2-Anxiolytics - Hypnotics PDF

2-ANXIOLYTICS - HYPNOTICS ASSOCIATE PROFESSOR. MAHMOUD ELDERBI D E P A R T M E NT O F P H A R M A C O L O G Y F A C U L T Y O F M E D I C I N E - A L M A RJ UNIVERSITY OF BENGHAZI 2024 OBJECTIVES Overview. Classification. Barbiturates Benzodiazepines. New dr...

2-ANXIOLYTICS - HYPNOTICS ASSOCIATE PROFESSOR. MAHMOUD ELDERBI D E P A R T M E NT O F P H A R M A C O L O G Y F A C U L T Y O F M E D I C I N E - A L M A RJ UNIVERSITY OF BENGHAZI 2024 OBJECTIVES Overview. Classification. Barbiturates Benzodiazepines. New drugs OVERVIEW: Anxiety Anxiety is mental disorders. it is an unpleasant state of tension, apprehension, or nervousness. Symptoms: 1. Sever: similar to those of Fear, such as tachycardia, sweating, trembling, and palpitations. 2. Mild: common life experiences and do not warrant treatment. Types: 1. GAD (Generalized Anxiety disorders) 4. Obsessive compulsive disorders OCD. 2. SAD (social anxiety disorders) 5.Panic disorders. 3. PTSD (Post-Traumatic stress disorders) 6.Agoraphobia. 7.phobias  INSOMNIA Sleep-wake cycle: During night: Melatonin secrete (8hours). During day: No melatonin (16hours). Other neurotransmitters: serotonin, NA, Ach and histamine Sleep disorders: insomnia, hypersomnia and Narcolepsy Insomnia: inability to initiate and maintain sleep. Types: transient, short-term and chronic Causes: Drugs such as ephedrine, alcohol withdrawal. Diseases such as hypertension, hormonal disturbance such as menopause, life events such as stress and poor sleep hygiene  CLASSIFICATION 1. Barbiturates 2. Benzodiazepines. 3. Other anxiolytics: Antidepressants and Buspirone 4. Other Hynpotics: 1.Non Benzodiazepine hypnotics( bind to α 1 subunit GABA-A receptor) Z ZOLPIDEM ZALEPLON ZOPICLONE 2.MELATONIN agonists: RAMELTEON. 3.Suvorexant. CLASSIFICATION DEPEND ON MECHANISM OF ACTION 1. GABA potentiators: Barbiturates. Benzodiazepines. Non benzodiazepines (Z compounds) 2. 5HT-agonist: Buspirone. 3. Melatonin(MT-R) agonist: Ramelteon 4. Orexin antagonist: Suvorexant 5. Antihistamines. 6. Tricyclic antidepressants: such as Doxepin  1. BARBITURATES: BARBITURATES CLASSIFIED ACCORDING TO THEIR DURATIONS OF ACTION SITE AND MECHANISM OF ACTION Site : Barbiturates depress the neurons and synapses of the mesenocephalic reticular activating system (RAS), reducing the electrical activity of the cortex. Barbiturates are GABA potentiators, they enhance GABA effect or stimulate its release (activate the inhibitory GABAA –R). Barbiturates promote GABA-induced chloride current. They increase the duration of the GABA-gated channel openings. They may be GABA-mimetic (high concentration), by direct activation of chloride-channels through binding sites distinct from the benzodiazepines (BDZ) binding sites.  PHARMACOKINETICS: Absorption: well absorbed Distribution: thiobarbitone is highly lipid soluble and cross BBB rapidly to the brain and then redistributed in the less vascular tissues. Maximum uptake occurs within 30sec. Giving a very rapid onset of action. The ultra- short duration of action (30 min.) is the result of rapid redistribution into the less vascular areas of the brain and to other tissues (e.g skeletal muscle and then adipose tissues). Excretion: phenobarbitone is excreted unchanged in the urine and its excretion is increased significantly by alkalinization of urine. 1. DEPRESSION OF CNS At low doses: sedation At high doses: hypnosis Anesthesia Coma Death 2. Respiratory depression Lethal dose: suppress the hypoxic & chemoreceptor response to CO2, and overdose is followed by respiratory depression & death 3. CVS High dose: hypotension due to suppression ganglionic transmission and suppress VMC. 4. Liver: Enzyme inducer and decrease effect of many drugs  THERAPEUTIC USES 1. ANESTHESIA: Selection of a barbiturate is strongly influenced by the desired duration of action. The ultra-short-acting barbiturates, such as thiopental, are used IV to induce anaesthesia. 2. Sedative/hypnotic Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. 3. ANTICONVULSANT: Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus, and eclampsia. Phenobarbital has been regarded as the drug of choice for treatment of young children with recurrent febrile seizures. However, phenobarbital can depress cognitive performance in children, and the drug should be used cautiously.  ADVERSE EFFECTS 1.CNS: Drowsiness & mental confusion 2. Hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes. 3. By inducing AminoLevulinic Acid (ALA) synthetase, barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria. 4. Abuse and dependence: Tolerance develops on repeated use. Abrupt withdrawal from barbiturates may cause: tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest. Overdose causes: Death Severe depression of respiration & central CV depression Treatment: Supportive care and gastric decontamination for recent ingestions. Contraindications: Pregnancy: Depress fetus. Drug interactions: Reduce effectiveness of many drugs such as phenytoin , contraceptives and many anticoagulants  2. BENZODIAZEPINES Benzodiazepines are widely used anxiolytic drugs. ADVANTAGES: 1. WIDE SAFETY MARGIN. 2. LITTLE CV & RESPIRATORY DEPRESSION. 3. FEWER DRUG INTERACTIONS. 4. LOWER ABUSE LIABILITY AND LEAST TO ALTER SLEEP PATTERN. 5. SPECIFIC ANTAGONIST FLUMAZENI L. COMPARISON OF THE DURATIONS OF ACTION OF THE BENZODIAZEPINES  MECHANISM OF ACTION The targets for benzodiazepine actions are the γ-aminobutyric acid (GABAA) receptors The GABAA receptors are composed of a combination of five α, β, and γ subunits that span the postsynaptic membrane PHARMACOKINETICS 1. Absorption and distribution The benzodiazepines are lipophilic. They are rapidly and completely absorbed after oral administration, distribute throughout the body, and penetrate into the CNS. 2. DURATION OF ACTION The half-lives of the benzodiazepines are important clinically, because the duration of action may determine the therapeutic usefulness. A short elimination t1/2 is desirable for hypnotics, although this carries the drawback of increased abuse liability and severity of withdrawal after drug discontinuation. 3. Metabolism: Most of the BZDs are metabolized in the liver to produce active products (thus long duration of action) such as chlordiazepoxide and diazepam. After metabolism these are conjugated and are excreted via kidney.  PREGNANCY & LACTATION: All benzodiazepines cross the placenta and may depress the CNS of the newborn if given before birth. The benzodiazepines are not recommended for use during pregnancy. Nursing infants may also be exposed to the drugs in breast milk Actions 1. REDUCTION OF ANXIETY At low doses, the benzodiazepines are anxiolytic. Reduce anxiety by selectively enhancing GABAergic transmission in neurons having the α2 subunit in their GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain. 2. SEDATIVE/HYPNOTIC All benzodiazepines have sedative and calming properties, and some can produce hypnosis at higher doses. The hypnotic effects are mediated by the α1-GABAA R. Temporary impairment of memory with the use of the BZD is also mediated by the α1-GABAA receptors. The ability to learn and form new memories is also impaired. 4. ANTICONVULSANT Mediated by α1-GABAA receptors 5. Muscle relaxant At high doses, the BZD relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located. Note: Baclofen is a muscle relaxant that is believed to affect GABA R at the level of the spinal cord.  THERAPEUTIC USES: 1. Anxiolytic (in GAD, panic disorders). 2. Insomnia (Triazolam). 3. Anticonvulsants (clonazepam, Lorazepam and Diazepam). 4. Preanesthetic medication (amnesia). 5. Muscle spasm (Diazepam). 6. Alcohol withdrawal syndrome  ADVERSE EFFECTS 1.Drowsiness and confusion 2.Cognitive impairment 3.Ataxia 4.Triazolam: Dose-dependent change in sleep pattern: dec REM and inc NREM and Tolerance 5.Impairment of mental and motor functions All of these effects can greatly impair driving and other psychomotor skills, especially if combined with ethanol. 6. Rebound insomnia 7. Hypotension and respiratory depression. 8. Dependence and abuse ADVERSE EFFECTS High doses of benzodiazepines & prolonged period. Abrupt discontinuation cause: withdrawal symptoms, including: Dependence confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. FLUMAZENIL: A BENZODIAZEPINE RECEPTOR ANTAGONIST It is Competitively antagonism Flumazenil is available only for IV administration. Onset is rapid, but the duration is short, with a half-life of about 1 hour. Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine. Administration of flumazenil may precipitate withdrawal in dependent patients or cause seizures if a BZD is used to control seizure activity. Seizures may also result if the patient has a mixed ingestion with TCA or antipsychotics. NEW ANXIOLYTICS - HYPNOTICS  ATYPICAL ANXIOLYTICS 1. Buspirone 2. Ipsapirone Pirones 3. Gepirone Buspirone relieves anxiety: -without causing marked sedative, hypnotic, or euphoric effects. - no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. Anxiolytic effects of buspirone is by acting as a partial agonist at brain 5-HT1A receptors. the anxiolytic effects of buspirone may take more than a week Unsuitable for management of acute anxiety states No rebound anxiety or withdrawal signs on abrupt discontinuance The drug is not effective in blocking the acute withdrawal syndrome resulting from abrupt cessation of use of BZD or other sedative-hypnotics Buspirone has minimal abuse liability The drug is used in generalized anxiety states GAD but is less effective in panic disorders Seratonin-syndrome: + MAOI  OTHER HYPNOTICS 1. Z compounds zolpidem , zaleplon and zopiclone. structurally unrelated to each other and to BZDs(non-benzodiazepine) Therapeutic efficacy as hypnotics is due to agonist effects on the α1-BZD site of the GABAA receptor Compared to benzodiazepines, Z compounds are -less effective as anticonvulsants or muscle relaxants -which may be related to their relative selectivity for GABAA receptors containing the α1 subunit. NEW DRUGS The clinical presentation of overdose with Z compounds is similar to that of BZD overdose and can be treated with the benzodiazepine antagonist flumazenil. Zaleplon and zolpidem have sustained hypnotic efficacy without occurrence of rebound insomnia on abrupt discontinuation. 2. MELATONIN RECEPTOR AGONISTS Ramelteon and tasimelteon They are selective agonists at the MT1 and MT2 subtypes of melatonin receptors. Mechanism of action: Melatonin is a hormone secreted by the pineal gland that helps to maintain the circadian rhythm underlying the normal sleep–wake cycle. The drugs Stimulate of MT1 and MT2 receptors, induce and promote sleep Advantages: Adverse effects 1. Minimal potential for abuse 1. Dizziness. 2. No dependence or withdrawal. 3. Long-term administration. 2. Fatigue. 3. somnolence. 4. Increase prolactin levels 3. SUVOREXANT It is an Orexin receptor antagonist. Mechanism of action: Orexin is a neuropeptide that promotes wakefulness. Antagonism of the effects of orexin suppresses the wake drive from this neuropeptide. Adverse effects: 1.signs of narcolepsy and cataplexy 2.Daytime somnolence 3.increased suicidal ideation Uses: Insomnia: initiate and maintenance 4. OTHER DRUGS: ANTIDEPRESSANTS ANTIHISTAMINES. 1. Doxepin Tricyclic antidepressants agent with SNRI mechanisms of antidepressant and anxiolytic action, is approved at low doses for the management of insomnia. 2. Trazodone and irtazapine. 3. older tricyclic TCA, with strong antihistamine properties are used off-label for the treatment of insomnia CASE I A 36-year-old male patient reports difficulty falling asleep for the past 2 weeks but needs to be able to wake up at 6 AM for work and doesn’t want any daytime sedation. Which medication is best to recommend for the treatment of his insomnia? A. Temazepam B. Flurazepam C. Zaleplon D. Buspirone