Lesson 12: Anxiolytic and Sedative Drugs PDF

Lesson 12 Anxiolytic and Sedative Drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  SUMMARY Introduction Anxiolytic drugs: 2.1. BENZODIAZEPINES 2.2. Selective serotonin reuptake inhibitors Insomnia 4. H...

Lesson 12 Anxiolytic and Sedative Drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  SUMMARY Introduction Anxiolytic drugs: 2.1. BENZODIAZEPINES 2.2. Selective serotonin reuptake inhibitors Insomnia 4. Hypnotic drugs: 4.1. BENZODIAZEPINES 4.2. Non-benzodiazepine hypnotics 4.3. Others: Melatonin  1. What is ANXIETY? ▪ It is a very common disorder and closely linked to the social and work environment (increasingly stressful, competitive and demanding). ▪ Normal feeling in certain situations related to the anticipation of unforeseeable dangers. It becomes pathological when the adaptive capacity of the individual is exceeded. Symptoms of anxiety: Cognitive: fear, irritability, overwhelm, insomnia, etc. Motor: tremor, muscle tension, etc. Vegetative: palpitations, sweating, nausea, dry mouth, etc. Behavioral: avoidance or flight from certain situations.  1. What is ANXIETY? Anxiety is due to excessive CNS activation: alteration in the adrenergic and serotonergic systems; attenuation of the GABAergic neurotransmitter system. ANXIETY 1. GABAergic System: GABA (gamma-aminobutyric acid) it is the main inhibitory NT in the brain (acts as a natural "calmer"). GABA LEVELS 2. Serotonergic system: serotonin is a NT that contributes to well-being and happiness. ANXIETY SEROTONIN 3. Adrenergic system: noradrenaline it is another NT that regulates mood, attention, and vigilance. Hyperactivity in this has been linked to anxiety. 4. Glutamatergic system: glutamate is the main excitatory NT in the brain. Imbalance in glutamatergic activity has been linked to anxiety. Treatment of anxiety 2. Anxiolytic drugs Psychotropic drugs that relieve or suppress the symptoms of anxiety without producing sleepiness or sedation. 2.1. BENZODIAZEPINES: also anticonvulsants, muscle relaxants and sleep inducers 2.2. SEROTONIN REUPTAKE INHIBITORS Treatment of anxiety 2.1. BENZODIAZEPINES Mechanism of action: GABA is the main inhibitory NT in the CNS. GABA-A receptor is the most abundant inhibitory receptor in the CNS. It is a receptor coupled to a selective ion channel for Cl- ions. BZDs potentiate the effect of GABA on its receptors, which allows a greater influx of Cl- ion into neurons, favouring hyperpolarisation (the neuron becomes less excitable) and a state of neuronal inhibition is produced. https://youtu.be/MRr6Ov2Uyc4?si=lkVW0rdZCuddVMvS Treatment of anxiety 2.1. BENZODIAZEPINES Pharmacokinetics: ▪ Very liposolubles: ▪ Good oral bioavailability. C max after approx. 1 hour. ▪ High plasma protein binding. Very good tissue distribution (in adipose tissue). ▪ Crosses the BBB and placenta. ▪ Administered orally, IV. In children, rectally, and in febrile convulsions IV. ▪ Hepatic metabolism: some give rise to active metabolites(diazepam) → t1/2 = 60h ▪ Have enterohepatic circulation (diazepam). ▪ In patients with hepatic alterations/elderly: easily metabolized BZP and intermediate t1/2 (lorazepam). ▪ Excretion in urine in the form of glucuronides. Treatment of anxiety 2.1. BENZODIAZEPINES ADRs: Wide therapeutic margin. Very safe and tolerated At high doses: Drowsiness, confusion. Amnesia. Incoordination. Impaired ability to drive vehicles. Dependence and tolerance (treatments > 6 months) Treatment of anxiety 2.1. BENZODIAZEPINES Drug Interactions: The effects increase if they are associated with: Other CNS depressants Alcohol. Antihistamines (metabolism/elimination) Hormonal contraceptives (elimination) Omeprazole (metabolism) Treatment of anxiety 2.1. BENZODIAZEPINES Pharmacological Effect: Anxiolytic: Reduction of anxiety and aggressiveness. Hypnosedative: sleep induction and sedation. Myorelaxant: Reduced muscle tone. Anticonvulsant. To reduce withdrawal: Give the lowest possible dose that is effective. Never stop treatment abruptly →reduce treatment gradually over several weeks. Treatments as short as possible, not exceeding 8-12 weeks(including the phase-out phase). Treatment of anxiety 2.1. BENZODIAZEPINES Types of benzodiazepines Classified by half-life in: Short half-life benzodiazepines (less than 6 hours) -Midazolam, Triazolam Intermediate half-life benzodiazepines (6-24 hours) - Alprazolam, Lorazepam, Oxazepam, Temazepam Long half-life benzodiazepines (more than 24 hours) Diazepam, Clonazepam, Flurazepam, Nitrazepam These categories help in selecting the appropriate benzodiazepine based on the desired duration of therapeutic effect. Treatment of anxiety 2.2. Selective serotonin reuptake inhibitors (SSRIs) Antidepressants, also effective in many cases of anxiety. Medium and long-term efficacy (3-4 weeks). Lack addictive potential. Most do not produce sedation: Fluoxetine, Paroxetine, Citalopram, Sertraline 3. What is INSOMNIA? Insomnia is characterized by nocturnal problems including prolonged latency to onset, decreased duration, numerous nocturnal awakenings and possibly early awakening in the early hours of the morning with difficulty falling asleep. Treatment of Insomnia 4. Hypnotic drugs Sleep, a vital function for our physical and mental well-being, is often disrupted by disorders such as insomnia, affecting our quality of life. 4.1. HYPNOTIC BENZODIAZEPINES: Lorazepam, Lormetazepam 4.2. Non-benzodiazepine hypnotics: Zolpidem, Zopiclone 4.3. Other hypnotics: melatonin Treatment of Insomnia 4.1. Hypnotic benzodiazepines Lorazepam, Lormetazepam Short action (10-20h),they are removed quickly. Decrease sleep onset latency, reduce number of nighttime awakenings and increase total sleep time. ADRs: daytime sleepiness, dizziness, headache, motor and cognitive retardation, memory loss, development of tolerance, dependence. Treatment of Insomnia 4.2. Non-benzodiazepine hypnotics Zolpidem, Zopiclone Structurally unrelated to BZDs. Agonists of GABA-A receptor. Poor anxiolytic and relaxant effects. Pharmacokinetics: Oral administration, strong binding to plasma proteins, hepatic metabolism. Onset of effect in 30 min. Duration: 6-8 h. ADRs:headache, somnolence, vertigo, confusion, amnesia, fatigue, tremor, palpitations, visual disturbances. Tolerance and dependence. Better tolerated than BZD. Treatment of Insomnia 4.3. Other hypnotics Melatonin Hormone that increases during the night and decreases during the day (regulates circadian rhythm). Melatoninergic receptor agonist drugs. Pharmacokinetics: Administered orally, important 1st pass effect. Rapid distribution, crosses BBB and placenta. Safer. Rare ADRs. Questions?????