By V. Osmund. University of Michigan-Ann Arbor.
This heart condition is associated with all of the following (E) Blockade of ganglionic transmission at sympa- EXCEPT thetic ganglia in the periphery (A) Antagonism of the inhibitory amino acid neu- rotransmitter glycine ANSWERS (B) The predominance of glycine as an inhibitory 1 proven zestril 2.5mg blood pressure headache. Glycine is the major inhibitory amino acid trans- amino acid transmitter in the spinal cord mitter in the spinal cord buy zestril 2.5 mg otc blood pressure lowering, and strychnine is a rela- (C) Antagonism of the inhibitory amino acid neu- tively selective antagonist of glycine. Strychnine has rotransmitter GABA very little if any action at the GABA receptor– (D) The convulsions lead to tonic extension of the chloride channel complex. Which of the following classes of agents is useful tention deﬁcit disorder are among only a few ap- in the treatment of attention deﬁcit hyperkinetic proved uses of the psychomotor stimulants of the disorder? Analeptic stimulants, such as pentylenetetrazol (B) Benzodiazepines and picrotoxin, act by inhibiting chloride inﬂux at (C) Xanthines the GABAA receptor–chloride channel complex. However, the concen- GABA receptor–chloride channel complex tration of cAMP that is required for such action is (B) Increased release of catecholamines from CNS above the threshold of CNS stimulation. Since the neurons methylxanthines are relatively potent antagonists of (C) Inhibition of cholinesterase leading to in- adenosine and since adenosine has been shown to creased acetylcholine levels be a reasonably potent inhibitor of both central and (D) Antagonism of CNS adrenoceptors to reduce peripheral neurons, the most likely mechanism by inhibition produced by catecholamines which CNS stimulation occurs is through antago- (E) Antagonism of nicotinic receptors that inhibit nism of adenosine receptors. The CNS stimulation produced by methylxanthines, are also indirectly acting sympathomimetics that in- such as caffeine, is most likely due to the antago- crease the release of catecholamines from sympa- nism of which of the following receptors? While amphetamine and (A) Glycine receptors other congeners possess additional actions on pe- (B) Adenosine receptors ripheral sympathetic nerves, this is the most likely (C) Glutamate receptors explanation for the cardiac stimulation observed (D) GABA receptors following the administration of these agents. Cardiac stimulation is an adverse effect associated with the use of the psychomotor stimulants, such as SUPPLEMENTAL READING amphetamine. From GABAA receptor diversity emerges a (C) Inhibition of a GABA-mediated negative uniﬁed vision of GABAergic inhibition. What types Wnessman who often spends long hours at the of pathological conditions can lead to excessive ofﬁce or in his automobile traveling to meet new somnolence? Sleep apnea is characterized by pauses in the past several years, the number of daytime respiration during sleep and usually excessive snor- episodes has begun to increase, and he recently be- ing. Patients with sleep apnea have EDS but often gan to lose mobility in his arms and legs during the awake without feeling rested. Your examination re- clearly deﬁned by determining whether he has a veals an individual who is in otherwise excellent speciﬁc human leukocyte antigen associated with health and mentation with no apparent signiﬁcant the disorder (HLA-DR2). He indicates that he has several periods colepsy is accomplished with psychomotor stimu- of EDS during the day and that the frequency of lants of the amphetamine type. While he feels modaﬁnil, pemoline, and dextroamphetamine all are well rested upon waking, he is especially concerned effective in managing the EDS periods, while about the recent loss of skeletal muscle function imipramine and clomipramine can be used to man- and fears that he may be developing some degener- age any cataplexy. Dailey DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Alprazolam 357 Lorazepam 357 Buspirone 356 Midazolam 359 Chloral hydrate 361 Oxazepam 357 Chlordiazepoxide 359 Prazepam 357 Clonazepam 359 Propranolol 361 Clorazepate 357 Temazepam 357 Diazepam 359 Triazolam 357 Flurazepam 357 Zephalon 360 Hydroxyzine 361 Zolpidem 360 The primary use of sedative–hypnotic and anxiolytic relieve symptoms of anxiety only at doses that produce drugs is to encourage calmness (anxiolytics or sedatives) noticeable sedation. All people are and relieve anxiety are consistently among the most subject to states of emotional tension and uneasiness. Whether they are pre- For otherwise healthy individuals, these occasions are scribed too frequently remains a matter of controversy. Other measures include ad- medical and surgical conditions, and it is often a symp- vice to avoid stimulants before retiring, maintenance of tom of psychiatric illness. When the symptoms become a proper diet, initiation of an exercise program, and intolerable or interfere with the treatment of the un- avoidance of stressful or anxiety-provoking situations. The ideal anxiolytic drug should calm the All central nervous system depressants have some patient without causing too much daytime sedation and ability to relieve anxiety. However, most of these drugs drowsiness and without producing physical or psycho- 355 356 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM logical dependence. Similarly, the ideal hypnotic drug Adverse Effects should allow the patient to fall asleep quickly and Like the benzodiazepines, buspirone appears to be safe should maintain sleep of sufﬁcient quality and duration even when given in very high doses. The most common so that the patient awakes refreshed without a drug side effects are dizziness, light-headedness, and head- hangover. Abuse, dependence, and withdrawal have not been low toxicity and should not interact with other medica- reported, and buspirone administration does not pro- tions in such a way as to produce unwanted or danger- duce any cross-tolerance to the benzodiazepines. Buspirone (BuSpar) is the ﬁrst example of a class of anxiolytic agents that can relieve some symptoms of anxiety in doses that do not cause sedation. Since the Mechanism of Action ﬁrst member of this group, chlordiazepoxide, was intro- duced, many congeners have been marketed. Most of Although buspirone has been shown to interact with a these drugs possess anxiolytic, sedative–hypnotic, and number of neurotransmitter systems in the brain, it ap- anticonvulsant properties. Thus, the clinical indications pears that its clinically relevant effects are mediated for speciﬁc benzodiazepines are not absolute. Chemistry Pharmacokinetics The basic chemical structure of the benzodiazepines consists of a benzene ring coupled to a seven-member Buspirone is well absorbed from the gastrointestinal heterocyclic structure containing two nitrogens (di- tract, and peak blood levels are achieved in 1 to 1.
Taub E best 2.5 mg zestril heart attack zippo, Uswatte G buy discount zestril 5 mg on line high blood pressure medication and lemon juice, Pidikiti R (1999) Constraint-Induced Movement Therapy: a new family of techniques with broad application to physical rehabilitation — a clinical review. Teskey GC, Flynn C, Goertzen CD, Monﬁls MH, Young NA (2003) Cortical stimu- lation improves skilled forelimb use following a focal ischemic infarct in the rat. Teskey GC, Monﬁls MH, VandenBerg PM, Kleim JA (2002) Motor map expansion following repeated cortical and limbic seizures is related to synaptic potentiation. Topka H, Cohen LG, Cole RA, Hallett M (1991) Reorganization of corticospinal pathways following spinal cord injury. Tsubokawa T, Katayama Y, Yamamoto T, Hirayama T, Koyama S (1993) Chronic motor cortex stimulation in patients with thalamic pain. Uy J, Ridding MC, Hillier S, Thompson PD, Miles TS (2003) Does induction of plastic change in motor cortex improve leg function after stroke? VandenBerg PM, Hogg TM, Kleim JA, Whishaw IQ (2002) Long-Evans rats have a larger cortical topographic representation of movement than Fischer-344 rats: a micro- stimulation study of motor cortex in naive and skilled reaching-trained rats. Werhahn KJ, Mortensen J, Kaelin-Lang A, Boroojerdi B, Cohen LG (2002a) Cortical excitability changes induced by deafferentation of the contralateral hemisphere. Werhahn KJ, Mortensen J, Van Boven RW, Zeuner KE, Cohen LG (2002b) Enhanced tactile spatial acuity and cortical processing during acute hand deafferentation. Wiesel TN, Hubel DH (1963) Single cell responses in striate cortex of kittens deprived of vision in one eye. Wiesel TN, Hubel DH (1965) Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. Wittenberg GF, Chen R, Ishii K, Bushara KO, Eckloff S, Croarkin E, Taub E, Gerber LH, Hallett M, Cohen LG (2003) Constraint-induced therapy in stroke: magnetic- stimulation motor maps and cerebral activation. Ziemann U, Corwell B, Cohen LG (1998a) Modulation of plasticity in human motor cortex after forearm ischemic nerve block. Ziemann U, Hallett M, Cohen LG (1998b) Mechanisms of deafferentation-induced plasticity in human motor cortex. Ziemann U, Muellbacher W, Hallett M, Cohen LG (2001) Modulation of practice- dependent plasticity in human motor cortex. Ziemann U, Wittenberg GF, Cohen LG (2002) Stimulation-induced within-represen- tation and across-representation plasticity in human motor cortex. Behavioral Basis of Focal 11 Hand Dystonia: Aberrant Learning in the Somatosensory Cortex Nancy N. ABSTRACT Focal hand dystonia (FHd) is a disabling movement disorder of unknown etiology that can develop in productive, motivated individuals who perform highly repetitive, intensive hand tasks. This chapter summarizes our research supporting aberrant learning as one origin of FHd. Our studies document degradation of the somatosen- sory representation of the hand in animals and patients with dystonic hand move- ments as characterized by large receptive ﬁelds (rfs), overlapped across adjacent digits and glabrous-dorsal surfaces, persistence of digital receptive ﬁelds across broad cortical distances, high ratio of amplitude to latency in somatosensory evoked ﬁeld responses, and decreased spread and abnormal sequencing of digit representa- 227 © 2005 by Taylor & Francis Group. Challenging, rewarded, repetitive behavioral tasks that require high speed, high force, precision and intense work cycles with minimal breaks can accelerate the expression of FHd, particularly when paired with physical characteristics such as joint and soft tissue inﬂexibility, poor posture, slow sensory processing with inac- curate sensory discrimination, imbalance of extrinsic and intrinsic muscles, and rapid reversals of digital ﬂexion and extension. The development of FHd may be mini- mized if individuals use the hands in a functional, mid-range position, take frequent breaks, work at variable speeds for short durations, attend to sensormotor feedback, and initiate digital movements with the intrinsic muscles. Attended, progressive, rewarded, learning based sensorimotor training consistent with the principles of neuroplasticity can facilitate recovery of task speciﬁc motor control in patients with focal hand dystonia. INTRODUCTION We perform delicate, complex, individuated, ﬁne motor movements with our hands. Task-speciﬁc, learning-based repetitive behaviors, drive selective changes in cell assemblies that differentiate and selectively specialize representations. These changes occur simultaneously with the emergence of more efﬁcient, accurate, and differentiated behaviors35,87,114,115,116 (Merzenich et al. Learning based activities, that are progressed in difﬁculty, rewarded, and attended, up-regulate neurotransmitters like dopamine and acetylcholine. For example, expansion of cortical representations, reduction in the size of receptive ﬁelds, narrowed columnar spread, co-selection of complemen- tary inputs, increased excitable neurons, enhanced salience and speciﬁcity of feed- back, increased myelination, strengthened synapses between coincident inputs, shortened integration time, and increased complexity of dendritic branching1,41,53,62,63,68,83–86,88–90,92,96–99,106,107,114–116,120,123,139,140,145 (Jenkins et al. Practice (mental or physical) not only modiﬁes neural structure, but enhances the learning of new tasks, improves task proﬁciency, and increases recovery following neural insults. However, there are inherent limits to neural plasticity due to physiological time constants, inhibition, and integration time121 (Byl and Merzenich, 2000e). When inputs occur within the inhibitory or integration period, they may no longer be registered as temporally distinct,3,31,45,90,105,124,139,140,144 with the stimulated skin sur- faces forming a uniﬁed rather than a unique spatial and temporal representation in © 2005 by Taylor & Francis Group. FOCAL HAND DYSTONIA (FHD) FHd is a disabling condition that can bring an early end to a successful career.
Drugs or their metabolites that are excreted antibiotics such as the tetracyclines generic 2.5 mg zestril prehypertension remedies, which can function as into sweat may be at least partially responsible for the chelating agents and bind calcium purchase zestril 2.5mg without prescription heart attack during sex, have a higher milk dermatitis and other skin reactions caused by some than plasma concentration. The ultimate concentration of the tors determining exposure of the infant include milk vol- individual compound in milk will depend on many fac- ume consumed (about 150 mL/kg/day) and milk tors, including the amount of drug in the maternal composition at the time of feeding. Fat content is highest blood, its lipid solubility, its degree of ionization, and in the morning and then gradually decreases until about the extent of its active excretion. A longer feed usually results in exposure of the chemical properties that govern the excretion of drugs infant to more of a fat-soluble drug, since milk fat con- into saliva and sweat also apply to the passage of drugs tent increases somewhat during a given nursing period. In contrast, the levels of weak organic acids will drugs is low in the neonate and does not approach full probably be lower than those in plasma. It follows, there- maternal plasma protein binding of drug will be associ- fore, that drug accumulation should be less in an older infant who breast-feeds than in a suckling neonate. Although abnormalities in fetal organ structure and function can result from the presence of certain drugs in TABLE 4. Breast-feeding should Antithyroid uracil compounds Barbiturates be discouraged when inherent drug toxicity is known or Caffeine when adverse pharmacological actions of the drug on the Ethanol infant are likely. Infant drug exposure can be mini- Glutethimide mized, however, through short intermittent maternal Morphine drug use and by drug dosing immediately after breast- Nicotine feeding. Concerning regulation of CYP-mediated drug me- (C) Large ionized water-soluble molecules tabolism, all of the following statements are true (D) Acidic compounds EXCEPT (A) Drugs that competitively inhibit CYP enzymes ANSWERS cause a decrease in concentrations of the object 1. CYP3A4 is the predominant cytochrome P450 with metabolism of the greatest number of drugs drug-metabolizing enzyme in the body, both in and thus most likely to be involved in drug–drug in- terms of amount of enzyme and the number of teractions? It has been estimated to (A) CYP3A4 carry out approximately 50% of the cytochrome (B) CYP2C9 P450–mediated reactions observed. The other en- (C) CYP2D6 zymes have been reported to carry out 30% (D) CYP2E1 (CYP2D6), 15–20% (CYP2C9) and 1–2% (both (E) CYP1A2 CYP2E1 and CYP1A2). Most glucuronic acid conjugates are less effec- glucuronosyl transferases will result in all of the fol- tive than the parent drug. The conjugate, however, lowing EXCEPT usually maintains the same pharmacological mecha- (A) Production of a more water-soluble moiety nism of action, although frequently of a lesser mag- that is more easily excreted nitude. Conjugation with glucuronic acid makes a (B) A new compound that may also possess phar- drug molecule more water soluble (A), and glu- macological activity curonic acid conjugates are more likely to be elimi- (C) A drug molecule that may be more susceptible nated by secretion into the bile (C) than are uncon- to biliary elimination jugated compounds. These glucuronide conjugates, (D) A drug molecule that may undergo enterohep- once secreted into the bile, may be cleaved by atic recirculation and reintroduction into the blood- -glucuronidases to liberate the parent compound, stream which can then be reabsorbed (D). Plasma proteins are too large to be ﬁltered by (A) Drugs that are ionized in the renal tubule are the glomerulus, so that any drug molecules bound more likely to undergo passive reabsorption than to these plasma proteins will not undergo ﬁltration. B is also not correct: low- (C) Only drug that is not bound to plasma proteins molecular-weight drugs are more likely to be ﬁl- (i. Drug presence in breast milk is most likely for: to undergo reabsorption, thus reducing the net elim- (A) Drugs highly bound to plasma proteins ination (D). Biochemical heterogeneity and site- excreted in breast milk because it is primarily a pas- speciﬁc tubular injury. The teeth were is metabolized to morphine, which produces most of found to be impacted, and removal necessitated the analgesic effect following codeine extensive surgery. The metabolism of codeine to procedure on one side of the mouth, the patient was morphine is carried out by cytochrome P450 2D6, given a prescription for acetaminophen 300 mg with an enzyme that exhibits genetic polymorphism. The codeine 30 mg (combination product) for the relief patient may be deﬁcient in CYP2D6 and thus of pain. The patient took the prescription as unable to convert codeine into its active metabolite, prescribed for approximately 2 days, but little pain morphine; hence analgesic efﬁcacy is lacking. Tracy Pharmacokinetics is the description of the time course DRUG CONCENTRATION–TIME of a drug in the body, encompassing absorption, distri- PROFILES AND BASIC bution, metabolism, and excretion. The time course of a drug in the body is frequently rep- Pharmacokinetic concepts are used during drug devel- resented as a concentration–time proﬁle in which the opment to determine the optimal formulation of a drug, concentrations of a drug in the body are measured ana- dose (along with effect data), and dosing frequency. For lytically and the results plotted in semilogarithmic form drugs with a wide therapeutic index (difference be- against time. A representative proﬁle of a drug given in- tween the minimum effective dose and the minimum travenously is presented in Figure 5. For example, nonsteroidal antiinﬂam- sampling results in minimal patient discomfort and matory drugs, such as ibuprofen, have a wide therapeu- since obtained values reﬂect the concentrations of drug tic index, and thus knowledge of the pharmacokinetic in the bloodstream.
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