programs perform at least as well as experienced clinical pharma- cokineticists and clinicians and better than inexperienced clinicians. Some clinicians use Bayesian pharmacokinetic computer programs exclusively to alter drug doses based on serum concentrations. An advantage of this approach is that consis- tent dosage recommendations are made when several different practitioners are involved in therapeutic drug monitoring programs. However, since simpler dosing methods work just as well for patients with stable pharmacokinetic parameters and steady-state drug concentrations, many clinicians reserve the use of computer programs for more difﬁcult situations. Those situations include serum concentrations that are not at steady state, serum concentrations not obtained at the speciﬁc times needed to employ simpler meth- ods, and unstable pharmacokinetic parameters. Many Bayesian pharmacokinetic com- puter programs are available to users, and most should provide answers similar to the one used in the following examples. He received a 100-mg loading dose of lidocaine at 0800 H and a continuous intravenous infusion of lidocaine was started at 0810 H at the rate of 2 mg/min. Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. In this patient case, it is unlikely that the patient is at steady state so the linear pharma- cokinetics method cannot be used. The pharmacokinetic parameters computed by the program are a volume of distribu- tion for the entire body (Varea) of 100 L, a half-life equal to 1. The continuous intravenous infusion equation used by the program to compute doses indicates that a dose of 180 mg/h or 3 mg/min [k0 = (180 mg/h) / (60 mg/h) = 3 mg/min] will produce a steady-state lidocaine concentration of 4. He received a 150 mg loading dose of lidocaine at 1300 H and a continuous intravenous infusion of lidocaine was started at 1305 H at the rate of 2 mg/min.
Skeletal Muscle Relaxants Most of the agents have similar actions cheap rumalaya liniment 60 ml online muscle relaxant topical, and there- fore discount rumalaya liniment 60 ml online muscle relaxant and alcohol, the same adverse reactions are seen effective 60 ml rumalaya liniment back spasms yoga. These consist Generic name Trade name most commonly of drowsiness purchase rumalaya liniment once a day muscle relaxant vs anti-inflammatory, dizziness, and light-head- Carisoprodol Rela, Soma edness. One agent, cyclobenzaprine (Flexeril), has a Chlorzoxazone Paraﬂex prominent anticholinergic component and frequently Cyclobenzaprine Flexeril causes dryness of the mouth along with sedation and Methocarbamol Robaxin, Delaxin Orphenadrine Norﬂex dizziness. Which of the following agents produces its thera- (A) Baclofen peutic action by causing a nondepolarizing block of (B) Mecamylamine end plate receptors at the skeletal neuromuscular (C) Pancuronium junction? Which of the following adjuvants to anesthesia has (C) Rapacuronium the potential to cause hyperkalemia, postoperative (D) Scopolamine muscle pain, muscle fasciculation, and prolonged (E) Succinylcholine apnea and paralysis in genetically sensitive pa- 2. For preanesthetic medication, he (B) Diazepam is given atropine to block secretions and a mild (C) Edrophonium sedative to reduce anxiety and induce sedation. A 45-year-old man in otherwise good health com- anesthesia with enthrane is begun with no major plains of muscle weakness early in the morning but complications. The tient displays muscle rigidity and a rapid increase in neurologist performs electromyography and notes temperature. This indicates (A) Atropine a defect at the prejunctional side of the neuromus- (B) Baclofen cular junction. A former respiratory therapist who once called (C) Lambert-Eaton myasthenic syndrome himself the Angel of Death was charged in the (D) Malignant hyperthermia deaths of six elderly nursing home patients. Which of the following agents blocks the release of breathing, even though the drug was not part of neurotransmitter from all cholinergic nerve end- their therapeutic regimen. A 45-year-old African-American woman diagnosed muscular blocking in widespread clinical use, partic- with myasthenia gravis was prescribed pyridostig- ularly as an aid for intubation. Its administration mine with a resulting improvement in muscle may produce muscle fasciculation and postopera- strength. Lambert-Eaton myasthenic syndrome is a rare produces no signiﬁcant improvement, and the diag- disorder of autoimmune attack against calcium chan- nosis is cholinergic crisis. In these patients, repetitive stimulation (B) Replacing pyridostigmine with neostigmine promotes facilitation of transmitter release, and this (C) Giving dantrolene to decrease sarcoplasmic re- is seen clinically as an improvement in muscle lease of calcium strength with increased physical activity. Nicotine and succinyl- cholinesterase does not affect neuromuscular trans- choline also act at the end plate receptors but cause mission except with regard to breakdown of succinyl- depolarization. Malignant hyperthermia is due to a defect in blocker that has essentially no activity at the end the contractile apparatus of skeletal muscle and not plate receptors, and scopolamine blocks cholinergic in neuromuscular transmission. The patient has a rare genetic defect that results Atracurium and rocuronium are nondepolarizing in susceptibility to malignant hyperthermia. Acute neuromuscular blockers that act speciﬁcally at the attacks are manifested by heat generation, muscle postjunctional receptors of the skeletal neuromus- rigidity, and high oxygen consumption, all of which cular junction. It has a fatality rate in ex- acting muscle relaxants that stimulate presynaptic cess of 70% if left untreated. These appear to trigger excessive re- overtreated with anticholinesterases, that is,, when lease of Ca from the sarcoplasmic reticulum due acetylcholinesterase at the neuromuscular junction is to a defect in the calcium release channels. The depolarizing neuromuscular to depolarization and desensitization of the end plate blocking agent succinylcholine may also appear to receptors so that they cannot respond to further stim- be a viable possibility. Unlike the irreversible organophos- since it is rapidly broken down to natural products phates, pyridostigmine has a short to intermediate du- by plasma cholinesterase and would not have been ration of action, and treatment should be to allow detected by the toxicological tests. Continuous in- can be used to reverse the effect of nondepolarizing trathecal baclofen infusion in severe spasticity after blockers. The disease the adductor pollicis using train-of-four 50-Hz stim- may be triggered by disorders of the thymus, which ulation reveals a progressive decrease in the com- contains a protein antigenically related to skeletal pound muscle action potential. Subsequent administration of edro- action potentials) and a postjunctional cause (such as phonium results in an improvement in muscle myasthenia gravis). The neurologist larizing neuromuscular blocker (mivacurium) fol- prescribes oral pyridostigmine and prednisone, lowed by a short-acting acetylcholinesterase inhibitor which lead to clinical improvement over the next (edrophonium) is an almost conclusive test for myas- few weeks. In many instances, edrophonium alone patient has a thymoma and increased titers of anti- may be used (the Tensilon test). Following removal of the thy- long-acting cholinesterase inhibitor that can provide moma, the patient no longer shows signs of muscle palliative relief, whereas prednisone is used to sup- weakness and appears to be in remission. The chloride channel ap- pears to contain other regulatory sites with high afﬁnity Doxapram Amphetamine Caffeine Nikethamide Methamphetamine Theophylline for such agents as the benzodiazepines, picrotoxin, alco- Pentylenetetrazol Methylphenidate Theobromine hol, neuroactive steroids, and the barbiturates. Other agents that appear to associated with the use of such psychomotor stimulants promote chloride conductance through this channel in- as amphetamine and many of its congeners. Glycine me- and strychnine, to synthetic compounds, such as diates inhibition of spinal cord neurons and is intimately pentylenetetrazol and doxapram. The wide range of involved in the regulation of spinal cord and brainstem chemical structures makes this particular class some- reﬂexes. Strychnine directly antagonizes this inhibition, what difﬁcult to categorize with respect to absorption, allowing excitatory impulses to be greatly exaggerated. However, most analeptic stimulants can be absorbed orally and have short dura- Clinical Uses tions of action. The pharmacological effect of most of these compounds is terminated through hepatic metab- As indicated, most of the analeptic stimulants were olism rather than renal excretion of unchanged drug. Doxapram (Dopram) is sometimes used to counteract postanesthetic respiratory depression Mechanism of Action and as an aid in chronic obstructive pulmonary disease. Convulsions produced by this class of is possible to ion-trap this weak organic base by acidify- agents (with the exception of strychnine) are usually ing the urine, thereby reducing its reabsorption in the tonic–clonic and are uncoordinated. Mechanism of Action The uncontrolled excitation that occurs after acci- dental or intentional strychnine ingestion (in the ab- There is good evidence that the facilitation of peripheral sence of normal inhibition) results in characteristic con- sympathetic nervous system transmission produced by vulsions. The possibility normally dominant, tonic extension of the body and all that amphetamines act indirectly. This hyperextension is known as monoamines) at monoaminergic synapses in the brain opisthotonos; at its extreme, it consists of a characteris- and spinal cord seems likely. However, amphetamine has tic posture in which the back is arched and only the effects beyond displacement of catecholamines; these in- back of the head and the heels are touching the surface clude inhibition of neuronal amine uptake, direct stimula- on which the victim is lying. Under the inﬂuence of strychnine, catecholamine action at certain subtypes of adrenocep- all sensory stimuli produce exaggerated responses. Interestingly, primary therapeutic consideration after strychnine poi- none of these actions explains the therapeutic beneﬁt of soning is to prevent convulsions, which may be fatal. Diazepam and clonazepam (see Chapter 33) appear to be moderately effective in preventing strychnine con- Clinical Uses vulsions, and either of these is the agent of choice. Barbiturates are often used to treat overdoses of all of The therapeutic indications for the psychomotor stimu- the analeptic stimulants. Amphetamines and the more extensively used methylphenidate paradoxically are quite effective in Pharmacokinetics calming a large proportion of children with this disor- Many psychomotor stimulants possess activities similar der. Pemoline (Cylert) is also used in the treatment of to those of amphetamine and have been discussed pre- attention deﬁcit disorder with hyperkinetic behavior. Of primary importance to our The mechanism by which these compounds are effec- discussion of the psychomotor stimulants are ampheta- tive in this disorder is not known.
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