1. Clinical toxicology of sedative-hypnotics
Domina Petric, MD

2. Direct toxic actions
Many of the common adverse effects of sedative-hypnotics result from dose-related depression of the CNS.
Relatively low doses may lead to drowsiness, impaired judgment and diminished motor skills.
This can lead to a significant impact on driving ability, job performance and personal relationships.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

3. Direct toxic actions
Sleep driving and other somnambulistic behavior with no memory of the event have occurred with the sedative-hypnotic drugs.
Benzodiazepines may cause a significant dose-related anterograde amnesia.
They can significantly impair ability to learn new information, particularly that involving effortful cognitive processes.
Retrieval of previously learned information is intact with benzodiazepines.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Direct toxic actions
The criminal use of benzodiazepines in cases of ˝date rape˝ is based on their dose-dependent amnestic effects.
Hangover effects are not uncommon following use of hypnotic drugs with long elimination half-lives.
Elderly patients are more sensitive to the effects of sedative-hypnotics.
Doses approximately half of those used in younger adults are safer for elderly patients and usually as effective.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

5. Direct toxic actions
The most common reversible cause of confusional states in the elderly is overuse of sedative-hypnotics.
At higher doses, toxicity may present as lethargy or a state of exhaustion.
An increased sensitivity to sedative-hypnotics is more common in patients with cardiovascular disease, respiratory disease and hepatic impairment.
Sedative-hypnotics can exacerbate breathing problems in patients with chronic pulmonary disease and in those with symptomatic sleep apnea.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

6. Direct toxic actions
Sedative-hypnotics are the drugs most frequently involved in deliberate overdoses.
The benzodiazepines are considered to be safer drugs than barbiturates.
Alprazolam is more toxic in overdose than other benzodiazepines.
Most serious cases of drug overdosage, intentional or accidental, involve polypharmacy.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

7. Direct toxic actions
With high doses and severe toxicity, the respiratory depression from central actions of the drug may be complicated by aspiration of gastric contents in the unattended patient.
This is more likely if ethanol is also present in the blood of the patient.
Cardiovascular depression further complicates successful resuscitation.
Airway, mechanical ventilation, maintenance of plasma volume, renal output and cardiac function!
Use of dopamine or other inotropic drug is sometimes indicated to preserve renal blood flow.
Hemodialysis or hemoperfusion may be used to hasten elimination of some of these drugs.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

8. Direct toxic actions
Flumazenil reverses the sedative actions of benzodiazepines and those of eszopiclone, zaleplon and zolpidem.
Duration of action is short and its antagonism of respiratory depression is unpredictable.
There is a risk of precipitation of withdrawal symptoms in long-term users of benzodiazepines.
The use of flumazenil in benzodiazepine overdose must be accompanied by adequate monitoring and support of respiratory function.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

9. Direct toxic actions
The extensive clinical use of triazolam may lead to serious CNS effects: behavioral disinhibition, delirium, aggression and violence.
Behavioral disinhibition may occur with any sedative-hypnotic drug.
Disinhibitory reactions during benzodiazepine treatment are more clearly associated with the use of very high doses and the pretreatment level of patient´s hostility.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

10. Direct toxic actions
Hypersensitivity reactions, including skin rashes, occur only occasionally with sedative-hypnotics.
FDA pregnancy category:
for individual benzodiazepines is either D or X
most barbiturates are D
eszopiclone, ramelteon, zaleplon and zolpidem are C
buspirone is B
Barbiturates enhance porphyrin synthesis and are absolutely contraindicated in patients with a history of acute intermittent porphyria, variegate porphyria, hereditary coproporphyria and symptomatic porphyria.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

11. Alterations in drug response
Depending on the dosage and the duration of use, tolerance occurs in varying degrees to many of the pharmacologic effects of sedative-hypnotics.
The lethal dose range is not altered significantly by the long-term use of sedative-hypnotics.
Cross-tolerance between the different sedative hypnotics, including ethanol, can lead to an unsatisfactory therapeutic response.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

12. Alterations in drug response
With the long-term use of sedative-hypnotics, especially if doses are increased, a state of dependence can occur.
Withdrawal from a sedative-hypnotic can have severe and life-threatening manifestations.
Withdrawal symptoms range from restlessness, anxiety, weakness and orthostatic hypotension to hyperactive reflexes and generalized seizures.
Symptoms of withdrawal are usually more severe following discontinuance of sedative-hypnotics with shorter half-lives.
Eszopiclone, zolpidem and zaleplon are exceptions.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

13. Alterations in drug response
Symptoms of withdrawal syndrome are less pronounced with longer-acting drugs.
Cross-dependence is the ability of one drug to suppress abstinence symptoms from discontinuance of another drug.
It is quite marked among sedative-hypnotics.
Longer-acting drugs such as chlordiazepoxide, diazepam and phenobarbital can be used to alleviate withdrawal symptoms of shorter-acting drugs, including ethanol.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Drug interactions
The most common drug interactions are interactions with other CNS depressant drugs.
That leads to additive effects, which can be useful in anesthesia practice.
Such interactions, if not anticipated, can lead to serious consequences: enhanced depression with concomitant use of many other drugs.
Additive effects can be predicted with concomitant use of alcoholic beverages, opioid analgesics, anticonvulsants and phenothiazines.
Less obvious, but very important, is enhanced CNS depression with a variety of antihistamines, antihypertensive agents and antidepressant drugs of the tricyclic class.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

15. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.
Katzung, Masters, Trevor. Basic and clinical pharmacology.