Term
| how does the therapeutic index (from sedation -> coma) compare between barbiturates and benzodiazepines? |
|
Definition
| benzodiazepines level off and don't really reach coma (wider therapeutic index, though reducible w/alcohol and dependency is a possibility), while barbiturates have a pretty direct path = more narrow therapeutic index. |
|
|
Term
| what are the sedation/anti-anxiety benzodiazepines? |
|
Definition
| alprazolam, buspirone, chlordiazepoxide, clorazepate, diazepam, halazepam, lorazepam, oxazepam, phenobarbital, and prazepam |
|
|
Term
| what are the hypnosis benzodiazepines? |
|
Definition
| chloral hydrate, estazolam, eszopiclone, flurazepam, lorazepam, quazepam, secobarbital, temazepam, triazolam, zaleplon, zolpidem |
|
|
Term
| does diazepam have active metabolites? |
|
Definition
| yes including desmethyldiazepam and oxazepam |
|
|
Term
| when are barbiturates used? |
|
Definition
| certain types of epilepsy, inducing a coma, and preventing withdraw from a CNS depressant |
|
|
Term
| what is the difference between pentobarbital and phenobarbital (barbiturates)? |
|
Definition
| pentobarbital is faster acting, phenobarbital is longer acting (pento is thus abused more) |
|
|
Term
| what characterizes zolpidem, zaleplon, and eszopiclone? |
|
Definition
| these are not benzodiazepines structurally but have the same pharmacologic effect |
|
|
Term
| what characterizes the pharmacokinetics of the benzodiazepines? |
|
Definition
| the rate of PO absorption depends on lipophilicity. triazolam thus has extremely rapid absorption (and is short acting) followed closely by diazepam (which is longer acting than triazolam). the less lipophilic chlordiazapoxide and lorazepam have a less rapid CNS onset. the bioavailability of several benzodiazepines including chlordiazepoxide and diazepam may however be unreliable after IM. |
|
|
Term
| what characterizes the pharmacokinetics of most barbiturates and older sedative-hypnotics? |
|
Definition
| most including the thiobarbiturates (thiopental) are very lipid-soluble = high rate of CNS entrance = rapid onset. however phenobarbital and meprobamate have low lipid solubility, and corresponding penetration of the brain. |
|
|
Term
| what characterizes the biotransformation of the benzodiazepines? |
|
Definition
| hepatic metabolism accounts for clearance of all benzodiazepines, most of which go through phase I rxns (including N-dealkylation and aliphatic hydroxylation - possible drug interactions) creating many pharmacologically active metabolites which are subsequently conjugated (phase II rxn) to form glucuronides, which are then excreted in urine. |
|
|
Term
| how long is the half-life for diazepam? |
|
Definition
| a few days - therefore accumulation can particularly be an issue in geriatric pts (decreased cognitive function) |
|
|
Term
| which benzodiazepines are converted into active metabolites? |
|
Definition
| chlordiazepoxide (convert to active desmethychlordiazepoxide, then active demoxepam [which converts to desmethyldiazepam (which converts to oxazepam)]), diazepam, prazepam, clorazapate (these 3 convert to active desmethyldiazepam [which converts to oxazepam, which is also available as itself for pts w/decreased liver/cognitive function]), alprazolam and triazolam (converted to active alpha-hydroxy metabolites), and flurazepam (convert to either active hydroxyethyl-flurazepam or desalkyl-flurazepam). lorazepam is also an immediately active benzodiazepine like oxazepam (do not accumulate in tissue). |
|
|
Term
|
Definition
| know which is a prodrug (clorazepate - not appropriate for liver dz pts). know which have no active metabolites (*estazolam, *lorazepam, *oxazepam - fast acting, no accumulation) |
|
|
Term
| why does the formation of active metabolites by some benzodiazepines complicate their pharmacokinetics? |
|
Definition
| b/c the elimination t1/2 of the parent molecule may have little relationship to the time course of the pharmacologic effects. parent BZDs and derived active metabolites having long t1/2s are more likel to produce cumulative CNS depressant effects w/multiple doses - while these effects occur less w/BZDs such as estalozam, oxazepam, and lorazepam which have shorter t1/2s and are metabolized directly to *inactive glucuronides. |
|
|
Term
| what characterizes metabolism of barbiturates? |
|
Definition
| except for phenobarbital, all barbiturates undergo extensive hepatic transformation (usually slow, except for thiopental) and most metabolites are inactive. elimination t1/2s of secobarbital and pentobarbital range from 18 hrs to 48 hrs in different individuals, but for phenobarbital, it is 4-5 days. multiple dosing w/barbiturates can lead to cumulative effects (excessive CNS depression). geriatric pts w/hepatoxicity can also extend the t1/2 of barbiturates. *barbiturates also can cause auto-induction, where they induce the own enzymes breaking themselves down (allows for increased tolerance, does not occur w/BZDs). |
|
|
Term
| what characterizes excretion of the BZDs and other sedative-hypnotics? |
|
Definition
| the H20-soluble metabolites of BZDs and other sedative-hypnotics are excreted mainly via the kidney - however, usually changes in renal function have no marked effect on parent drug elimination (only trace amounts of BZDs appear in urine unchanged). |
|
|
Term
| what characterizes excretion of phenobarbital? |
|
Definition
| there is limited (20-30%) urinary excretion of unchanged phenobarbital, a weak acid w/pKa of 7.4. the *elimination rate can thus be increased significantly by alkalinization which increases ionization. |
|
|
Term
| what are the pharmacokinetics of barbiturates, BZDs, and zolpidem? |
|
Definition
| they bind to the molecular components of the GABA-A receptor in the neuronal membranes of the CNS, which operates as a Cl- channel (usually activated by GABA, the major inhibitory NT in the CNS). this allows in more Cl-, which hyperpolarizes the cell, making it more resistant to firing. |
|
|
Term
| how do BZDs specifically affect the Cl- membranes in the CNS? |
|
Definition
| they increase the *frequency of Cl- channel openings (do not directly initiate Cl- current). [GABA itself will trigger Cl- channel opening/neuron hyperpolarization via interaction w/alpha+beta subunits]. |
|
|
Term
| what characterizes the GABA-A receptors on the Cl- channel? |
|
Definition
| the GABA-A receptors exhibit molecular heterogeneity w/5+ membrane-spanning subunits arranged in pentameric combinations (commonly 2 alpha-1 subunits, 2 beta-2 subunits, 1 gamma-2 subunit). this heterogeneity may be linked to the molecular basis for varied pharmacologic actions of BZDs and related meds. |
|
|
Term
| what are the pharmacologic effects associated w/the different GABA-A receptor subunit agonists (only described preclinically)? |
|
Definition
| alpha-1: sedation, hypnosis, amnesia, possibly antiseizure. alpha-2: anxiolytic, muscle-relaxation. alpha-5: some memory impairment. -> these are the only GABA-A receptor subunits which BZDs interact with. |
|
|
Term
| what characterizes the GABA-A Cl- channel receptor complex? |
|
Definition
| it is one of the most versatile, drug-responsive physiologic receptors, interactive w/BZDs, barbiturates, zolpidem, alcohol, IV anesthetics (etomidate/propofol), anticonvulsants (gabapentin/vigabatrin), and the antihelmintic agent ivermectin. -> most of these drugs facilitate or mimic GABA activity. |
|
|
Term
| what parts of the neuraxis are affected by BZD-potentiated GABAergic inhibition? |
|
Definition
| the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex, and cerebral cortex. (BZDs do not substitute for GABA) |
|
|
Term
| where are the nonBZDs zolpidem and zaleplon active? |
|
Definition
| at the BZ-1 subtype of GABA-A Cl- channel receptor complex, which only contains alpha-1 subunits (related to sedation, hypnotic, amnesia, and possibly antiseizure action - preclinically) |
|
|
Term
| have endogenous BZ ligands for BZD receptors been isolated? |
|
Definition
|
|
Term
| how do barbiturates specifically affect the Cl- membranes in the CNS? |
|
Definition
| barbiturates appear to increase the *duration of GABA-gated Cl- channel openings and at high concentrations, also *possibly GABA-mimetic (directly activating Cl- channel openings). this involves binding sites distinct from BZ binding sites. barbiturates also appear less selective than BZDs in that they *depress action of excitatory NTs (glutamate) and *exert nonsynaptic membrane effects in parallel w/effect on GABA neurotransmission (this multiplicity of action may be the basis for the ability of barbiturates to induce full surgical anesthesia, more pronounced CNS depressant actions and the lower margin of safety compared to BZDs). |
|
|
Term
| what characterizes the convulsant drugs picrotoxin and bicuculline? |
|
Definition
| these CNS excitatory agents act adversely on Cl- channels. picrotoxin blocks Cl- activity and bicuculline interferes w/GABA binding. |
|
|
Term
|
Definition
| a synthetic BZD derivative which reverses the actions of BZDs as well as zolpidem/zaleplon/eszopiclone - but not barbiturates/meprobamate/ethanol. it can be used to dx an unknown OD. ADRs: agitation, increased brain activity, confusion, dizziness, nausea (may precipitate severe abstinence sundrome in pts who exhibit physiologic BZD dependence). onset of action is rapid via IV and t1/2 is short (.7-1.3 hrs) due to rapid hepatic clearance - therefore *repeated dosing is required as BZDs have a longer duration of action and adequate monitoring/support of respiratory function will likely be necessary. |
|
|
Term
| what characterizes the sedative effect of BZDs, barbiturates, and most older sedative-hypnotic drugs? |
|
Definition
| these exert calming effects w/concomitant reduction of anxiety at low doses. in most cases, anxiolytic actions are accompanied by some decrease in psychomotor and cognitive functions. at anti-anxiety doses, disinhibition may be produced = euphoria, impaired judgment, and loss of self-control. BZDs also cause dose-dependent anterograde amnesia (inability to remember events occurring during actual pharmacological effect). |
|
|
Term
| what are the effects of BZDs on sleep stages? |
|
Definition
| decreased latency of sleep onset (time to fall asleep), increased duration of stage 2 (NREM) sleep, decreased duration of stage 4 (NREM slow-wave) sleep and decreased REM sleep. production of rapid onset of sleep and prolongation of stage 2 NREM can be useful and the significance of less REM/slow wave sleep is not clear, but has been shown to cause anxiety/irritability. REM will rebound after abrupt termination of drug therapy (more likely w/short t1/2 and high dose drugs). administration for >1-2 weeks creates some tolerance and less interference w/sleep patterns. |
|
|
Term
| what are the effects of zolpidem and zaleplon (nonBZD hypnotics) on sleep? |
|
Definition
| zolpidem: decreased REM, minimal effect on slow-wave sleep. zaleplon: decreased latency of sleep onset; minimal effect on total sleep time, NREM, and REM sleep. less amnesia/day-after somnolence/psychomotor impairment than any other sed-hyp - but if 2x dose, rebound insomnia is possible and it potentiates other CNS depressants. |
|
|
Term
| what characterizes anesthesia and the drugs used to induce it? |
|
Definition
| high doses of barbiturates depress the CNS to stage III of general anesthesia (GA). the speed of GA onset and duration of the effect is related to the specific physiochemical properties of the meds. for example, thiopental (barbiturate) is very lipid soluble, enters the brain rapidly after IV, and is often employed for induction of GA. thiopental's short duration of action is due to rapid tissue redistribution from the brain; which is useful in recovery from anesthesia. |
|
|
Term
| what are the BZDs used for in terms of anesthesia? |
|
Definition
| diazepam, lorazepam, and midalozam are used IV as adjunct for GA in preop sedation. large doses contribute to prolonged postanesthetic respiratory depression - related to a relatively long t1/2 and formation of active metabolites. |
|
|
Term
| what characterizes the anticonvulsant activity of the sedative-hypnotics? |
|
Definition
| most sedative-hypnotics inhibit development and spread of epileptiform activity in the CNS. several BZDs including diazepam, clonazepam and nitrazepam are sufficiently selective in anticonvulstant activity w/o marked CNS depression to be used in management of seizure states. the barbiturates phenobarbital and metharbital (converted to phenobarbital) are effective in tx of generalized tonic-clonic seizures. |
|
|
Term
| what characterizes the muscle sedative activity of the sedative-hypnotics? |
|
Definition
| some, esp carbamated molecules (mephenesin) and BZDs inhibit polysynaptic reflexes and internuncial transmission. high doses depress transmission at the skeletal neuromuscular junction - can relax contracted voluntary muscle in joint disease or muscle spasm. |
|
|
Term
| what characterizes the effect on respiration by the sedative-hypnotics? |
|
Definition
| hypnotic doses in healthy pts produce actions comparable to changes which occur during natural sleep, but these effects are dose-related. depression of the medullary respiratory center is the usual cause of death in OD. in pulmonary dz pts, therapeutic doses can cause significant resp depression. |
|
|
Term
| what characterizes the CV activity of the sedative-hypnotics? |
|
Definition
| doses up to hypnotic levels have no effect on CV function in healthy pts. however in hypovolemic states, heart failure and other diseases which impair CV function, normal doses can depress the CV - probably due to depression of the medullary vasomotor centers. toxic doses can depress myocardial contractility and peripheral effects - may cause circulatory collapse. effects are greater w/IV. |
|
|
Term
| what characterizes tolerance w/the sedative-hypnotics? |
|
Definition
| this is common aspect of chronic use - may result in a need for increased dose to promote sleep. there is partial cross-tolerance which occurs among these meds and etoh, but the mechanisms are not well understood. w/barbiturates, this occurs in part due to enzyme induction (pharmacokinetic) but the major cause is pharmacodynamic. BZDs cause down-regulation of brain BZ receptors (pharmacodynamic). there is evidence that the lethal dose range is not altered significantly by chronic use of these drugs however. development of a severe physiologic dependence is greater than any other drug group, including opioids. withdrawal rxns can be life-threatening and range from restlessness, anxiety, weakness, and orthostatic hypotension to hyperactive reflexes and generalized weakness (dose-dependent). withdrawal effects are usually more severe w/discontinuance of shorter-half life drugs vs the longer acting ones. |
|
|
Term
| what characterizes the tolerance effect w/zolpidem and zaleplon? |
|
Definition
| these only have a a few reports of tolerance development when used for less than 4 wks. also, when they do occur, withdrawal symptoms are minimal. |
|
|
Term
| what characterizes cross-dependence w/the sedative-hypnotics? |
|
Definition
| there is an ability of one drug to suppress abstinence symptoms from discontinuance of another drug (very significant among the sed-hyp rxs). this provides the rationale for therapeutic regimens in tx of withdrawal, where longer acting drugs such as diazepam/chlordizepoxide and phenobarbital can be used to tx withdrawal symptoms of shorter-acting drugs including etoh. |
|
|
Term
| what characterizes drug abuse w/the sedative-hypnotics? |
|
Definition
| this is directly related to the pharmacologic effects: relief of anxiety, euphoria, disinhibition and promotion of sleep - therefore most of these drugs are schedule III or IV. most sed-hyp rxs cause physiologic dependence during chronic use: increased anxiety, insomnia and CNS excitability. high doses + abrupt termination = severe withdrawal, but this is less severe w/drugs w/lower t1/2s. chronic use of drugs w/short t1/2s (triazolam) may cause some withdrawal even between doses (daytime anxiety). |
|
|
Term
|
Definition
| this outlier anxiolytic relieves anxiety w/o causing marked sedative or euphoric effects - unlike BZDs, buspirone has no hypnotic, anticonvulsant or muscle relaxant properties (no direct interaction w/GABAergic systems). buspirone may exert anxiolytic effects as a partial agonist at braib 5-HT1A receptors - also has affinity for brain dopamine-2 receptors. pts using this drug show no rebound anxiety or withdrawal signs after abrupt discontinuance, but is not effective at blocking acute withdrawal symptoms after abrupt termination of chronic BZD/other sed-hyp use. thus there is little abuse liability. unlike BZDs, the anxiolytic effects may take > 1 wk to develop, therefore, not useful for tx of acute anxiety states or panic disorders. it may be employed to tx generalized anxiety disorders. rapid PO absorption and extensive 1st pass metabolism into several active metabolites, therefore hepatotoxicity decreases clearance and increases plasma levels and erythromycin/ketoconazole increase plasma levels. rifampin increases clearance and decreases plasma levels. less pyschomotor impairment than diazepam and does not potentiate CNS depression of other sedative hypnotics, etoh or TCAs. however, tachycardia, palpitations, nervousness, GI distress, and paresthesias may occur more frequently than w/BZDs and may cause dose-dependent miosis. BP may be elevated in pts on MAO inhibitors. |
|
|
Term
| what characterizes zolpidem? |
|
Definition
| this is structurally unrelated to BZDs, though it has hypnotic actions. it binds selectively to the BZ-1 subtype (only has alpha-1 subunits) of BZDs receptors and facilitates GABA-mediated neuronal inhibition. its actions may be reversed by flumazenil, and unlike BZDs, it has minimal muscle relaxing and anticonvulsant effects. amnesic effects have been reported at doses higher than recommended. rapid onset of action. duration of hypnotic action = trizolam, but causes minor effects on sleep patterns at recommended hypnotic doses (can suppress REM sleep at higher doses). rebound insomnia may occur on abrupt discontinuance of higher doses. respiratory depression occurs if large doses are taken w/other CNS depressants, including ethanol. the risk of tolerance/dependence w/prolonged use is less than w/BZDs. it is rapidly biotransformed to inactive metabolites and t1/2 = 1.5-3.5 hrs. dosage reductions recommended in hepatic dysfunction, elderly pts, and those taking cimetidine. rifampin decreases t1/2. |
|
|
Term
| what characterizes zaleplon? |
|
Definition
| basically the same as zolpidem |
|
|
Term
|
Definition
| a nonBZD hypnotic, unrelated in structure to other BZDs but similar in pharmacologic effect. its effect is believed to result from interaction w/GABA-receptor complexes at binding domains located close or allosterically coupled to BZ. |
|
|
Term
|
Definition
| a melatonin receptor agonist, approved for insomnia characterizes by difficulty w/sleep onset - not a controlled substance. similar to other hypnotics, exacerbation of insomnia, emergence of cognitive/behavioral abnormalities, and worsening of depression have been reported w/use. this should not be used in pts w/severe hepatic impairment, in combination w/fluvoxamine, and only w/caution in pts taking other CYP inhibitors. more common ADRs include h/a, somnolence, fatigue, dizziness, nausea, exacerbated insomnia, diarrhea, myalgia, depression, dysgeusia, and arthralgia. |
|
|
Term
| what are the older sed-hyp not really used any more? |
|
Definition
| ethchlorvynol, glutethimide, methyprylon, meprobamate, and chloral hydrate (trichloroethanol, trichloroacetic acid) |
|
|
Term
| what are the therapeutic uses for sed-hypnotics? |
|
Definition
| relief of anxiety, insomnia tx, sedation/amnesia before medical/sx procedures, epilepsy/seizure state tx, IV component of balanced anesthesia, reduction of ethanol/other sed-hyp withdrawal, muscle relaxation, and dx aids in tx or psychiatry. |
|
|
Term
| what characterizes tx of anxiety states? |
|
Definition
| psychologic, behavioral, and physiologic responses which characterize anxiety can take many forms. typically, psychic awareness of anxiety is accompanied by: enhanced vigilance, motor tension, and ANS hyperactivity. anxiety is also often 2ndary to organic disease states such as acute MI, angina pectoris and GI ulcers - which require their own specific therapy. there are other secondary (situational) anxiety states which occur infrequently: anticipation of something frightening or family illness. these cases should be self-limiting, but acute use of sed-hypnotics is ok. premedication prior to sx is appropriate as well. |
|
|
Term
| why do both cheese and alcohol potentially cause sleep problems? |
|
Definition
| both contain tyramine, which is converted to catecholamines |
|
|
Term
| what needs to be done is a pt presents w/chronic anxiety as a primary complaint? |
|
Definition
| review the dx criteria in the diagnostic and statistical manual of mental disorders to determine if the dx is correct and if tx should include drug therapy. excessive or unreasonable anxiety about life circumstances (GAD), panic disorders, and agoraphobia are amenable to drug therapy usually in conjunction w/psychotherapy. often anxiety is a symptom of psychiatric problems and may require use of an antidepressant or antipsychotic drug. |
|
|
Term
| what characterizes use of BZDs for tx of anxiety states? |
|
Definition
| alprazolam is very effective in tx of panic disorders and agoraphobia (more selective here than other BZDs) the choice of a BZD in tx of anxiety needs to be based on: 1) relatively high therapeutic index and availability of flumazenil. 2) low risk of drug interactions (esp those w/no active metabolites). 3) slow elimination rates (favors persistence of useful CNS effects). |
|
|
Term
| what are the disadvantages of BZDs? |
|
Definition
| risk of psychological dependence, formation of active metabolites, amnesiac effects (anterograde), cost, and additive CNS depression when given w/other meds. buspirone does not have most of these disadvantages and may be more selective (however, slow onset of action restricts use to GAD). for tx of GAD and certain phobias, antidepressants such as paroxetine and venlafaxine are now DOC - but have minimal effectiveness in acute anxiety states. |
|
|
Term
| what drugs should not be combined? |
|
Definition
| combinations of antianxiety drugs, alcohol, antihistimatic or anticholinergic drugs. |
|
|
Term
| what characterizes the use of beta-blocking agents for anxiety? |
|
Definition
| drugs such as propranolol can be used when anxiety affects muscular performance (musicians, etc) due to sympathetic overactivity. some improvement in nonsomatic components of anxiety may also occur. ADRs: lethargy, vivid dreams, and hallucinations |
|
|
Term
| what characterizes rx tx of sleep problems? |
|
Definition
| nonpharmacologic therapies for sleep problems include: proper diet, exercise, avoiding stimulants before sleep, comfortable sleeping environment, and going to sleep at a regular time. some pts will need a sed-hyp for a limited period - but abrupt termination of most meds in this category can cause rebound insomnia. |
|
|
Term
| what drugs can lead to more daytime sedation in pts on BZD therapy for sleep disorders? |
|
Definition
| slow elimination rates (lorazepam) or biotransformation into active metabolites (flurazepam). nightly use can produce tolerace - which may cause the pt to increase the dose to produce the desired effect. for sleep disorders, zolpidem or zaleplon are generally preferred. chronic prescribing of hypnotics is considered irrational and a dangerous medical practice. |
|
|
Term
| what characterizes ADRs associated w/sed-hyp drugs resulting from dose-related depression of CNS? |
|
Definition
| relatively low doses: drowsiness, impaired judgment, decreased motor skills. this may significantly impair job performance, personal relationships, and driving ability. BZDs may cause substantial dose-related anterograde amnesia, which is ok clinically (endoscopy etc) - but can significantly decrease pts ability to learn new information - particularly that involving complex cognitive processes, or lead to abuse as criminal "date rape" drugs. |
|
|
Term
| which pts will have increased sensitivity to sed-hyp drugs? |
|
Definition
| pts w/CV disease, respiratory disease (chronic pulm dz, symptomatic sleep apnea), hepatic impairment, and geriatric pts. |
|
|
Term
| what can excessive use of sed-hyp drugs lead to? |
|
Definition
| serious CNS effects including behavioral disinhibition (more clearly associated w/use of high doses and pretreatment level of pt hostility), delirium, aggression, and violence. |
|
|
Term
| why are BZDs "safer" if used in intentional ODs? |
|
Definition
| they have flatter dose-response curves. however, other factors such as concomitant ingestion of other CNS depressants (etoh) need to be evaluated. |
|
|
Term
| what characterizes the potential for rescue in a BZD OD? |
|
Definition
| if the discovery of an OD is early and conservative tx is started quickly, the outcome is rarely fatal - even after high doses (if non-BZD sed-hyp, pt viability is less possible esp if found late). in severe toxicity, respiratory depression is complicated by aspiration of gastric contents in an unattended pts - which is more likely to occur w/etoh. |
|
|
Term
| what is treatment for pts experiencing brain stem vasomotor control and direct myocardial depression due to sed-hyp usage? |
|
Definition
| ensuring patent airway (mechanical ventilation if needed) and maintenance of plasma volume, renal output, and cardiac function. positive inotropic drugs such as dopamine may be necessary to preserve renal flow - and where indicated, hemodialysis/hemoperfusion may be employed to increase elimination. |
|
|
Term
| can pts survive after taking 70-90 zolpidem caps? |
|
Definition
| yes, w/flumazenil tx and supportive therapy |
|
|
Term
| is teratogenicity possible w/BZDs? |
|
Definition
| yes, possible but unproven |
|
|
Term
| what is the association between barbiturates and porphyrin synthesis? |
|
Definition
| barbiturates increase porphyrin synthesis and are thus contraindicated in pts w/a hx of acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and symptomatic porphyria. |
|
|
Term
| what are the centrally acting skeletal muscle relaxants used in tx of spasticity? what does this tx consist of? |
|
Definition
| baclofen and diazepam. spastic disorders are abnormalities in skeletal muscle tone, due to pathological changes in descending CNS motor tracts. characteristics include: hyperactive tonic stretch reflexes, jerky/exaggerated movements, muscle weakness and pain, loss of dexterity, and flexor muscle spasms. this occurs in cerebral palsy, MS and strokes and also involve abnormalities in function of the bowel/bladder. pharmacologic therapy may decrease these symptoms by modifying the stretch reflex arc and interfering directly w/skeletal muscle via decreasing activity of the I-1 fibers which excite the primary motoneuron and increasing the action of the inhibitor internuncial neurons. baclofen interferes w/release of excitatory transmitters and diazepam facilitates GABA-mediated presynaptic inhibition. |
|
|
Term
| what are the centrally acting skeletal muscle relaxants which possess anticholinergic action? |
|
Definition
| cyclobenzaprine and orphenadrine |
|
|
Term
| what is the effect of the fact that many pharmacologic agents described as depressants of spinal polysynaptic reflex arcs (phenobarbital, mephenesin) have nonspecific depression of synapses involved in the stretch reflex in tx of excess skeletal tone? |
|
Definition
| this could decrease desired inhibitor activity as well - currently available drugs do provide significant relief from painful muscle spasms, but are less effective in improving meaningful function. |
|
|
Term
| what characterizes diazepam as a central muscle relaxant? |
|
Definition
| diazepam acts at all GABA-A synapses, reducing spasticity partly mediated in the spinal cord and to some degree effective in pts w/transected cords. it can be used in pts w/muscle spasm of almost any origin - however it produces sedation in most pts at doses required to significantly decrease muscle tone. |
|
|
Term
| what characterizes baclofen as a central muscle relaxant? |
|
Definition
| baclofen was designed to be an orally active GABA-mimetic agent, hitting the GABA-B receptors = hyperpolarization, due to *increased K+ conductance. this hyperpolarization in the entire CNS = decreased Ca++ influx = presynaptic inhibition and decreased release of excitatory NTs in the brain/cord. it may also reduce pain in pts w/spasticity by decreasing release of substance P in the cord. baclofen produces less sedation (but some drowsiness) than diazepam (but the same level of reduced spasticity). tolerance may occur chronically and increased seizure activity has been reported in epileptic pts - need slow withdrawal. baclofen may be administered intrathecally if needed, which should reduce peripheral ADRs - but may result in tolerance, excessive somnolence, respiratory depression, and coma (catheter in subarachnoid space is also hard to maintain). |
|
|
Term
| can gabapentin be used as a spasmolytic? |
|
Definition
|
|
Term
|
Definition
| a GABA-A and GABA-B agonist, it is a prodrug w/active metabolites, including GABA itself. (potential as a spasmolytic) |
|
|
Term
|
Definition
| an inhibitory amino acid NT w/pharmacologic activity as it crosses the BBB. (potential as a spasmolytic) |
|
|
Term
|
Definition
| a drug which is only labeled for use in ALS which possibly inhibits glutamatergic transmission in the CNS |
|
|
Term
|
Definition
| a strong alpha-2 agonist (reduces NT release from the presynaptic membrane) which is related to clonidine (but has less CV effects). possibly useful against spasticity/pain - but ADRs include drowsiness, hypotension, dry mouth and aesthenia. |
|
|
Term
|
Definition
|
|
Term
|
Definition
| a hydantoin derivative related to phenytoin, which has direct action (*not central) in decreasing skeletal muscle strength by interfering w/excitation-contraction coupling in muscle fibers (decreases interaction/involvement of Ca++). can be used to treat malignant hyperthermia, but may cause muscle weakness and sedation. |
|
|
Term
| what characterizes use of botulinum toxin as a muscle relaxant? |
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Definition
| this may be locally injected for tx of generalized spastic disorders (cerebral palsy) - blocks ACh vesicle release. |
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Term
| what are the centrally acting skeletal muscle relaxants used in tx of spasms? |
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Definition
| carisoprodol, chlorphenesin, chlorzoxazone, metaxalone, and methocarbamol - these are also classified as interneuronal or polysynaptic blocking drugs, used to tx pain/discomfort of muscle spasms - associated w/acute anxiety or acute musculoskeletal disorders. the primary goal of these drugs is to decrease skeletal muscle tone w/o loss of voluntary motor function and w/no effect on consciousness - however most currently available produce sedation (thus prolonged use is undesirable). they interfere w/the transmission of impulses in the polysynaptic motor reflex pathways in the spinal cord/brainstem, but synaptic blocking is weak. there is also direct depression of higher centers (basal ganglia) that regulate motor activity. cyclobenzaprine (related to tricyclic antidepressants) and orphenadrine (CNS depression/possible psychological dependence) are w/in this group and have anti-ACh action. |
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