1/24/2021

Lecture 14 Clinical Toxicology

Central Nervous System Depressants

Dr. Ammar Almulathanon

College of Pharmacy, University of Mosul

Central nervous system depressants

1) Sedative–hypnotic drugs
A. Barbiturates
B. Benzodiazepines
C. Other Sedative–Hypnotic Agents: Chloral hydrate, Meprobamate

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Barbiturates
Barbiturates have been used as
1) Hypnotic and sedative agents
2) Induction of anesthesia
3) Treatment of epilepsy and status epilepticus

They have been largely replaced by newer drugs and calls to poison control centers
have decreased significantly.

Today, barbiturate poisonings are common in intentional (suicidal) poisonings, but

less frequently encountered in accidental poisoning.

Classification

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Mechanism of toxicity
All barbiturates cause generalized depression of neuronal activity in the brain. This
action is believed to be due to a direct gamma-aminobutyric acid (GABA)-like
effect, or to stimulation of GABA release which mediate chloride entry and results
in synaptic inhibition. Barbiturates prolong the duration of the chloride channel
openings produced by GABA.

Clinical presentation

• Wide range of CNS effects varying from sedation to hypnosis, to anesthesia, and
eventually to complete paralysis of central voluntary and involuntary functions.

• Respiratory depression is the major toxic event that follows barbiturate ingestion
and usually causes early death.

• Hypothermia results from direct depressant action on the thermoregulatory

center.

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• At the highest doses, blockade of sympathetic ganglia triggers hypotension,

bradycardia, and decreased inotropy, with consequent decreased cardiac
output.

• Decreased gastrointestinal motility, which may lead to increased drug

absorption.

• Respiratory acidosis results from accumulation of carbon dioxide, shifting pH

balance to the formation of carbonic acid.

Toxic dose
 The toxic dose of barbiturates varies widely and depends on
• The drug
• The route and rate of administration
• Individual patient tolerance

 In general, toxicity is likely when the dose exceeds 5–10 times the normal
hypnotic dose.

 Short-acting barbiturates are highly lipid soluble and potentially more toxic than
long acting barbiturates, which are less lipid soluble. They reach higher CNS
concentrations and cause greater depression than long-acting barbiturates
(phenobarbital).

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The potentially fatal oral dose of the shorter-acting agents such as pentobarbital is
2–3 g, compared with 6–10 g for phenobarbital.

 Several deaths were reported after rapid IV injections of as little as 1–3 mg of

methohexital per kilogram.

Treatment
 Decontamination
Activated charcoal orally, gastric lavage

 Enhanced elimination
• Alkalinization of the urine with sodium bicarbonate to a pH of 7.5 to 8.0
increases clearance of long-acting barbiturates, while short- and intermediate-
acting compounds are not affected by changes in urine pH.
Barbiturates are weak acids with pKas ranging from 7.2 to 8.5. Increasing the urine
pH increases the fraction of ionized drug in the urine and thus decreases the amount
of unionized drug available for passive tubular reabsorption.

Urine alkalinization is contraindicated in patients with renal insufficiency and

cerebral or pulmonary edema.

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• Hemodialysis or hemoperfusion may be necessary for severely intoxicated

patients (ie, with intractable hypotension).

Hemodialysis is recommended in patients with renal or cardiac failure, electrolyte

abnormalities, or acid-base disturbances.

Hemodialysis is more effective in removing long-acting barbiturates than short-

acting compounds because there is less protein and lipid binding of the former.

• Repeat-dose activated charcoal has been shown to decrease the half-life of

phenobarbital and its metabolites.

Benzodiazepines (BZDs)
• Their increased therapeutic index, relative to barbiturates, and lack of anaesthetic
properties have promoted the substitution of benzodiazepines for barbiturates.

• In general, death from BZDs overdose is rare unless the drugs are combined with
other CNS depressant agents, such as ethanol, opioids, and barbiturates.

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Mechanism of toxicity
• BZDs enhance the action of the inhibitory
neurotransmitter gamma-aminobutyric acid
(GABA) by binding to a specific site on the GABAA
receptor . BZDs increase the frequency of the
chloride channel openings produced by GABA.

• At extremely high doses, neuromuscular blockade may occur. Also, after

intravenous injection, peripheral vasodilation causes a fall in blood pressure.

• Respiration is not markedly affected, even with hypnotic doses of most

benzodiazepines.

• Respiratory arrest is more likely with newer short-acting benzodiazepines such as

triazolam, alprazolam, and midazolam.

• Cardiopulmonary arrest has occurred after rapid injection of diazepam,

possibly because of CNS-depressant effects or because of the toxic effects of the
diluent propylene glycol.

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Clinical presentation

• Mild toxicity is characterized by ataxia and drowsiness.

• In moderate toxicity, the patient is aroused by verbal stimulation.

• Patients in severe toxicity are unresponsive except to deep pain stimulation (coma
stage 1). In general, respiratory depression and hypotension are rare.

Treatment
• Flumazenil
It is a specific benzodiazepine receptor antagonist that completely reverses sedative,
anxiolytic, anticonvulsant, ataxic, anesthetic, comatose, and muscle relaxant effects
of benzodiazepines. (Antidote)

Flumazenil may also reverse CNS depression from certain nonbenzodiazepine

sedatives and hypnotics (eg, zolpidem, zaleplon, and eszopiclone).

It has no effect on other GABAergic drugs (eg, barbiturates, opioids, or alcohol)

intoxication.

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Flumazenil has some important potential drawbacks:

1. It may induce seizures in patients who have co-ingested medications with
proconvulsant activity such as tricyclic antidepressants and theophylline. Because
BZDs have a therapeutic role as anticonvulsants, flumazenil should not be given
to such patients.

2. It may induce acute withdrawal, including hyperexcitability, tachycardia, and

seizures in patients who are addicted to benzodiazepines.

3. Resedation is common when the drug wears off after 1–2 hours, and repeated
dosing or a continuous infusion is often required.

• Decontamination
Activated charcoal , gastric lavage

• Enhanced elimination
There is no role for diuresis, dialysis, or hemoperfusion because of their high
protein binding.

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Other Sedative–Hypnotic Agents

1) Chloral hydrate
Chloral hydrate is rarely used as a hypnotic today.

Clinical presentation:
• It is metabolized to trichloroethanol, which also has CNS depressant activity. In
addition, trichloroethanol may sensitize the myocardium to the effects of
catecholamines, resulting in cardiac arrhythmias.

• Chloral hydrate is also a gastrointestinal irritant and commonly causes nausea

and vomiting.

• It can also cause hepatic injury and renal failure.

2) Meprobamate

Clinical presentation
• Hypotension owing to depressed myocardial function.

• Coma has been associated with blood concentrations between

10 and 20 mg/dL.

• It has a tendency to clump in the stomach, forming a pharmacobezoar.

• Death results from irreversible shock, respiratory depression, and pulmonary

edema.

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Treatment
• Tachyarrhythmias from chloral hydrate caused by myocardial sensitization may be
treated with propranolol or esmolol.

• Decontamination by activated charcoal or Gastric lavage

• Enhanced elimination
Meprobamate has a relatively small volume of distribution, and hemodialysis may
be useful for deep coma complicated by intractable hypotension.

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