1. 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

2. What is anxiety ? Physical and emotional distress which interfere with normal life.

3. How Anxiety Affects Performance

4. “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.

5. 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.”

6. 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

7. Types of anxiety disorders 1- Generalized anxiety disorder 2- Panic disorder

8.  3- Phobia  4-Post traumatic stress disorder 5- Obsessive compulsive disorder

9. Treatment of anxiety  Psychotherapy  Anxiolytics

10. Classification of anxiolytic drugs: 1. Benzodiazepines ( BDZ ). 2. 5HT 1A agonists. 3. 5HT reuptake inhibitors. 4. Tricyclic Antidepressants 5. MAO inhibitors 6. Beta-adrenergic blockers

11. Benzodiazepines

12. Mechanism of Action  Benzodiazepines act by binding to BZ receptors in the brain   enhance GABA action in the brain

14. 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).

15. Can be classified according to the duration of action into short, medium & long- acting

17. Pharmacological Actions  Anxiolytic action.

18. 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.

19. 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

20. Therapeutic Uses Treatment of epilepsy Diazepam – Lorazepam In anesthesia  Preanesthetic medication (diazepam).  Induction of anesthesia (Midazolam, IV)

21. Adverse Effects Ataxia (motor incoordination) Cognitive impairment. Hangover: (drowsiness, confusion) Tolerance & dependence Risk of withdrawal symptoms Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion. Use of benzodiaze pine Reduced anxiety Effect wears off Even more anxious

22. Adverse Effects  Toxic effects: respiratory & cardiovascular depression in large doses.

23. Drug interactions Examples CNS depressantsAlcohol & Antihistaminics of effect of benzodiazepines Cytochrome P450 (CYT P450) inhibitors Cimetidine & Erythromycin t ½ of benzodiazepines CYT P450 inducersPhenytoin & Rifampicin t 1/2 of benzodiazepines

24. Dose should be reduced in o Liver disease o Old people. Precaution Should not be used in  pregnant women or breast-feeding.  People over 65.

25. 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

26. 5HT 1A agonists Buspirone  Acts as agonist at brain 5HT 1A receptors  Rapidly absorbed orally.  T½ : (2 – 4 h).  Liver dysfunction   its clearance.

27. 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.

28. Uses of buspirone As anxiolytic in mild anxiety & generalized anxiety disorders.

29. 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

30. 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

31. 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

33. 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).

34. Side effects of tricyclic antidepressants  Atropine like actions (dry mouth-blurred vision).  α-blocking activity (Postural hypotension).  Sexual dysfunction.  Weight gain.

35. 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.

36. Side effects of SSRIs  Nausea, diarrhea  Sexual dysfunction  Dry mouth  Seizures  Sleep disturbance

37. 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.

38. Synopsis of anxiolytics CLASSES OF ANXIOLYTICS USES BenzodiazepinesGeneralized anxiety disorders, OCD, phobia, panic attack SSRIs (Fluoxetine) Generalized anxiety disorders, OCD, phobia, panic attack Tricyclic antidepressants (doxepin, imipramine ) anxiety with depression. panic attacks 5HT1A agonists (Buspirone) Mild anxiety Not effective in panic attack Beta blockers (propranolol, atenolol) Phobia (social Phobia)

39. Synopsis of anxiolytics CLASSES OF ANXIOLYTICS Adverse effects BenzodiazepinesAtaxia, confusion, dependence, tolerance, withdrawal symptoms, SSRIs (Fluoxetine) weight gain, sexual dysfunction Dry mouth Tricyclic antidepressants (doxepin, imipramine ) weight gain, sexual dysfunction, atropine like actions 5HT1A agonists (Buspirone) Minimal adverse effects Beta blockers (propranolol, atenolol) Hypotension

40. 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.

41. 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

42. 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