Sedative-Hypnotic Drugs

Dr. Hiwa K. Saaed, BSc, HD, MSc. PhD

Department of Pharmacology & Toxicology College of Pharmacy/ University of Sulaimani

Sedative-Hypnotic Drugs

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Sedative-Hypnotic drugs
The sedative-hypnotics belong to a chemically heterogeneous class of drug. The most important are: Benzodiazepines (BZs), 1963 Barbiturates, (1963) New drugs: buspirone, zolpidem, and Zaleplon Miscellaneous: carbamates, alcohol

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Anxiety
Is tension or apprehension which is a normal response to certain situations in life. It is a universal human emotion, but when it becomes excessive and disproportionate to the situation, it becomes disabling and needs treatment.

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Sedatives (anxiolytics)
is a drug that produces calming or quietening effect and reduces excitement Drugs that have an inhibitory effect on the CNS to the degree that they reduce:
Nervousness Excitability Irritability without causing sleep
With as little effect on motor or mental functions as possible
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Hypnotics
Hypnotic is a drug that induces sleep resembling natural sleep. Both sedation and hypnosis may be considered as different grades of CNS depression.

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Dose-dependent depression of CNS

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 Tolerance: reduction in drug effect requiring an increase in dosage to maintain the same response. Physiological dependence: removal of the drug evokes unpleasant symptoms, usually the opposite of the drugs effects Psychological dependence: the drug taker feels compelled to use the drug & suffers anxiety when separated from drug.
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Mechanisms of action Most S-H drugs facilitate the actions of GABA, a major inhibitory transmitter in the CNS, GABAA receptor activation leads to increased Cl- ion influx; GABAB receptor activation causes increased efflux of K+. Both mechanisms result in membrane hyperpolarization.
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The pentapeptide structure of the GABAA receptor has binding sites for BZs and for other drugs, including Barbiturates and ethanol.

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BZs Mechanism of action

BZs potentiate GABA increase frequency of Cl- ion channel opening, causes hyperpolarization raise firing threshold and thus inhibits the formation of action potentials.

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Barbiturates Mechanism of action

Barbiturates interact with GABA receptors, the binding site is distinct from that of the BZs. Barbiturates potentiate GABA action on Clentry into the neuron by increase the duration of Cl- ion channel opening.

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Barbiturates Mechanism of action

In addition, barbiturates can block excitatory glutamate receptor. at high doses (anesthetics conc. Of pentobarbital), also open Cl- ion channels directly and block high frequency Na+ channels). Flumazenil does not block the effects of barbiturates.
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Benzodiazepines:
Are the most commonly used anxiolytic drugs. They have largely replaced barbiturates & meprobamet, because the BZs are safer and more effective
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Bzs Classification
Short acting (2-8 hrs) midazolam triazolam Intermediate (10-20 hrs) temazepam, lorazepam, alprazolam, oxazepam, nitrazepam, estrazolam Long acting (1-3 days): chlordiazepoxide, diazepam, flurazepam, clonazepam, chlorazepate
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Actions and therapeutic doses:

BZs have neither antipsychotic activity nor analgesic. They dont affect ANS

Therapeutic Uses
Sedation Sleep induction Skeletal muscle relaxation Anxiety relief: alprazolam is the DOC Treatment of alcohol withdrawal Agitation Depression Epilepsy: clonazepam Balanced anesthesia
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Actions and therapeutic doses:

Reduction of anxiety at low dose alprazolam is the DOC diazepam) are preferred in patients require Rx for prolonged period of time. Sedative and hypnotic actions at higher dose not all, three most commonly prescribed BZs are: long acting flurazepam, intermediate temazepam short acting triazolam. and Two non BZs: Zolpidem & Zaleplon.
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Actions and therapeutic doses:

Anterograde amnesia; short acting BZs used in premedication for endoscopic, bronchoscopic, angioplasty Anticonvulsant; clonazepam is useful in chronic Rx of epilepsy, Alcohol withdrawal symptoms: chlordiazepoxide, chlorazepate, diazepam & oxazepam are useful in the Rx of alcohol withdrawal.
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Actions and therapeutic doses:

Muscle relaxant at higher doses; diazepam is useful in the Rx of skeletal muscle spasm Other actions: in higher doses BZs decrease BP and increase HR. diazepam decreases nocturnal gastric acid secretion

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Tolerance
Chronic use leads to tolerance (cross with other S-H drugs), possibly via downregulation of BZ receptors. The antianxiety effects of the BZ are less subject to tolerance than sedative and hypnotic effects.

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Dependence & Withdrawal symptoms

Abrupt discontinuation, particularly if high doses used for prolong period. 1. Confusion, 2. anxiety, 3. agitation, 4. restlessness, 5. insomnia 6. tension WD symptoms with BZs are less intense than with ethanol or barbiturates;
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Adverse effects of BZs:

Drowsiness and confusion Ataxia at high doses-precludes activities like driving Cognitive impairment:
long term recall, acquisition of knowledge

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BZs antagonist
Flumazenil: I.V only, reverses the effect of the BZs (competitive antagonist), onset is rapid, and duration is short.

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Miscellaneous; non benzodiazepines Zolpidem and Zaleplon they:

act on BZ1 (a subtype of BZ receptor family), are more selective hypnotics are not effective in chronic anxiety, for seizure disorders, or for muscle relaxing. Possibly less tolerance occur with prolong use and lower abuse liability and dependence than BZs.
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Zolpidem and Zaleplon

they show no withdrawal effects, Minimal rebound insomnia Rapidly absorbed, rapid onset with short duration (2-3 hrs) Zaleplon is very similar to zolpidem in its hypnotic action, but it causes fewer residual effect on pseudomotor and cognitive function compared with zolpidem or the BZs due to short t1/2 < 1hr
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Buspirone: totally different anxiolytic from BZs, no effects on GABA systems, possible partial agonist at 5-HT1A receptors some affinity for D2 & 5-HT2A. Indication: Indicated for generalized anxiety disorders but takes 1 to 2 weeks to exert anxiolytic effects.
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 Buspirone lucks anticonvulsant and Muscle relaxant property of BZs and cause minimal sedation. No additive CNS depression with other drugs. Adverse effects: hypothermia, increase prolactin, headache, dizziness, nervousness
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Barbiturates: Formerly used as sedative hypnotic replaced by BZs, because barbiturates induce: 1. tolerance, 2. drug metabolizing enzyme, 3. physical dependence 4. and very severe withdrawal symptom.
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Classification
Long acting (1-2 days) Phenobarbital; anticonvulsant Short (3-8hrs) Pentobarbital, secobarbital and amobarbital Use: sedative & Hypnotic Ultrashort (20 min) Thiopental Use: I.V induction of anesthesia
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Adverse effects of Barbiturates:

Dose-dependent CNS depression, with nystagmus and ataxia progressing to respiratory depression, coma, and possible mortality. no specific antidote in overdose. Additive CNS depression with other drugs.

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Metabolites:
Hepatic metabolism (some to active metabolite). Induction of Cytochrome P450 is characteristic and may lead to drug interactions. Because of increase heme synthesis, they are contraindicated in porphyrias Porphyrias: a hereditary disorder of hemoglobin metabolism causing mental disturbance, extreme sensitivity to light and excretion of dark pigments in the urine.
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Non barbiturate sedative: Chloral hydrate: is a trichlorinated derivative of acetaldehyde that is converted to the active metabolite, trichloroethanol in the body.

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Miscellaneous antihistamines: hydroxyzine, diphenhydramine and doxylamine

antihistamine with antiemetic activity, it has low tendency for habituation and thus is useful for patients wit anxiety who have a history of drug abuse.

Propranolol has efficacy in performance anxiety and social phobias. TCA and SSRI Opiod analgesics Ethanol
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