NONBENZODIAZEPINE -

SEDATIVES
TOXICITY

DR MUHAMMAD HAMZA DOSSA

INTRODUCTION

 The term sedative-hypnotic refers to any drug designed to produce

sedation and sleepiness.
 These drugs can be divided into the benzodiazepines and non-
benzodiazepines.
 One is most likely to encounter toxicity from these sedative drugs as part
of accidental or nonaccidental overdose, as well as after an assault or
trauma.
 Many nonbenzodiazepines were developed and are marketed for the
treatment of Insomnia.
Common non-benzodiazepines agents in use are :

 Buspirone
 Meprobamate
 Chloral hydrate
 Melatonin
 Zolpidem, zaleplon, and zopiclone
BUSPIRONE

 Available by brand names as BUSPAR , NANZO, BUSRON

 Anxiety Disorders: 10-15 mg/day PO divided q8-12hr; may increase every

2-3 days by 5 mg/day to 15-30 mg/day PO divided q8-12hr;

 Not to exceed 60 mg/day

 Deliberate overdoses with 250 mg and up to 300 mg buspirone have

resulted in drowsiness in about 50% of individuals.
 dosage of 375 mg/day, and produced side effects including nausea,
vomiting, dizziness, drowsiness, miosis, and gastric distress.
 In early clinical trials, buspirone was given at dosages even as high as
2,400 mg/day, with akathisia, tremor, and muscle rigidity observed.
 One death has been reported in association with 450 mg buspirone
together with alprazolam, diltiazem, alcohol, cocaine
BUSPIRONE

 Buspirone is approved for treatment of anxiety disorders.

 Other off-label uses include treatment of depression and nicotine
dependence.
 Buspirone is a partial agonist at the serotonin-1A receptor and an
antagonist of the dopamine-2 receptor.
 The resultant effect are primarily suppression of CNS serotoninergic
activity and enhancement of dopaminergic and, possibly, noradrenergic
activity.
 Following ingestion, absorption is rapid and nearly complete, with
significant first-pass metabolism in the liver.
 Primary elimination is renal, with additional substantial fecal elimination.
BUSPIRONE

 Common adverse effects with buspirone use include sedation, GI

discomfort, vomiting, and dizziness.
 In therapeutic dosing, buspirone does not appear to cause psychomotor
depression and has no potential for abuse or withdrawal.
 The effects observed with a buspirone overdose would likely be an
exaggeration of adverse effects.
 In general, the drug is well tolerated in overdose, and the treatment is
largely supportive.
 Animal toxicity studies indicate the potential for buspirone to provoke
seizures, and one human case report noted the occurrence of a
generalized tonic-clonic convulsion approximately 36 hours after a
buspirone overdose.
 Because of its serotoninergic properties, buspirone has been
associated with serotonin syndrome.
MEPROBAMATE

 Available brand names include : MEPROGESIC, PANOGESIC,

POLYZYMA-T.

 Anxiety : 1200-1600 mg/day PO divided q6-8hr;

 The recommended dose of meprobamate is 400 milligrams PO three or
four times daily, with a maximum total daily dose of 2400 milligrams.

 Not to exceed 2.4 g/day

 In an overdose, meprobamate tablets may form a gastric bezoar,
requiring physical removal of the undissolved mass of tablets through an
endoscope; therefore, administration of activated charcoal should be
considered even after 4 or more hours or if levels are rising.
MEPROBAMATE

 Meprobamate is marketed as an anxiolytic drug.

 Following ingestion, meprobamate is rapidly absorbed, with a duration
of action of 6 to 10 hours.
 Following metabolism in the liver, the metabolites and 10% to 20% of the
unchanged drug are eliminated by the kidneys.
 With meprobamate overdose, sedation, coma, and cardiopulmonary
depression are seen.
 Ingestion of a large number of meprobamate tablets has been reported
to form a gastric bezoar, and prolonged coma has been attributed to
such retained drug within the stomach.
 If this occurs, endoscopic removal of the mass or multidose activated
charcoal would appear useful.
MEPROBAMATE

 Meprobamate have significant potential for abuse and dependence.

 A withdrawal syndrome has been described in which patients can
develop tremor, anxiety, insomnia, and anorexia, usually within 12 to 48
hours of abstinence.
 Visual and auditory hallucinations and seizures have been described
during withdrawal, although these later effects are observed less
consistently.
CHLORAL HYDRATE

 Available with brand names as : APNOTEK, CEDATE & CHLORAL

HYDRATE .
 ALL AVAILABLE IN ONLY SYRUP FORM.

 The hypnotic dose in adults is 500 to 1000 milligrams PO.

 For children the hypnotic dose is 50 milligrams/kg PO and the sedation

dose is 80 to 100 milligrams/kg PO.

 NOT TO EXCEED 2 G/24HR

CHLORAL HYDRATE

 Chloral hydrate was first marketed as a sedative in 1869, making it the

oldest sedative hypnotic agent still available.
 It remained quite popular until the early 1900s, when barbiturates largely
supplanted its use.
 Chloral hydrate is primarily used for procedural sedation in young
children because of its relatively wide therapeutic index, the lack of
significant respiratory depression, and the ability for oral administration,
although it is not without risk.
 Following ingestion, chloral hydrate is quickly absorbed and rapidly
reduced to trichloroethanol, an active metabolite, via alcohol
dehydrogenase.
 Renal excretion of chloral hydrate is minimal.
CHLORAL HYDRATE: “knock-out drops” or “Mickey
Finn”

 Co-ingested chloral hydrate and ethanol have a synergistic effect.

 The metabolism of ethanol results in increased amounts of the reduced
form of nicotinamide adenine dinucleotide, which, in turn, promotes the
conversion of chloral hydrate to trichloroethanol.
 In addition, because of competition by chloral hydrate for alcohol
dehydrogenase, there is decreased metabolism of ethanol.
 These interactions result in more elevated levels of both trichloroethanol
and ethanol than would be seen if either was ingested alone.

 The resultant profound sedation yields the terms “knock-out drops” or

“Mickey Finn” for this combination.
 At therapeutic doses, chloral hydrate results in mental status depression,
but airway and respiratory reflexes are not impaired.
 Paradoxical hyperactivity occurs in 1% to 2% and vomiting is seen in 3%
to 10% of children given doses of 50 to 100 milligrams/kg PO.
 With an overdose, chloral hydrate can produce coma.
 An important feature of chloral hydrate overdose is cardiovascular
instability, manifested by decreased cardiac contractility, myocardial
electrical instability, and increased sensitivity to catecholamines.
 Commonly encountered cardiac dysrhythmias include premature
ventricular contractions, ventricular fibrillation, torsade de pointes, and
asystole.
 GI irritation, including nausea, vomiting, and hemorrhagic gastritis, has
been observed.
 A diagnostic clue is the common presence of a pear-like odor.
CHLORAL HYDRATE

 Treatment of chloral hydrate overdose and toxicity is largely supportive.

 With coma, endotracheal intubation may be necessary.
 IV β-adrenergic blockers should be used to treat ventricular
dysrhythmias seen with chloral hydrate overdose.
 Torsade de pointes should be managed with IV magnesium sulfate or
ventricular overdrive pacing.
 Chronic consumption of chloral hydrate can result in dependency and
addiction.
 A withdrawal state, similar to ethanol, has been described
MELATONIN

AVAILABLE BRANDS : Melatonin Time Release, Sleep3, Bio-Melatonin,

Health Aid Melatonin

 Insomnia : 3-5 mg PO QHS

Difficulty falling asleep : 5 mg PO 3-4 hour before sleep period x 4 weeks
MELATONIN

 Melatonin is an endogenous hormone that is normally secreted by the

pineal gland.
 It is involved with the circadian sleep–wake cycle.
 Melatonin is available without prescription at doses ranging from a
physiologic dose of 0.3 milligram up to a pharmacologic dose of 10
milligrams.
 Two primary melatonin receptor subtypes are found in the human CNS.
The MT1 receptor is located primarily in the hypothalamic
suprachiasmatic nucleus and is involved in the effect melatonin has on
circadian rhythm.
 The MT2 receptor is found primarily in the retina, presumably involved in
the interaction between incoming light, melatonin, and the circadian
cycle. The MT2 receptor is also found in the hypophysial pars tuberalis
and is possibly responsible for the effects of melatonin on reproduction.
MELATONIN

 Following ingestion, peak plasma melatonin concentrations occur within

40 to 50 minutes.
 Melatonin has a short plasma half-life and a short duration of action in
therapeutic doses.
 Melatonin is metabolized by initial conversion to O-desmethylmelatonin
and 6-hydroxymelatonin. Both are subsequently conjugated as either a
glucuronide or a sulfate and then excreted by the kidneys.
 At therapeutic dosing, side effects from melatonin include fatigue,
headache, dizziness, and irritability.
 Data on melatonin overdoses are limited, but overdose would be
expected to result in an exaggeration of therapeutic effects, primarily
sedation and disorientation without any significant life-threatening
effects.
ZOLPIDEM, ZALEPLON, AND ZOPICLONE

ZOLPIDEM ZALEPLON ESZOPICLONE

STILNOX, ZORELAX

Insomnia (Sleep Onset & Insomnia Insomnia

Maintenance) :   Starting dose: 1 mg PO HS
10 mg PO qHS initially; for nonelderly adults (both
5 mg PO/SL/oral spray Qhs men and women)
20 mg may be needed for Dose may be increased to
may use 10 mg PO/SL/oral occasional patient that 2-3 mg HS if clinically
spray qHS if needed does not indicated
Higher doses are known to
Range: 5-20 mg/day cause next morning
drowsiness/impairment
ZOLPIDEM, ZALEPLON, AND ZOPICLONE

 These are three non-benzodiazepine sedative-hypnotics used to treat

insomnia.
 All three promote sleep by enhancing CNS γ-aminobutyric acid activity
but differ in their pharmacodynamic and pharmacokinetic profiles.
 All three drugs bind to the benzodiazepine binding site on the
postsynaptic γ-aminobutyric acid subtype A1 receptor, although they
have different binding affinities to the α-1 and α-2 subunits.
 Zaleplon has a very short half-life (about 1 hour), as opposed to the
somewhat longer half-lives of zolpidem and zopiclone.
 All three drugs were initially promoted as an improvement upon
benzodiazepines for the treatment of insomnia. They were to be safer,
produce less psychomotor impairment with therapeutic doses, and be
not addictive and not associated with a withdrawal state.
 With experience, all three drugs have been found to impair psychomotor
function, create tolerance and dependence, and be associated with
withdrawal states characterized by insomnia, anxiety, agitation, and
delirium.
 Zaleplon, presumably because of its shorter elimination half-life, appears
to produce less tolerance and withdrawal symptoms than zolpidem or
zopiclone.
ZOLPIDEM ZALEPLON

 hepatic metabolism  Absorption occurs rapidly but can be

 Dosage restrictions are recommended delayed if zaleplon is co-ingested with a
for those with hepatic impairment and high-fat meal.
those with chronic renal insufficiency.  Extensive first-pass hepatic metabolism.
 Common adverse effects include  Elimination is primarily renal, with some
somnolence and nausea. fecal elimination as well.
 Because of occasional psychomotor  In therapeutic doses, zaleplon is not
impairment, individuals should not drive associated with any dependence or
or engage in hazardous activity the day withdrawal state when taken for up to 5
following use of zolpidem. weeks.
 Numerous reports of sleep walking or  A doses up to 10 milligrams, no
vivid dreams after its consumption. psychomotor or memory impairment is
Following overdose, sedation (including observed, but a dose of 20 milligrams is
coma) and vomiting can occur. associated with some impairment.
 Fatalities usually occur with co-  Reports of overdose with zaleplon are
ingestants, rather than with zolpidem by limited, but one could expect sedation,
itself incoordination, and, possibly, headache
to occur
ZOPICLONE
 Zopiclone is rapidly absorbed and hepatically metabolized into
active (N-oxide metabolite) and inactive (N-dimethyl metabolite)
compounds.
 Nearly half of the parent drug is excreted in the lungs following
decarboxylation.
 Reports of zopiclone or eszopiclone overdose indicate sedation
to be the primary observed effect.
 Prolonged coma was reported in an elderly patient who
ingested a large amount of eszopiclone.
 Rare cases of methemoglobinemia and mild hemolytic anemia
have been reported after large zopiclone overdoses.