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139 Cards in this Set
- Front
- Back
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define sedative
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drug/compound which reduces anxiety and exerts a calming effect with little or no effect on motor or mental functions
degree of CNS depression caused should be minimal consistent with therapeutic efficacy |
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define hypnotic
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drug/compound which produces drowsiness and encourages the onset and maintenance of a state of sleep that resembles the natural sleep state as much as possible
hypnotic effects involve more pronounced depression of CNS than sedation (achieved by most sedative drugs by just increasing the dose |
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what are the long-acting barbiturates?
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long-acting have a half-life of 12-36 hours
barbital phenobarbital |
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for what is phenobarbital currently used?
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antiepileptic
renal excretion, so must have well-functioning kidneys |
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what are the short-acting barbiturates (half-life of 4-8 hours)?
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pentobarbital
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for what is pentobarbital currently used?
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anxiolytic
liver metabolism and excretion, so renal function can be poor |
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what are the ultra-short-acting barbiturates?
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have a half-life of 9 hours, but action only lasts 15-20 minutes b/c of redistribution
thiopental |
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for what is thiopental currently used?
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induction of anesthesia
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on what is the duration of action of ultra-short-acting barbiturates dependent?
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redistribution
group has high lipid solubility of this group, little renal excretion occurs, eliminated by metabolism over 99% of thiopental is excreted as a metabolite |
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on what is the duration of action of short-acting barbiturates dependent?
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hepatic metabolism (mainly) and renal excretion
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on what is duration of action of the long-acting barbiturates dependent?
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renal excretion
since these drugs have low lipid solubility, they have trouble reaching hepatic enzymes |
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how are barbiturates metabolized?
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liver microsomal enzymes
even poorer substrates (long-acting barbs) induce their own metabolism since the enzymes metabolize other drugs as well, barbs induce the metabolism of other compounds as well |
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what are the uses for barbiturates?
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1) sedative-hypnotic effects - no longer common as sleeping pills
2) induction of anesthesia - thiopental 3) anxiolytic 4) anticonvulsant |
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what are the effects of barbiturate overdose?
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1) MEDULLARY RESPIRATORY CENTER DEPRESSION
2) hypotension due to depressed myocardial contractility and vascular tone by central and peripheral effects |
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how can barbiturate overdose be treated?
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respiratory support
gastric lavage (if ingestion is recent) alkalinize urine (ion traps barbs) |
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what are the drug interactions involved with barbiturates?
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1) CNS depressants (alcohol) can potentiate the CNS depression
2) enzyme induction leads to altered metabolism of other drugs, so their doses must be increased |
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what is the tolerance seen with barbiturates?
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loss of effects upon repeated administration of the same dose; effects can be regained with increased dosage
- occurs for sedative-hypnotic effect - no tolerance to anticonvulsant effect - NO tolerance to the lethal effect (respiratory depression) |
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what are the two sources of tolerance to barbiturates?
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1) metabolic - enzyme induction causes increased rate of metabolism of the barbs
2) changes in brain sensitivity due to down-regulation of barbiturate sites on the GABA receptor |
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what causes the dependence to barbiturates?
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changes in brain sensitivity to the barbiturates, due to down-regulation of the barb sites on GABA receptors
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what are the minor signs of barbiturate/ethanol/benzodiazepine dependence?
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on withdrawal of the drug:
anxiety muscle twitching tremors dizziness insomnia |
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what are the major signs of barbiturate/ethanol/benzodiazepine dependence?
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upon withdrawal of the drug:
convulsions delirium death |
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what are the suffixes associated with benzodiazepines?
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-zepam
-zolam chlordiazepoxide is the exception |
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which benzodiazepine has a very rapid elimination?
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triazolam
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which benzodiazepine has a rapid elimination?
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oxanzepam
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which benzodiazepines have intermediate elimination?
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lorazepam
temazepam alprazolam chlordiazepoxide (slow-intermediate elimination) |
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which benzodiazepines have slow elimination?
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diazepam
prazepam flurazepam halazepam chlordiazepoxide (slow-intermediate elimination) |
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why is the half-life of benzodiazepines often not related to the duration of action?
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several benzodiazepines have active metabolites that have the benzo effects
long-acting benzos cause a hangover effect if taken for sleep |
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what is the final metabolic step of all benzodiazepines?
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glucuronidation
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which benzodiazepines have a short duration of action?
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triazolam
midazolam alprazolam |
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what is the effect of increased age on the effects of benzodiazepines?
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increased age -> increased Vd -> increased half-life -> hangover effect
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why have benzodiazepines overtaken barbiturates for use in hypnotic effect?
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benzos don't cause the anesthesia, whereas barbs do
benzo with a short duration of action (triazolam, alprazolam, midazolam) is best |
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what benzodiazepines are used for antianxiety effects?
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benzos with a long duration of action
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what is the problem with using benzodiazepines as anticonvulsants?
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tolerance develops
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what is the only benzodiazepam used for skeletal muscle relaxation?
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diazepam
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what benzodiazepam is useful in treating panic attacks?
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alprazolam
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what are the drawbacks to using triazolam as a sedative-hypnotic?
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(1) breakthrough insomnia
- wake up in middle of night any given night (2) nightmares and changes in sleep stages - lack of REM sleep (3) tolerance -> increase dose (4) abstinence causes huge rebound insomnia (2), (3), and (4) are common to all benzos |
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what are the drawbacks to using any benzodiazepine as a sedative-hypnotic?
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(1) nightmares and changes in sleep stages
- lack of REM sleep (2) tolerance -> increase dose (3) abstinence causes huge rebound insomnia |
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what causes the breakthrough insomnia associated with triazolam?
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brain fights the sedative effect of triazolam
solution: use a hypnotic with a long half-life |
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why is diazepam a poor hypnotic, but a good anxiolytic?
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diazepam has a long duration of action because it has a very long-lived metabolite that stays in the blood for ten days or more after a dose
- this makes it a poor hypnotic b/c it causes a hangover effect - this also makes it a good anxiolytic |
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how do benzodiazepines compare to barbiturates?
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1) similar uses
2) benzos are more efficacious in anxiolytic effects 3) benzos have a higher therapeutic index 4) benzos have less severe withdrawal symptoms with long-acting benzos, though they are equally bad with short-acting if terminated abruptly |
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what is the significance of the higher therapeutic index of benzodiazepines compared to barbiturates?
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barbiturates can cause anesthesia and eventually lead to respiratory depression and coma
benzodiazepines never cause anesthesia, let alone respiratory depression or coma (an entire bottle wouldn't kill someone) |
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when are withdrawal symptoms seen with benzodiazepines?
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short-acting benzos can cause withdrawal signs/symptoms if dosing is terminated abruptly (seen only in patients that abuse the short-acting benzodiazepines)
long-acting benzos don't produce withdrawal signs/symptoms |
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what are the adverse effects of benzodiazepines?
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CNS depression
paradoxical effects tolerance dependence **overall, these drugs are safer than acetaminophen** |
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what CNS depression is caused by benzodiazepines?
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- daytime sedation (mild, so not perfect anxiolytics)
- impairment of mental and motor function - enhanced effects of other CNS depressants (EtOH becomes dangerous) |
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what paradoxical effects are caused by benzodiazepines?
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nightmares
CNS activation (unmanageable, impatient, anxiety) especially seen with short-acting benzos |
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what forms of tolerance are seen with benzodiazepines?
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- no tolerance to anxiolytic effects
- tolerance develops to hypnotic effects - tolerance develops to anticonvulsant effects |
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what accounts for the remarkable safety of the benzodiazepines?
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benzos work by enhancing the actions of neural inhibitionthat is mediated by GABA (increased inward chloride current)
this leads to a self-limited neuronal depression b/c if the CNS decreases GABA release, the effect of benzos is decreased barbs can do this AND at higher doses can mimic the actions of GABA by directly opening the Cl channel, so they can produce profound CNS depression |
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buspirone
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anxioselective anxiolytic (causes no sedative effects) - good for relief of worry/irritability
stimulates serotonin (5-HT1A receptors) no EtOH synergism 2-3 week onset |
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zolpidem
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chemically distinct from benzos, but acts via benzo receptor
hypnotic with no rebound insomnia and no withdrawal effects tolerance develops, but it's minimal Trade Name: Ambien |
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eszopiclone
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chemically, not a benzo, but acts like a benzo (binds same site of GABA receptor and enhances GABA-induced opening of Cl channel)
Unique Characteristic: for at least 6 months there is no tolerance FDA labeling for chronic insomnia Trade Name: Lunesta |
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flumazenil
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benzodiazepine receptor antagonist
reverses effects of a benzo OD in 5-10 minutes |
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what is the result of flumazenil administration on a patient with TCAD overdose?
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patients who OD on a benzo often OD on a TCAD as well
if this is the case, flumazenil can precipitate a seizure flumazenil can also precipitate seizures in patients who have become dependent upon a benzo |
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therapeutic advantage of clonazepam
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useful in Tx of general absence seizures
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DOC in treating panic disorders
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alprazolam
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therapeutic advantage of flurazepam/quazepam
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less potent and more slowly eliminated
no rebound insomnia on d/c of treatment |
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advantages of zolpidem
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no withdrawal effects
minimal rebound insomnia little/no tolerance with prolonged use |
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disadvantages of zolpidem
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no anti-convulsant or muscle relaxing properties
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advantages of buspirone
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- useful in long-term treatment of chronic anxiety with symptoms of irritability and hostility
- doesn't potentiate CNS depression of alcohol - low potential for addiction |
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disadvantages of buspirone
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slower onset of action than benzos
no muscle relaxation/anticonvulsant activity |
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disadvantages of barbiturates
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induce tolerance
induce drug-metabolizing enzymes induce physical dependence cause severe withdrawal symptoms |
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advantages of thiopental
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rapid onset of action
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what questions should be asked about the history of a patient who has taken a poison?
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how much? of what? when?
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what physical exam findings are important in a patient who has taken poison?
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vital signs - amphetamine/cocaine stimulate HR
eyes - pilation/constriction of pupils mouth - burns/odors skin abdomen - bowel sounds nervous system - seizures |
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what is indicated by pinpoint pupils in an unconscious person?
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heroin overdose
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what is indicated by hot and dry skin?
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antimuscarinic overdose
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what is the effect of hypoventilation on arterial blood gas?
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elevated partial pressure of carbon dioxide
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what causes poor tissue oxygenation? what does this cause?
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hypoxia, hypotension, cyanide poisoning
results in metabolic acidosis (low partial pressure of carbon dioxide) |
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what can cause a low PO2?
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aspiration pneumonia or drug-induced pulmonary edema
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what is the result of carbon monoxide poisoning on PO2?
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since PO2 measures only oxygen dissolved in the plasma and not total blood oxygen content, the PO2 may appear normal despite a significant oxyhemoglobin deficiency in carbon monoxide poisoning
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what routine lab tests are valuable in toxicologic diagnosis?
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arterial blood gases
electrolytes renal function tests (creatinine) serum osmolality EKG |
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what is the normal anion gap?
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12-16 meq/L
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how is the anion gap calculated?
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Na, K, HCO3, and Cl are measured
anion gap = (Na + K) - (HCO3 + Cl) normal = 12-16 mEq/L |
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when does the anion gap increase? what causes it to increase?
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increases in the presence of unmeasured anions
when acidic poisons are ingested, the protons are released and subsequently bind to bicarb to form carbonic acid which is converted to CO2 and H2O by carbonic anhydrase the deprotonated poison anion replaces bicarb so the anion gap is increased |
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what drugs can cause metabolic acidosis?
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methanol
ethylene glycol salicylates paraldehyde |
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what drugs can cause lactic acidosis?
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drugs that induce seizures
iron phenformin hypoxia metformin |
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what drugs can cause ketoacidosis?
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ethanol
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how is metformin OD monitored?
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monitored using anion gap, because overdose causes lactic acidosis
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why is creatinine of little use in treating a poison?
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the levels rise too slowly to be helpful (takes a couple days to increase even with severe damage)
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on what is the serum osmolality dependent?
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sodium
glucose blood urea nitrogen |
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what is the normal value for serum osmolality?
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280-290 mosm/L
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how is osmolar gap calculated?
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osmolar gap = measured osmolality - calculated osmolality
normal value is zero; if there is a significant difference, another osmotically active intoxicant molecule (alcohols) is present measured osmolality is determined from freezing point depression calculated osmolality is determined from Na, glucose, BUN |
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what EKG abnormality is typical of TCAD overdose?
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widening of the QRS complex
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what EKG abnormality is typical of antiarrhythmic overdose?
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widening of the QRS complex
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what EKG abnormalities are typical of digitalis poisoning?
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atrioventricular block
multiple ventricular arrhythmias |
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what substances commonly cause an osmolar gap?
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ethanol
methanol ethylene glycol (antifreeze) isopropanol |
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how are skin poisons removed?
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rinsing skin
removing clothes |
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what are the contraindications to induced emesis?
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seizures
absence of gag reflex ulcerated oral mucous membranes |
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what is absolutely essential when inducing emesis in a poisoned patient?
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airway must be protected
suction must be readily available |
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ipecac syrup
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oral emesis-inducing compound
works in 15-30 minutes via local and CNS effects |
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gastric lavage
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aka stomach pumping
useful in removing poisons for 6 hours after ingestion of a poison; up to 24 hours if gastric emptying is delayed with an anti-muscarinic cannot be performed in children because the required tube is too small and clogs easily |
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sodium sulfate
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cathartic agent which hastens the removal of toxins from the GI tract and reduces absorption
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activated charcoal
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given in sufficient quantity to bind many toxins
should not be given simultaneously with ipecac because it binds ipecac |
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when should methods of enhancement of elimination of toxins be considered?
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after appropriate diagnostic and decontamination procedures
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how can renal elimination of toxins be enhanced?
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forced diuresis (useful for salicylate or phenobarbital OD)
alteration of urinary pH |
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peritoneal dialysis
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relatively simple and available technique
inefficient at removing most drugs |
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hemodialysis
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more efficient than peritoneal dialysis
efficiency is a function of the molecular weight, water solubility, protein binding, endogenous clearance, and distribution in the body of the specific toxin LOW MOLECULAR WEIGHT & HIGH WATER SOLUBILITY |
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hemoperfusion
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blood pumped from the patient via a venous catheter through a column of adsorbent material and then recirculated to the patient
especially good for high molecular weight toxins with poor water solubility (lipophilic) |
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what properties are important for using hemodialysis to remove a toxin?
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toxin must have a low molecular weight and be highly hydrophilic
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what properties are important for using hemoperfusion to remove a toxin?
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toxin must have a high molecular weight and be highly lipophilic
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acetylcysteine
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antidote to acetaminophen OD (administered IV)
best results if given within 12 hrs of OD follow liver fcn tests and acetaminophen blood levels |
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atropine + 2-PAM
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2-PAM = pralidoxime
antidote for anticholinesterases, organophosphates, physostigmine |
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deferoxamine
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chelating agent (antidote for iron salts)
judge severity of poisoning by WBC count, hyperglycemia, vomiting and diarrhea, CNS depression urine becomes wine-red |
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for what is ethanol an antidote?
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methanol/ethylene glycol
slows ADH and thereby the conversion of alcohols to toxic intermediates |
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naloxone
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antidote for narcotic drugs
specific antagonist of narcotic receptors given IV, IM, or subQ |
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physostigmine salicylate
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antidote for anticholinergic overdose
may cause bradycardia, miosis, fasciculations, salivation, lacrimation, increased bronchial secretions, urination, or diarrhea must have atropine ready to reverse excess effects |
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Fab Fragments
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antidote for digoxin poisoning
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simple asphyxiants
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gases that cause hypoxia by displacement of oxygen
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chemical asphyxiants
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gases that act within the body to prevent utilization of oxygen (CO and CN)
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how is cyanide absorbed?
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absorbed well by all routes
toxic amounts can even be absorbed through the skin |
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what form of iron has a high affinity for cyanide?
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ferric state (Fe3+)
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what is the mechanism of action of cyanide poisoning?
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when absorbed, CN reacts readily with the trivalent iron of cytochrome oxidase in mitochondria, which then inhibits cellular respiration and results in hypoxia
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what is involved in the treatment for cyanide poisoning?
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(1) oxidation of the ferrous heme in hemoglobin to its ferric form by amyl nitrite or sodium nitrite
(2) methemoglobin competes strongly for CN, facilitating its removal from cytochrome c oxidase, acting as a sink for the CN (3) CN is converted to SCN via the action of rhodanese, a mitochondrial enzyme (4) methemoglobin is returned to its ferrous form by the addition of methylene blue |
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what is included in the KIT?
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the KIT is an antidote for CN poisoning; it includes:
- amyl nitrite - oxidizes ferrous heme in some of the hemoglobin to its ferric form - thiosulfate - provides sulfur needed for the conversion of CN to SCN - methylene blue - reduces ferric hemoglobin to its ferrous form |
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why does oxidized hemoglobin compete so efficiently with cytochrome c oxidase for cyanide?
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law of mass action
though not all hemoglobin is converted to the oxidized form, there is so much hemoglobin in the body that the portion which is converted far outnumbers the cytochrome c oxidase molecules |
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what is the appearance of blood in CN poisoning?
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oxygen isn't being utilized, so venous blood is oxygenated and is almost as bright red as arterial blood
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what is responsible for oxidizing hemoglobin in the cyanide antidote kit?
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amyl nitrite
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where does sulfur come from to detoxify cyanide in the cyanide antidote kit?
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thiosulfate
the mitochondrial enzyme, rhodanese, converts the cyanide to thiocyanate and removes the cyanide from the oxidized hemoglobin |
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how is hemoglobin returned to its reduced form in the cyanide antidote kit?
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methylene blue, which is included in the kit
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how is carbon monoxide absorbed?
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entirely through the lungs
requires active respiration |
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how is carbon monoxide excreted?
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by the lungs
rate of excretion depends on what patient is breathing: t1/2 = 320 min on room air t1/2 = 80 min on 100% O2 t1/2 = 20 min on hyperbaric therapy CO + HbO2 <=> O2 + COHb (driven left by oxygen) |
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what is the mechanism of action of CO toxicity?
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CO competes with oxygen for binding sites on Hb (binds at 1/10 the rate of oxygen, but released at 1/2400 the rate of oxygen), leading to hypoxia
oxygen dissociation curve is shifted |
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how does the blood appear in CO poisoning?
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venous blood is bright red (as red as the arterial blood)
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how does carbon monoxide interfere with oxygen transport?
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prevents oxygen binding by competitive inhibition at the ferrous iron in heme
increases the affinity of heme for oxygen |
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how does CO change the Hb saturation curve?
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normal: Hb is 85% saturated with oxygen in the alveoli; Hb is 60% saturated with oxygen in the tissues; 25% of oxygen is released in tissues
with CO: Hb is 50% saturated with oxygen in the alveoli; Hb is 35% saturated in the tissues; 10-15% of oxygen is released in tissues |
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how do chelating agents work?
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chemical groups, such as -OH, -SH, and -NH donate electrons for bonding with heavy metals
complexes formed are excreted in urine or feces |
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what are the chelating agents?
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ferroxamine
dimercaprol penicillamine ethylenediamine tetraacetate (EDTA) |
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what does lead do when it is absorbed from the respiratory or GI tract?
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it is bound to erythrocytes and widely distributed initially into soft tissues such as bone marrow, liver, kidney, and testes (t1/2 in these tissues is 30 days)
most lead then eventually goes to the skeleton (t1/2 bound to bone is >20 years) |
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what organ system is most sensitive to lead poisoning?
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hematopoietic system
lead induces critical derangements in heme biosynthesis, leading to excretion of porphyrins and their precursors in urine |
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what hematopoietic enzyme is inhibited by lead?
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delta-aminolevulinate dehydratase
(enzyme responsible for converting delta-aminolevulinate to porphobilinogen) lead poisoning causes increased delta-aminolevulinate levels |
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what are the sources of lead for lead poisoning?
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old plumbing in old houses
peeling paint in old houses solders pottery |
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what are the symptoms of lead poisoning?
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wrist drop (fatigued extensor muscles)
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what is the treatment for lead poisoning?
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first, stop exposure
first line drug: EDTA long term drug: penicillamine |
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why is penicillamine a useful drug for long term treatment of lead poisoning?
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it is less nephrotoxic than the alternatives (e.g. EDTA)
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what is the treatment for arsenic poisoning?
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lavage and catharsis for recent intake
dimercaprol (BAL) used to chelate arsenic in chronic poisoning |
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what is BAL?
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british antilewisite
aka dimercaprol heavy metal chelating agent with two sulfhydryl groups to chelate metals |
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what are the toxic effects of arsenic?
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1) severe GI distress leading to "rice water" stools and vomiting
2) bone marrow depression (chronic poisoning) 3) uncouples Ox-Phos, so dec. ATP production in mitochondria |
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acute mercury poisoning
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inhalation of inorganic mercury
initially causes damage to kidney, then at higher doses to CNS chelation achieved with BAL (dimercaprol) |
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chronic mercury poisoning
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inorganic mercury presents as diffuse set of Sx involving gums and teeth, GI disturbances, and neurologic/behavior changes - treated with penicillamine or BAL
organic mercury presents as neurologic and psychiatric disease - caused by ingesting methylmercury from fish - chelation therapy works poorly |
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meprobamate
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carbamate used as an anxiolytic
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