2. treatment of_anxiety_disorders_angel_

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2. treatment of_anxiety_disorders_angel_

  1. 1. Treatment of Anxiety Disorders time to onset of effects Antidepressant drugs are used totreat anxiety disorders. These drugshave a latency to onset of clinicallymeaningful effects, typically 3 to 4weeks or longer Benzodiazepines have a rapid onsetof effect (30 minutes to one hour)
  2. 2. Anxiety Disorders Panic Disorder (PD) Obsessive Compulsive Disorder (OCD) Social Anxiety Disorder (Social Phobia) Post-traumatic Stress Disorder (PTSD) Generalized Anxiety Disorder (GAD) Specific Phobia (Simple Phobia)
  3. 3. Neurotransmitters Implicated inAnxiety Gamma-amino butyric acid (GABA)  GABA-benzodiazepine receptor complex Norepinephrine (NE)  Brainstem locus coeruleus Serotonin (5-hydroxytryptamine, 5-HT)
  4. 4. Anxiolytic Drugs Discovery  meprobamate (1954)  chlordiazepoxide (1957)  First of many benzodiazepines
  5. 5. Panic Disorder With and without agoraphobia Panic attacks (unexpected) Anticipatory anxiety Generalized anxiety Avoidance (agoraphobia) Somatic symptoms
  6. 6. Pharmacologic Treatment of PanicDisorder Antidepressants (latency to onset of effects)  TCAs - imipramine, clomipramine  MAOIs  SSRI/SNRI - first choice for many patients Benzodiazepines (rapid onset of effects)  First choice if rapid effect needed  alprazolam (Xanax®)  clonazepam (Klonopin®) Combinations
  7. 7. Adverse Effects SSRI/SNRI  Activation - may cause initial jitteriness  Gradual dose escalation recommended  Sexual dysfunction  Gastrointestinal side effects  Withdrawal syndrome Benzodiazepines  Sedation  Potentiation of alcohol, other CNS depressants  Dependence  Psychomotor impairment, Ataxia  Amnesia  Withdrawal syndrome
  8. 8. Non-pharmacologic Treatment of PanicDisorder Cognitive Behavioral Therapy (CBT) Frequently, pharmacologic treatment and CBT are used in combination
  9. 9. Obsessive Compulsive DisorderCommon Obsessions Common Compulsions Contamination  Checking Aggression  Cleaning/washing Religious  Counting/Mental rituals Safety/harm  Repeating Need for symmetry  Ordering/arranging Somatic fears  Hoarding
  10. 10. Treatment of OCD Drugs that increase synaptic serotonin
  11. 11. Treatment of OCDserotonin reuptake inhibitors (SRIs)  clomipramine (Anafranil®) [a tricyclic]Approved for OCD  fluoxetine (Prozac®)  fluvoxamine (Luvox®)  paroxetine (Paxil®) SSRIs  sertraline (Zoloft®)  *citalopram (Celexa®)  *escitalopram (Lexapro®)  *SNRI antidepressants are also used *Off label use
  12. 12. Treatment of OCD Full effects of drug treatment may take 10-12 weeks Cognitive Behavioral Therapy (CBT) is effective Combination (CBT + drug therapy) may be better Treatment is usually chronic Partial responders often receive augmentation with atypical antipsychotic drugs (not an approved indication for these drugs)
  13. 13. Social Anxiety Disorder Generalized  Nearly all social situations Discrete  Performance anxiety
  14. 14. Treatment of Social Anxiety Disorder SSRI/SNRI High potency benzodiazepine (BZD)  alprazolam  clonazepam MAOIs Beta blockers for performance anxiety  propranolol 10-40 mg one hour before  Reduces sympathetic symptoms (sweating, tremor) +CBT
  15. 15. Post-traumatic Stress Disorder (PTSD) Traumatic event Re-experiencing the event  Recall, flashback, dreams  Intense psychological distress with exposure Avoidance Increased arousal
  16. 16. Treatment of PTSD SSRI - sertraline and paroxetine approved Off label treatments  Beta blockers to ⇩ autonomic arousal  Li+ and antiepileptic drugs  development of PTSD resemblance to “kindling”  cf. Bipolar Disorder treatments
  17. 17. Treatment of Generalized AnxietyDisorder (GAD) Benzodiazepines buspirone (Buspar®) Antidepressants  TCA (e.g., imipramine)  SSRI  SNRI (venlafaxine, duloxetine)
  18. 18. GABA-A Receptor Endogenous ligand is GABA  GABA is the major inhibitory CNS neurotransmitter  Opens the Cl- ionophore  Inhibits neuronal firing The GABA-Benzodiazepine receptor complex  Ligand-gated ion channel  Selectively conducts Cl- through its pore  causes hyperpolarization of the neuron
  19. 19. GABA-BZD receptor complex Benzodiazepines  Allosterically modulate the GABA receptor  Potentiate the effect of GABA Other substances bind this receptor complex  e.g., EtOH, barbiturates Benzodiazepines increase the frequency of the chloride ion channel opening at the GABAA receptor Barbiturates increase the duration of chloride ion channel opening at the GABAA receptor
  20. 20. Benzodiazepine Indications GAD Panic Disorder EtOH withdrawal Hypnotic Anticonvulsant  diazepam, lorazepam Preanesthetic, procedural sedation  midazolam, lorazepam
  21. 21. Examples of benzodiazepinesAnxiolytics Brand name Dose rangechlordiazepoxide (Librium®) 10-100 mgdiazepam (Valium®) 2-20 mgalprazolam (Xanax®) .75-10 mglorazepam (Ativan®) .5-10 mgHypnoticsflurazepam (Dalmane®) 15-30 mgtriazolam (Halcion®) .125-.25mg
  22. 22. Benzodiazepine Adverse Effects Sedation  Effect exploited for use as hypnotics Amnesia  Particularly with triazolam  Effect exploited for use in anesthesia (midazolam) and conscious sedation/procedural sedation Psychomotor impairment, Ataxia Potentiation of alcohol, other CNS depressants Risk for dependence Withdrawal syndrome
  23. 23. Benzodiazepine Intoxication/Overdose Intoxication is similar to alcohol  Sedation  Psychomotor impairment  Dizziness/Ataxia  Amnesia Overdose  All of the above  Confusion/agitation  Severe sedation/lethargy  Respiratory depression  Unresponsiveness
  24. 24. Benzodiazepine Withdrawal Anxiety/agitation Sleep disturbance Myoclonic jerks Sensory disturbances  Paresthesias Muscle cramps Dizziness After high dose usage, withdrawal may include:  Seizures  Delirium
  25. 25. Drug-drug interactions Potentiation of CNS depressants BZDs increase the half-life of digoxin Increase BZD levels  cimetidine, disulfiram, isoniazid, estrogen  Inhibit metabolism  fluvoxamine ⇧ alprazolam levels (CYP3A4) Decrease BZD levels  Antacids ⇩ absorption  Tobacco, rifampin (enzyme induction)
  26. 26. Benzodiazepine antagonist flumazenil (Romazicon®)  Reverses effects of drugs acting at the benzodiazepine receptor  does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor; e.g., ethanol, barbiturates, or general anesthetics)  does not reverse the effects of opioids  used to reverse BZD conscious sedation  may be useful in suspected BZD overdose  Onset 1-2 minutes; duration of effect 4-5 hours
  27. 27. Non-benzodiazepine Treatments forAnxiety buspirone (Buspar®) SSRI SNRI  venlafaxine (Effexor®)  duloxetine (Cymbalta®) clonidine (Catapres®)
  28. 28. Non-benzodiazepine Treatments forAnxiety buspirone clonidine
  29. 29. buspirone Presynaptic 5-HT1A full agonist  Hypothesized 5-HT excess  ⇩ Neuronal firing  ⇩ 5-HT synthesis Postsynaptic partial agonist  With 5-HT excess, acts as antagonist  With 5-HT deficit, acts as agonist No effects on BZD-GABA receptor complex
  30. 30. buspirone Unlike BZD Absence of:  Sedation  Muscle relaxant properties  Anticonvulsant effects  Abuse potential  Psychomotor performance impairment
  31. 31. buspirone May be preferred for  Elderly  Patients with medical conditions May improve sexual dysfunction secondary to SSRI May be antidepressant in higher doses Slower onset than BZD  Full effect may take days to weeks
  32. 32. buspirone adverse effects Dizziness Headache Nausea Nervousness Lightheadedness Agitation
  33. 33. clonidine Alpha-2 agonist
  34. 34. clonidine NE overactivity can cause anxiety symptoms Alpha-2 antagonists cause ⇧ NE Alpha-2 agonist can be anxiolytic Especially on adrenergic symptoms  Tachycardia  Sweating  Tremor
  35. 35. Hypnotics  OTC – diphenhydramine*  TCA*  trazodone (Desyrel®)*  doxepin (Silenor®) H1 antagonist*  Benzodiazepines  Non-benzodiazepine  Similar GABAergic mechanism  ramelteon (Rozerem®)*  melatonin agonist *Not a controlled substance
  36. 36. Examples of Benzodiazepine andNon-benzodiazepine Hypnotics Benzodiazepine  flurazepam (Dalmane®)  temazepam (Restoril®)  triazolam (Halcion®) Non-benzodiazepine  zolpidem (Ambien®)  zaleplon (Sonata®)  zopiclone (Imovane®)  eszopiclone (Lunesta®)

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