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Antianxiety drugs ILOs By the end of this lecture you will be able to Define different types of anxiety disorders Classify types of drugs used for treatment of anxiety Recognize the different characteristics of antianxiety drugs What is anxiety ? Physical and emotional distress which interfere with normal life. “I always thought I was just a worrier. I’d feel keyed up and unable to relax. At times it would come and go, and at times it would be constant. It could go on for days. I’d worry about what I was going to fix for a dinner party, or what would be a great present for somebody. I just couldn’t let something go.” “I’d have terrible sleeping problems. There were times I’d wake up wired in the middle of the night. I had trouble concentrating, even reading the newspaper or a novel. Sometimes I’d feel a little lightheaded. My heart would race or pound. And that would make me worry more. I was always imagining things were worse than they really were. When I got a stomachache, I’d think it was an ulcer.” “I was worried all the time about everything. It didn't matter that there were no signs of problems, I just got upset. I was having trouble falling asleep at night, and I couldn't keep my mind focused at work. I felt angry at my family all the time.” Emotional Symptoms of anxiety irrational and excessive fear and worry Irritability Restlessness Trouble concentrating Feeling tense Physical Symptoms of Anxiety Sweating Tachycardia Stomach upset Frequent urination or diarrhea Sleep disturbances (Insomnia) Fatigue Types of anxiety disorders 1- Generalized anxiety disorder 2- Panic disorder 3- Phobia 4-Post traumatic stress disorder 5- Obsessive compulsive disorder Treatment of anxiety Psychotherapy Anxiolytics Classification of anxiolytic drugs: 1. Benzodiazepines ( BDZ ). 2. 5HT1A agonists. 3. 5HT reuptake inhibitors. 4. Tricyclic Antidepressants 5. Beta-adrenergic blockers 6. MAO inhibitors Benzodiazepines Mechanism of Action Benzodiazepines act by binding to BZ receptors in the brain enhance GABA action in the brain PHARMACOKINETICS are lipid soluble well absorbed orally, can be given parenterally Chlordiazepoxide- Diazepam (IV only NOT IM) widely distributed. cross placental barrier (Fetal depression). excreted in milk (neonatal depression). Can be classified according to the duration of action into short, medium & long- acting Pharmacological Actions Anxiolytic action. Pharmacological Actions Depression of cognitive and psychomotor function Sedative & hypnotic actions Anterograde amnesia Minimal depressant effects on Cardiovascular system Respiratory system Some have anticonvulsant effect: Clonazepam, diazepam. Therapeutic Uses Anxiety disorders: Short term relief of severe anxiety General anxiety disorder Obsessive compulsive disorder Panic attack with depression Alprazolam (antidepressant effect) Sleep disorders (Insomnia). Triazolam, Lorazepam, Flurazepam Therapeutic Uses Treatment of epilepsy Diazepam – Lorazepam In anesthesia Preanesthetic medication (diazepam). Induction of anesthesia (Midazolam, IV) Use of benzodiaze pine Adverse Effects • Ataxia (motor Even more anxious Reduced anxiety incoordination) Effect wears • Cognitive impairment. off • Hangover: (drowsiness, confusion) • Tolerance & dependence • Risk of withdrawal symptoms Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion. Adverse Effects Toxic effects: respiratory & cardiovascular depression in large doses. Drug interactions Examples CNS depressants Cytochrome P450 (CYT P450) inhibitors CYT P450 inducers Alcohol & Antihistaminics of effect of benzodiazepines Cimetidine & Erythromycin t ½ of benzodiazepines Phenytoin & Rifampicin t 1/2 of benzodiazepines Dose should be reduced in o o Liver disease Old people. Precaution Should not be used in pregnant women or breast-feeding. People over 65. Quiz? Which one of the following is most likely to result from treatment with moderate doses of diazepam? (A) Alleviation of the symptoms of major depressive disorder (B) Agitation and possible hyperreflexia with abrupt discontinuance after chronic use (C) Improved performance on tests of psychomotor function (D) Retrograde amnesia 5HT1A agonists Buspirone Acts as agonist at brain 5HT1A receptors Rapidly absorbed orally. T½ : (2 – 4 h). Liver dysfunction its clearance. Buspirone Only anxiolytic No hypnotic effect. Not muscle relaxant. Not anticonvulsant. No potentiation of other CNS depressants. Minimal psychomotor and cognitive dysfunctions. Does not affect driving skills. Minimal risk of dependence. No withdrawal signs. Uses of buspirone As anxiolytic in mild anxiety & generalized anxiety disorders. Disadvantages of buspirone Slow onset of action (delayed effect) Not effective in severe anxiety/panic disorder. GIT upset, dizziness, drowsiness Drug Interactions with CYT P450 inducers and inhibitors Quiz? Which of the following statements about buspirone is correct: A. It binds to 5HT receptors in the central nervous system B. It has marked sedative activity C. It is chemically related to benzodiazepines D. It causes marked central nervous system depression when combined with alcohol E. It possesses muscle relaxant activity Beta Blockers Propranolol – atenolol Act by blocking peripheral sympathetic system. Reduce somatic symptoms of anxiety. Decrease BP & slow HR. Used in performance anxiety. Are less effective for other forms of anxiety Tricyclic Antidepressants Doxepin- imipramine – desipramine Act by reducing uptake of 5HT & NA. Used for anxiety especially associated with depression. Effective for panic attacks. Delayed onset of action (weeks). Side effects of tricyclic antidepressants Atropine like actions (dry mouth-blurred vision). α-blocking activity (Postural hypotension). Sexual dysfunction. Weight gain. Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine acts by blocking uptake of 5HT Orally Delayed onset of action (weeks). Long half life Used for panic disorder – OCD Generalized anxiety disorders - phobia. Side effects of SSRIs Nausea, diarrhea Weight gain or loss Sexual dysfunction Dry mouth Seizures Sleep disturbance Monoamine oxidase inhibitors (MAOIs) Phenelzine act by blocking the action of MAO enzymes. Used for panic attacks and phobia. Require dietary restriction Avoid wine, beer, fermented foods as old cheese that contain tyramine. Side effects Dry mouth, constipation, diarrhea, restlessness, dizziness. Synopsis of anxiolytics CLASSES OF ANXIOLYTICS USES Benzodiazepines Generalized anxiety disorders, OCD, phobia, panic attack Generalized anxiety disorders, OCD, phobia, panic attack SSRIs (Fluoxetine) Tricyclic antidepressants (doxepin, imipramine ) 5HT1A agonists (Buspirone) Beta blockers (propranolol, atenolol) anxiety with depression. panic attacks Mild anxiety Not effective in panic attack Phobia (social Phobia) Synopsis of anxiolytics CLASSES OF ANXIOLYTICS Benzodiazepines SSRIs (Fluoxetine) Tricyclic antidepressants (doxepin, imipramine ) 5HT1A agonists (Buspirone) Beta blockers (propranolol, atenolol) Adverse effects Ataxia, confusion, dependence, tolerance, withdrawal symptoms, weight gain, sexual dysfunction Dry mouth weight gain, sexual dysfunction, atropine like actions Minimal adverse effects Hypotension The wife of a 24-year-old computer programmer considers him to be of a "nervous disposition. " He is easily startled, worries about inconsequential matters, and sometimes complains of stomach cramps. At night he grinds his teeth in his sleep. There is no current history of drug abuse. Q1 Assuming that the symptoms experienced by this young man are not related to a medical condition, the most appropriate drug treatment would be the judicious use of (A) Buspirone (B) Midazolam (C) Triazolam (D) Phenelzine Q2 Regarding the characteristic properties of the drug prescribed for this young man, the physician should inform the patient to anticipate (A) Additive CNS depression with alcoholic beverages (B) A significant effect on memory (C) That the drug will take a week or so to begin working (D) A need to gradually increase drug dosage because of tolerance (E) That if he stops taking the drug abruptly he will experience withdrawal signs