Sedative-Hypnotic Drugs_Pharmacology.pptx

Pharmacology

1. Sedatives-hypnotics

2. Drug Classification Benzodiazepines Alprazolam , Midazolam, Estazolam , Triazolam Clonazepam, Diazepam , Flurazepam , Lorazepam , Oxazepam , Temazepam Chlordiazepoxide , Clorazepate Benzodiazepine antagonist Flumazenil Other anxiolytic drugs Antidepressants Buspirone Barbiturates Amobarbital , Pentobarbital, Phenobarbital , Secobarbital , Thiopental Other Hypnotic Agents Antihistamines Eszopiclone , Ramelteon , Zaleplon , Zolpidem

3. Anxiety Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an unknown source). The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. Episodes of mild anxiety are common life experiences and do not warrant treatment. However, severe, chronic, debilitating anxiety may be treated with antianxiety drugs (anxiolytics ) and/or some form of psychotherapy. Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic agents .

4. Sedatives Vs Hypnotics Sedatives: Sedatives are aimed at calming anxiety and reducing nervous system over-activity without inducing sleep. Hypnotics : H ypnotics are designed to induce and sustain sleep, addressing conditions like insomnia.

5. Benzodiazepines (BZPs); Alprazolam , Diazepam , Chlordiazepoxide BZPs are widely used anxiolytic drugs. MoA The targets for BZPs actions are the γ- aminobutyric acid (GABAA) receptors. Binding of GABA to its receptor triggers an opening of the central ion channel, allowing chloride through t he pore. The influx of chloride ions decreases neurotransmission by inhibiting the formation of action potentials. BZPs modulate GABA effects by binding to a specific, high-affinity site; benzodiazepine (BZ) receptors. BZPs increase the frequency of channel openings produced by GABA. #Binding of a BZPs to its receptor site increases the affinity of GABA for the GABA-binding site (and vice versa ). #GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).]

6. P/K PO- better absorption, lipophilic, distribute throughout the body, crosses BBB Metabolized by liver and excreted renally . Cross the placenta and may depress the CNS of the newborn /Nursing infants may also be exposed to the drugs in breast milk. Pharmacological Actions Reduction of anxiety : At low doses, the benzodiazepines are anxiolytic. Sedative/hypnotic : These have sedative and calming properties, and some can produce hypnosis at higher doses. Anterograde amnesia : Temporary impairment of memory may occur with use of the benzodiazepines. The ability to learn and form new memories is also impaired. Anticonvulsant : Several benzodiazepines have anticonvulsant activity. This effect is partially, although not completely, mediated by α1-GABAA receptors. Muscle relaxant : At high doses, the benzodiazepines relax the spasticity of skeletal muscle. Baclofen is a muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord .

7. C/U Anxiety disorders : Treatment of the anxiety symptoms secondary to panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, performance anxiety, posttraumatic stress disorder, obsessive–compulsive disorder (OCD), and extreme anxiety associated with phobias, such as fear of flying. Eg ; Clonazepam , lorazepam , diazepam , alprazolam, etc. Sleep disorders : as hypnotic agents Amnesia : as premedication for anxiety-provoking and unpleasant procedures, such as endoscopy, dental procedures, and angioplasty. They cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures. Eg ; Midazolam - to facilitate amnesia while causing sedation prior to anesthesia. Seizures : Clonazepam, lorazepam , and diazepam, etc. Muscular disorders : Diazepam; useful in the treatment of skeletal muscle spasms

8. A/ Es Drowsiness and confusion; most common Ataxia Cognitive impairment (decreased long-term recall and retention of new knowledge) Precautions and C/Is Should be used cautiously in patients with liver disease . Should be avoided in patients with acute angle closure glaucoma. Alcohol and other CNS depressants enhance the sedative–hypnotic effects of the BZPs . Dependence; Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given for a prolonged period. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. Benzodiazepines are, however, considerably less dangerous than the older anxiolytic and hypnotic drugs. As a result, a drug overdose is seldom lethal unless other central depressants, such as alcohol, are taken concurrently.

9. Dose Diazepam PO; 2 to 10 mg orally 2 to 4 times a day Alprazolam PO; 0.25-0.5mg, TID. Max; 4 mg per day. Chlordiazepoxide PO; 5-10 mg TID-QID. Max; 25 mg TID-QID

10. Barbiturates Formerly the mainstay of treatment to sedate patients or to induce and maintain sleep, but they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance and physical dependence and are associated with very severe withdrawal symptoms. PO- well absorbed, distribute throughout the body including CNS. Readily cross the placenta and can depress the fetus. These agents are metabolized in the liver and inactive metabolites are excreted renally . MoA The sedative–hypnotic action of the barbiturates is due to their interaction with GABAA receptors, which enhances GABAergic transmission. Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings. In addition, barbiturates can block excitatory glutamate receptors. All of these molecular actions lead to decreased neuronal activity . The binding site of barbiturates on the GABA receptor is distinct from that of the benzodiazepines.

11. Pharmacological Actions Depression of CNS: At low doses, the barbiturates produce sedation. At higher doses, the drugs cause hypnosis, followed by anesthesia, and, finally, coma and death. Respiratory depression: Barbiturates overdose may cause respiratory depression followed by even death. C/U Anesthesia : Anticonvulsant : Phenobarbital has specific anticonvulsant activity. Sedative/hypnotic : Barbiturates have been used as sedatives to relieve anxiety, nervous tension, and insomnia.

12. A/ Es Drowsiness , impaired concentration, and mental and physical sluggishness. Hypnotic doses of barbiturates produce a drug “hangover” that may lead to impaired ability to function normally for many hours after waking. Nausea and dizziness Precaution and C/Is Hypersensitivity reactions Contraindicated in patients with acute intermittent porphyria. Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness , restlessness, N & V, seizures, delirium, and cardiac arrest. Severe depression of respiration is coupled with central CV depression and results in a shock-like condition with shallow, infrequent breathing. Dose Phenobarbitone ; 30-120 mg orally, IM, or IV in 2 or 3 divided doses Maximum dose: 400 mg during a 24h period

13. Zolpidem PO; rapidly absorbed. It provides a hypnotic effect for approximately 5h. It shows few withdrawal effects, exhibits minimal rebound insomnia, and little tolerance occurs with prolonged use. MoA Zolpidem selectively binds to the benzodiazepine receptor subtype BZ1 . Rest is similar to BZPs. Zolpidem has no anticonvulsant or muscle-relaxing properties. C/U Insomnia Muscle relaxant ; can act as a minor muscle relaxant Restoration of brain function ; Research have shown - it is rapid and effective in restoring brain function in patients who are in a vegetative state after brain injury.

14. A/ Es Nightmares, agitation, anterograde amnesia, headache, GI upset, dizziness, and daytime drowsiness. Precautions and C/Is Hypersensitivity reactions Worsening of depression and/or suicidal ideation may occur with zolpidem therapy. Consider this risk of respiratory depression before using zolpidem in patients with compromised respiratory function. Withdrawal symptoms may occur if the zolpidem dose is tapered off rapidly or discontinued. Dose 5-10 mg, PO, OD, immediately prior to bedtime

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