Sedative Hypnotics and anxiolytics Dr. Yieldez Bassiouni

Terminology Anxiolytics: Minor Tranquilizers treat excitment and anxiety Sedative-Hypnotics: Sedation and sleep

Sedative hypnotics are drugs used for the treatment of anxiety and sleep disorders. A sedative Sometimes called anxiolytic, or minor tranquilizer, reduces anxiety and exerts a calming effect A hypnotic drug produces drowsiness and encourage the onset and maintenance of sleep

Anxiety disorders Generalized anxiety disorder (GAD)= excessive anxiety lacking any clear reason Panic disorder (sudden attacks of severe fear accompanied by sweating, tachycardia, chest pains,….) Phobias (strong fears of snakes, open spaces, flying) Post-traumatic stress disorder (anxiety triggered by recall of past stressful experiences) Obsessive compulsive disorder (OCD) e.g. fear of contamination

Examples of Sedative-Hypnotic drugs: 1- Benzodiazepines 2- Buspirone 3- Zolpidem 4- Barbiturates 5- Ethyl alcohol NB: BZs and barbiturates share very similar properties but BZs have a much safer pharmacological profile All have the same Mechanism of action (acting on GABA) except Buspirone

Graded dose-dependent depression of the CNS function is a characteristic of sedative-hypnotics Individual drugs differ in the relationship between the dose and the degree of CNS depression

BENZODIAZEPINES

Benzodiazepines (BZs) are the most widely used sedative-hypnotic drugs They have replaced barbiturates for most uses, particularly for treatment of anxiety and sleep disorders

How Do BZs Work?

A model of the GABAA receptor-chloride ion channel The receptor consists of five or more membrane-spanning subunits. GABA interact with alpha or beta subunits triggering chloride channel opening with resultant membrane hyperpolarization. Binding of BZs to gamma subunits potentiates effects of GABA, (facilitates the process of channel opening).

BZs increases the frequency of channel opening by a given concentration of GABA, but no change in the mean open time

1-BZs bind to specific BZ receptors 3- Opens chloride (Cl) channels, causing an influx of Cl ions 4- hyperpolarization of the neuron and inhibition of neuronal firing 1-BZs bind to specific BZ receptors 2-GABA binds with the GABA A-receptor

Pharmacokinetics BZS are well absorbed orally, giving a peak plasma concentration in about 1 hour They bind strongly to plasma proteins, and their high lipid solubility causes many to accumulate in body fat given by mouth or i.v. (e.g. diazepam in status epilepticus, midazolam in anesthesia) BZs are all metabolized and excreted in the urine

Classificaion of BZs According to duration of action: Very = ultra -short (< 6 h): Triazolam Short (12-18 h): Lorazepam (Ativan) Medium (24 h): Alprazolam (Xanax), Long (24-48 h): Diazepam (Valium) The longer acting agents form active metabolites with long half-lives

Pharmacological Actions

The main effects of BZs are: 1- Reduction of anxiety and aggression 2- Sedation & induction of sleep 3- Reduction of skeletal muscle tone and coordination 4- Anticonvulsant (antiepileptic) effect 5- Anterograde amnesia ., they obliterate memory of events experienced while under their influence

Therapeutic uses

1) as anxiolytic Short-term treatment of acute anxiety states Alprazolam for panic disorders. With the possible exception of alprazolam , benzodiazepines do not have antidepressant effects

2) for insomnia BZs decrease rapid eye movement (REM) sleep, which is associated with dreaming For short-term courses, as tolerance , dependence, hangover may occur Temazepam, nitrazepam

3) Reduction of muscle tone and coordination Increased muscle tone is a common feature of anxiety states in humans and may contribute to the aches, pains and headache The relaxant effect of BZs may therefore be clinically useful

4) As anticonvulsants Through effects on GABAA receptors Clonazepam has selective anticonvulsant action ( epilepsy) Diazepam i.v. in status epilepticus to control life-threatening seizures

5) Muscular disorders Strong muscle-relaxing properties In cases of : - muscle spasm - spastic disorders (MS, cerebral palsy)

6) Treatment of alcohol withdrawal symptoms By ameliorating the alcohol withdrawal syndrome The commonly used drug is Diazepam

7) as a pre-ansthetic medication for : i) Anxiolytic effects ii) Amnesia (impair short-term memory) 8) To control extreme mania (diazepam)

BZ antagonist “Flumazenil” Mechanism of action Flumazenil acts as a competitive antagonist to the binding of BZs to their receptors Flumazenil is a short-acting drug while, most BZs have longer half-lives, therefore, repeated i.v. administration of flumazenil is required to avoid relapse into the sedative state

Therapeutic uses 1- To reverse the sedative effect of BZs used during anesthesia 2- For diagnosis of self-poisoning and also for treatment of acute BZs overdose 3- Hepatic encephalopathy as flumazenil may improve the mental status of these patients 4- Flumazenil can antagonize the hypnotic effect of zolpidem

Advantages

Why BZ have replaced barbiturates ?? 1- Less tolerance & physical dependence 2- They cause less disturbance in sleep patterns 3- Barbiturates causes drug interaction because they are enzyme inducers e.g. They increase metabolism of warfarin due to induction of cytochrome P450 thus making it less effective  

4- BZ are Safe in overdose while Barbiturates have lower therapeutic index (easily overdosed) They don’t produce marked and fatal CNS depression Symptoms of overdose of BZ are less than of barbiturates and can be treated with Flumazenil 5- BZs produce minimal sedation and motor impairment 6- A Benzodiazepine antagonist is available (Flumazenil)

Advanges as Hypnotics REM sleep ( rapid eye movement) is less affected if compared with the same effect of other hypnotics ( barbiturates) Artificial interruption of REM sleep causes irritability and anxiety even if the total amount of sleep is not reduced

Side Effects of BZ

Drowsiness and confusion, amnesia BZ may paradoxically produce an increase in irritability and aggression in some individuals (particularly if short- acting drugs are given (triazolam) Hypotension in old patients Ataxia occurs at high doses and interfere with motor coordination (e.g. driving a car) BZs enhance the depressant effect of other drugs ; alcohol, in a more than additive way

Tolerance and dependence If high doses of BZs are given over a prolonged period, weight gain as well as physical dependence may develop Abrupt discontinuation of BZs causes withdrawal symptoms, including confusion, anxiety, restlessness, tremor and dizziness Short-acting BZs (triazolam) cause more withdrawal effects Less than Barbiturates

Contraindications

1.Pregnancy, labour and lactation: During pregnancy Late in pregnancy or around the time of labour and delivery During the period of breast feeding 2. In patients with myasthenia gravis: due to the muscle relaxing effect of BZs 3.Pre-existing CNS depression

II. BUSPIRONE (Buspar) Mechanism of action: Advantages of buspirone: Buspirone is a partial agonist at 5HT1A receptor with anxiolytic activity but little sedation. It is this action that is thought to mediate its anxiolytic and antidepressant effects It is primarily used to treat generalized anxiety disorder (GAD) Advantages of buspirone: 1.Unlike BZs, buspirone has no sedative hypnotic, anticonvulsant, or muscle relaxant properties 2. It has minimal abuse liability

Disadvantages of buspirone: 3.Buspirone causes less psychomotor impairment than BZs and does not affect driving skills 4. The drug does not potentiate the CNS depressant effects of other sedative-hypnotics e.g. ethyl alcohol Disadvantages of buspirone: Its anxiolytic effect takes several weeks to develop . (useful in chronic anxiety states) Buspirone is ineffective in controlling panic attacks or severe anxiety states

Side effects Buspirone has side effects quite different from those of BZs. Main side effects are nausea, dizziness, headache , restlessness, sleepiness Less troublesome than the side effects of BZs

Drug interactions Drugs which increase plasma level of buspirone Haloperidol Itraconazole ( anti-fungal) Drugs which decrease plasma level of buspirone Rifampicin Carbamazepine

IV. BARBITURATES Barbiturates are non-selective CNS depressants. They can produce varying degrees of CNS depression ranging from mild sedation to general anesthesia

Barbiturates have been largely replaced by BZs, because of the following: High incidence of tolerance and physical dependence following chronic use Barbiturates have a low therapeutic index (they are dangerous in overdose) Barbiturates are enzyme inducers especially cytochrome P450 system, they increase the rate of metabolic degradation of many other drugs, so liable to cause drug interactions They don’t have an antagonist

Mechanism of Action: Barbiturates like BZs, cause activation of GABAA receptor and opening of the Cl- channel associated with the receptor The neuronal membrane is hyperpolarized and less likely to fire They bind to a different site on the GABAA receptor/chloride channel, and their action is less specific.

Actions : At low doses, barbiturates produce sedation At higher doses, they cause hypnosis followed by anesthesia Overdosage may cause respiratory depression and death

CNS depression death ★ anesthesia ★ hypnosis ★ BZDs sedation ★ medullary depression★ Barbiturates anesthesia ★ hypnosis ★ BZDs sedation ★ antianxiety★ Relative concentration CNS depression

Classification Ultra-short acting: Thiopental Na is an i.v. anesthetic that acts within seconds with short duration of action Short-acting: Pentobarbital and secobarbital act for 3-8 hours Long-acting: Phenobarbital (> than 24 h)

Therapeutic Uses: 1- Anesthesia: Thiopental Na is used iv to induce anesthesia 2- As sedative-hypnotic agents: Barbiturates have been replaced by BZs 3-Anticonvulsants: Emergency treatment of convulsions in status epilepticus by thiopental as the last approach

4-Phenobarbital is used in long-term management of tonic-clonic seizures and eclampsia 5- To lower serum bilirubin in Neonatal jaundice (kernicterus) Barbiturates such as phenobarbital can increase the conjugation of bilirubin and reduces this risk by inducing the activity of glucuronyl transferase enzyme

Side effects 1-CNS effects: drowsiness can interfere with motor & mental performance; hangover. In large doses, barbiturates cause marked depression of CNS (may be fatal) 2- Induction of P450 thus the rate at which they are metabolized increases over the first few days of administration. Also, it leads to increased metabolism of other drugs e.g. estrogen and warfarin ( oral contraceptives and oral anticoagulants) 3-Tolerance and physical dependence with prolonged use 4-Teratogenicity

Contraindications: Because of enzyme induction, barbiturates are also dangerous to patients suffering from the metabolic disease known as acute intermittent porphyria During labour Old age Severe respiratory diseases

III. ZOLPIDEM, Z drugs Mechanism of action: Zolpidem is a non-benzodiazepine hypnotic that binds selectively to a subset of the BZs receptor family and facilitates GABA-mediated neuronal inhibition Zolpidem has a rapid onset and a short duration of action (about 4 hours) Its action is antagonized by flumazenil Zopiclone is similar to zolpidem ultrashort

Advantages Disadvantages Rapid onset less daytime sleepiness Less tolerance or dependence with prolonged use It has no effect on psychomotor skills Antagonized by flumazenil Least effect on REM Short duration of action Nightmares GIT upset Safe, however, respiratory depression occurs only if large doses of zolpidem are ingested together with other central depressants

Hypnotic drugs On the basis of electroencephalography measurements, several levels of sleep can be recognized. Of particular psychological importance are rapid eye movement (REM) sleep, which is associated with dreaming, and slow-wave sleep, which corresponds to the deepest level of sleep when the metabolic rate and adrenal steroid secretion are at their lowest and the secretion of growth hormone is at its highest. Most hypnotic drugs reduce the proportion of REM sleep, although BZs affect it less than other hypnotics, and zolpidem least of all. Artificial interruption of REM sleep causes irritability and anxiety

Hypnotic drugs Benzodiazepines (e.g. Temazepam , nitrazepam) Related drugs working on the BZ receptor (e.g. zolpidem, zopiclone) Sedating antihistamines (e.g. Diphenhydramine promethazine), which cause drowsiness and are used for occasional insomnia. They can impair performance the day after

V. ETHYL ALCOHOL (Ethanol) Ethyl alcohol (ethanol) is the most abused drug in the world. Ethyl alcohol in low to moderate amounts relieves anxiety and causes euphoria Large dose causes hypnosis and respiratory depression which may be fatal

Mechanism of action Ethanol enhances GABA- mediated synaptic inhibition Ethanol inhibits excitatory NMDA glutamate receptors

Treatment of Chronic Alcoholism Hospitalization, psychotherapy and nutritional therapy may be needed. Drug therapy includes: BZs (e.g. diazepam) are used to prevent alcohol withdrawal symptoms. They are preferred over barbiturates because of their wide margin of safety. The dose must be tapered slowly over several weeks

Disulfiram The drug given by itself to nondrinkers has little effects however, it causes extreme discomfort to patients who drink alcohol (Flushing, throbbing headache, nausea, vomiting, sweating, hypotension and confusion)

Mechanism of action Disulfiram acts by inhibiting aldehyde dehydrogenase thus, alcohol is metabolized as usual but acetaldehyde accumulates. Acetaldehyde will form the toxic intermediates; methanol and formaldehyde

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