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antipsychotics.ppt
- 1. Chris Pelic M.D. Associate Dean for Students Assistant Professor of Psychiatry Medical University of South Carolina
- 2. Learn the dopamine hypothesis of schizophrenia Learn basic proposed mechanism of antipsychotics Understand the difference between first generation and second generation antipsychotics Learn common side effects of antipsychotics
- 3. Early 1950’s accidental discovery Found antihistamine chlorpromazine (phenothiazine) exerted antipsychotic effects. Was used as anxiolytic before surgery Through side chain substitutions, more drugs developed ?13 first generation antipsychotics are still available Atypical second generation drugs - 1989
- 4. 1959 serendipitous discovery of Clozaril Used in 1972 in Europe but withdrawn 3 years later after several cases of agranulocytosis and death Re-introduced in 1988 after trial demonstrated its clinical superiority but required monitoring Other atypical agents soon followed Most consider atypical agents first line tx
- 5. Clozapine 1950 1960 1970 1980 1990 2000 2002 2006 Reserpine Chlorpromazine Fluphenazine Thioridazine Haloperidol Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Kaplan HI et al. Kaplan and Sadock’s Synopsis of Psychiatry. 7th ed.1994. Black DW et al. Introductory Textbook of Psychiatry. 2001. Palidperidone
- 6. **from Michael D. Jibson, M.D., Ph.D. Ira D. Glick, M.D ASCP CURRICULUM edition 4
- 7. 1. Nigrostriatal tract- (extrapyramidal pathway) begins in the substantia nigra and ends in the caudate nucleus and putamen 2. Mesolimbic tract - originates in the midbrain tegmentum and innervates the nucleus accumbens and adjacent limbic structures 3. Mesocortical tract - originates in the midbrain tegmentum and innervates anterior cortical areas 4. Tuberoinfundibular tract - projects from the arcuate and periventricular nuclei of the hypothalamus to the pituitary
- 8. 1. Nigrostriatal tract- extrapyramidal pathway 2. Mesolimbic tract – positive symptoms 3. Mesocortical tract – positive symptoms/cognition 4. Tuberoinfundibular tract - prolactin
- 9. Clinical efficacy of antipsychotics correlates with dopamine D2 blockade Psychotic symptoms can be induced by dopamine agonists **from Michael D. Jibson, M.D., Ph.D., Ira D. Glick, M.D ASCP CURRICULUM edition 4 Carlsson A, Am J Psychiatry 1978;135:164; Seeman P, Synapse 1987:1:133
- 10. Normal subjects have 10% of dopamine receptors occupied at baseline Schizophrenic subjects have 20% of dopamine receptors occupied at baseline **from Michael D. Jibson, M.D., Ph.D., Ira D. Glick, M.D ASCP CURRICULUM edition 4 Laruelle M, Quart J Nuc Med 1998;42:211
- 11. 65% D2 receptor occupancy is required for efficacy 80% D2 receptor occupancy is correlated with EPS Shorter time of D2 receptor occupancy is correlated with lower EPS **from Michael D. Jibson, M.D., Ph.D., Ira D. Glick, M.D ASCP CURRICULUM edition 4 Kapur S & Remington G, Biol Psychiatry 2001;50:873
- 12. Atypical antipsychotics are high in serotonin activity Serotonin agonists (e.g., LSD) produce psychotic symptoms Dopaminergic activity is modulated by serotonin
- 13. Active psychosis ◦ most common reason for hospitalization ◦ most responsive to medications ◦ Hallucinations, delusions, paranoid, disorganization Negative symptoms ◦ poor response to medication ◦ progress most rapidly during early acute phases of illness ◦ alogia, poor grooming, flat affect, poor motivation
- 15. FDA indications; schizophrenia, schizoaffective d/o, bipolar disorder, irritability associated with autism, tourette’s OFF LABEL: PTSD, MR, ODD, ADHD, Personality disorders Hiccups, motion sickness, pruritus Delirium, aggression, agitation, anxiety *Many of the above uses are off label but accepted. Inform pt and family *
- 16. Dopamine receptor blocking in the brain (5 receptor subtypes with D1, D2, D3, D4 playing most significant role) 1. Full antagonist – most agents 2. Partial agonist – aripiprazole Serotonin receptor blocking in the brain (5HT2a, 1a, or 5HT2c appears to play a role) 1. Full antagonist – most atypical agents with different ratios 2. Partial agonist - aripiprazole **Other receptors: acetylcholine, histamine, NE, alpha receptors, and glutamate
- 17. Different meds work on a different combination of receptors In general, atypical agents work at D1, D2, D4, 5HT2a or 5HT2c, receptors as an antagonist or partial agonist (aripiprazole) Typical agents mostly work as D2 antagonists non-selectively
- 18. Reduce hallucinations Reduce delusions?? Probably not much. Reduce paranoia Calm patient and reduce agitation PRODUCE SIDE EFFECTS (e.g. sedation, weight gain, orthostatic hypotension, EPS, etc)
- 19. THE MEDS…
- 20. Typical agents=1st generation 1. Older 2. Cheaper 3. Work more on positive symptoms 4. Primarily D2 blockade and anticholinergic activity 5. High potency vs Medium vs Low potency
- 21. Possible Benefit Antipsychotic effect Possible Side Effects EPS dystonia parkinsonism akathisia tardive dyskinesia Endocrine changes: prolactin elevation galactorrhea gynecomastia menstrual changes sexual dysfunction
- 22. Parkinsonian effects – changes balance between cholinergic and dopaminergic neurons (dopamine blockade leads to excess of cholinergic influence) Tardive dyskinesia Akathisia/akinesia Orthostatic hypotension Constipation/Urinary retention Weight gain Confusion Sexual dysfunction Seizures NMS Metabolic problems (glucose, lipids)
- 23. Akinesia (lack of movement, Parkinson-like) Dystonic Reaction (muscle spasms of face, neck, back) Dyskinesia (Blinking or twitches) Akathisia (Inability to sit still)
- 24. Tardive Dyskinesia ◦ Hyperkinesia (lingual or facial) Blinking Lip smacking Sucking or chewing Rolls or protrudes tongue Grimaces ◦ Choreathetoid extremity movement Clonic jerking fingers, ankles, toes ◦ Tonic contractions of neck or back
- 25. Anticholinergic meds - benztropine, diphenhydramine for EPS Dopamine agonists – amantadine for EPS Beta-blockers - propranolol for akathisia Reduce the dose Change meds Stop the neuroleptic (NMS, ?TD) You don’t – use them to the patient’s benefit (e.g. sedation, weight gain)
- 26. Medical emergency ¼ cases culminate in coma, stupor, and death Unexplained hyperthermia with an increase in muscle tone Usually after med increase or initiation Elevated CK, elevated WBC, stiffness, fever, autonomic instability, confusion Treat with dantrolene, bromocryptine fluids, benzos, and maybe ECT Don’t rechallenge before 2 weeks
- 27. Phenothiazines 1. Aliphatic, e.g. chlorpromazine (thorazine) and trifluopromazine (vesprin). 2. Piperazine, e.g. perphenazine (trilafon), trifluoperazine (stelazine), fluphenazine (prolixin), acetophenazine (tindal) 3. Piperidine, e.g. thioridazine (mellaril), mesoridazine (serentil)
- 28. Thiothixenes 1. Thiothixene (Navane) 2. Chlorprothixene (Taractan)
- 29. Butyrophenones 1. Haloperidol (Haldol) Dihydroindolines 1. Molindone (Moban) Diphenylbutylpiperidines 1. Pimozide (Orap)
- 30. High Potency 1. Haldol (Haloperidol) 2. Prolixin (Fluphenazine) 3. Stelazine (Trifluoperazine) 4. Orap (Pimozide) 5. Navane (Thiothixene)
- 31. Medium Potency 1. Inapsine (Droperidol) 2. Loxitane (Loxapine) 3. Moban (Molindone) 4. Trilifon (Perphenazine)
- 32. Low Potency 1. Thorazine (Chlorpromazine) 2. Mellaril (Thioridazine) 3. Serentil (Mesoridizine)
- 33. MOST antipsychotics can prolong the Qtc interval of the heart (avoid if >500msec) MOST antipsychotics lower seizure threshold Typical antipsychotics – more problems with EPS, anticholinergic effect Atypical antipsychotics – more problems with metabolic side effects
- 34. Haloperidol – High potency (high D2 blockade, lower anticholinergic effects) Fluphenazine - High potency Thorazine – low potency (lower D2 blockade, higher anticholinergic effects) Thioridazine – low potency
- 35. Butyrophenone EPS common but sedation, hypotension not Comes in tabs, elixir, shot (IM or IV) Has depot form q4weeks High potency Most commonly used 1st generation antipsychotic
- 36. Piperazine Most potent High potential for EPS Has IM and IM 2 week depot shot Low potential for sedation
- 37. Sedating/low EPS risk Potential for severe hypotension (be very careful with IV use) Low potency Very anticholinergic Used for intractible hiccups
- 38. Piperidine Low potency – high anticholinergic activity High likelihood of QTc prolongation Associated with retinitis pigmentosa Not used clinically much
- 39. Atypical agents 1. Newer 2. More expensive 3. May work on both positive and negative symptoms 4. Lower incidence of EPS, TD, NMS 5. Act on D1, D2, D4, serotonin receptors (as well as NE, glutamate, histamine)
- 40. D2 antagonism ------------------------------------- Positive symptom efficacy, EPS, endocrine effects 5-HT2A antagonism ------------------------------- Negative symptom efficacy, reduced EPS High 5-HT2A/D2 affinity ratio ------------------ Antipsychotic efficacy, reduced EPS (compared to D2 antagonism alone) 5-HT1A agonism ----------------------------------- Antidepressant and anxiolytic activity, improved cognition, reduced EPS 5-HT1D antagonism ------------------------------- Antidepressant activity 5-HT2C antagonism ------------------------------- Antidepressant activity Mixed 5-HT/NE neuronal ---------------------- reuptake inhibition Antidepressant and anxiolytic activity 1 antagonism --------------------------------------- Postural hypotension H1 antagonism -------------------------------------- Sedation, weight gain M1 antagonism -------------------------------------- Anticholinergic side effects (eg, cognitive impairment)
- 41. Ziprasidone Risperidone Olanzapine Quetiapine Clozapine D2 ++++ ++++ ++ + + 5-HT2A +++++ +++++ ++++ + ++++ 5-HT2C +++++ ++++ ++++ – ++ 5-HT1A ++++ + – + + 5-HT1D* ++++ + + – – 1-adrenergic ++ ++++ ++ ++ ++++ M1-muscarinic – – ++++ ++ ++++ H1-histaminergic ++ ++ ++++ ++++ ++++ 5-HT/NE reuptake† ++ – – (-5-HT)(+NE) (-5-HT)(+NE) Affinity represented as: +++++ very high, ++++ high, ++ moderate, + low, – negligible. *Bovine binding affinity; †rat synaptosomes; all other affinities human.
- 42. Clozapine Risperidone Aripiperazole
- 43. Dibenzodiazepine class (CAT B) (D1, D2, D4, 5HT2 activity) Gold standard - more selective D blockade & serotonin activity Reserved for more refractory cases High metabolic risk Low EPS, may help TD Risk for seizures (dose dep), hypotension, weight gain, sialorrhea Risk of agranulocytosis is 1% Requires weekly WBC count – looking at WBC/ANC
- 44. D2 – blocker, 5 HT2a blocker Above 6mg - EPS more likely (acts more like haldol) Potential for weight gain, sedation, orthostatic hypotension, sexual dysfunction Comes in tabs, dissolvable tabs (mtab), elixir, LONG ACTING (Consta) Known to increase prolactin levels Metabolic risk
- 45. Partial agonist of dopamine and serotonin Usual effective dose is starting dose of 15mg High potential for akathisia Dosed in am with food Has IM form for acute agitation Little metabolic risk ? About efficacy or speed of action
- 46. Major active metabolite of risperidone FDA approved for schizophrenia OROS delivery system (like concerta) Works similarly to risperdal. Marketed as having less side effects?
- 47. Thienobenzodiazepine class (similar to clozaril) Very sedating and high likelihood of significant weight gain 10-100lbs Monitor lipids, glucose Comes in tab, dissolvable Zydis form, IM Very effective
- 48. Sedating, potential for orthostatic hypotension, and weight gain Very low EPS/TD risk Often used off label
- 49. Benzothiazolyl - piperazine class ?Potential for QTc prolongation but not necessary to do EKG if no h/o cardiac disease Low side effects/Take with food (will lower blood levels if you don’t). Food=400+calories Low doses you see activation, high doses you get dopamine blockade
- 50. Haloperidol (Haldol) decanoate Fluphenazine (Prolixin) decanoate Risperidone depot (Risperdal Consta)
- 51. Advantages ◦ Ensured compliance ◦ Lower total doses compared with oral medication may reduce side effects Disadvantages ◦ Poor patient acceptance ◦ Minimal flexibility in dosing
- 52. Christopher Pelic M.D. Associate Dean for Students Medical University of South Carolina
- 53. Some slides adapted from: David N. Osser, M.D. Harvard Medical School ASCP Model Curriculum December, 2007 Version
- 54. Introduction to anxiety Understand mechanism, effect, and side effects of barbiturates, benzodiazepines, buspirone, propranolol, hydroxyzine, and other antianxiety agents Learn basic agents for sleep disorders (e.g. zolpidem)
- 55. Anxiety – feeling of apprehension and fear 25% lifetime prevalence of any anxiety disorder (Nat. Co-morbidity Survey 1994) Many more have situational anxiety related to “normal” fears and use of medication for short term relief can be appealing. (Pomerantz JM, 2007)
- 56. Alcohol, bromide, and paraldehye preparations were initially used 1903 barbital was first barbiturate used but toxicity and dependency issues developed 1950 meprobamate was developed (non- barbiturate) but highly addicting
- 57. Late 1950’s Librium (chlordiazepoxide) – first benzodiazepine Few years later Valium (diazepam) was developed with 3-10 X potency Early 1960’s Imipramine (TCA) was found to be useful for panic disorder MAOIs began being looked at for anxiety SSRI and Buspirone used in late 80s and 90s
- 58. Due to stigmatization, patients often seek a quick, private remedy. Self-medication with alcohol and drugs of abuse is common, and reinforced by social acceptance – and even by psychiatric clinicians
- 59. Used early in 20th century for anxiety and sedative hypnotic Now rarely used as anticonvulsant and anesthetic Steep drug response curve – dangerous Induces liver enzymes (e.g. other drugs) Potential for dependence/withdrawal Withdrawal can be life threatening Work on GABAa receptor – Increases Cl- Phenobarbital, thiopental
- 60. Contraindicated in porphyria
- 61. Long acting Rarely but used as anticonvulsant Slow onset One of most used barbiturates Notorious inducer of other medications
- 63. Highly lipid soluble Rapid onset Short duration of action IV general anesthetic
- 64. Work on GABA a – specific benzo. site on this receptor Leads to hyper-polarization BZ1 receptor (w1) – sedation and hypnosis BZ1 receptor (w2) – cognition, motor functioning - Replaced barbiturates CLINICAL USES: anxiety, muscle relaxation, hypnosis, anticonvulsant, catatonia, preop, sleep
- 65. Long Acting Benzodiazepines ◦ Chlordiazepoxide (Librium) ◦ Diazepam (Valium,) ◦ Flurazepam (Dalmane) ◦ Chlorazepate (Tranxene) ◦ Clonazepam (Klonopin) ◦ Quazepam (Doral) ◦ Halezapam (Paxipam) Medium Acting Benzodiazepines ◦ Lorazepam (Ativan) ◦ Temazepam (Restoril) Short acting Benzodiazepines ◦ Oxazepam (Serax) ◦ Alprazolom (Xanax) ◦ Triazolam (Halcion) ◦ Estazolam (Prosom) ◦ Midazolam (Versed)
- 67. Action within limbic system Mainly used for short term Abuse/dependence potential Tolerance/withdrawal potential
- 68. Decreases sleep latency Use in caution with pts with COPD, OSA
- 69. Inhibition of polysynaptic transmission at spinal and suprasinal locations Diazepam used most often in this capacity for back spasms
- 70. Used in preventing or abolishing seizures Often used for status IM (lorazepam) or IV (diazepam) preferred
- 71. Used before procedures Facilitates anesthesia Conscious sedation Can produce anterograde amnesia
- 72. Lipid solubility Half life Short half life/High Lipid solubility=Good PRN but more addicting Long half life/Less Lipid solubility=less addicting and worse PRN
- 73. Long half life/highly lipid solubility Used for withdrawal Used for PRN anxiety Can accumulate secondary to redistribution Used IV for seizures Used for back/muscle spasms
- 74. Drug of choice for status epilepticus (IM) Highly lipid solubility but short half life Used PRN anxiety Used a lot for alcohol withdrawal
- 75. High potential for addiction High lipid solubility/short acting Requires frequent dosing Used mainly for PRN uses (e.g. panic attacks)
- 76. More selective anticonvulsant activity Used for longer term management of anxiety, mania, restless leg syndrome
- 77. Quick onset Mid acting benzodiazepine Used most for sleep
- 78. Used most perioperatively More rapid elimination Quick onset and more potent than diazepam
- 79. Benzodiazepine antagonist Used to reverse overdose or anesthesia Can precipitate seizures/acute withdrawal Rarely used
- 80. Glucuronidation: lorazepam oxazepam, temazepam, alprazolam, triazolam (used in pts with liver disease) Nitroreduction: clonazepam Demethylation and oxidation: diazepam, chlordiazepoxide, chlorazepate
- 81. Cytochrome inhibitors: metoprolol, propranolol, disulfiram, omeprazole, erythromycin, fluoxetine. Anticholinergics: additive cognitive impairment especially in the elderly Additive CNS depression with other sedatives Clozapine added to ongoing BZ may rarely give severe sedation, delirium, respiratory depression/death
- 82. oxazepam (Serax) 15 mg diazepam (Valium) 5 mg lorazepam (Ativan) 1 mg alprazolam (Xanax) 0.5 mg clonazepam (Klonopin) 0.25 mg
- 83. Anxiety Agitation Tremulousness Insomnia Dizziness Headaches Seizures Exacerbation of psychosis
- 84. Dependence, addiction, abuse – by far most common in alcoholics and other drug abusers Elderly – watch for increased fall risk with long half-life drugs Memory impairment Impaired motor coordination, auto driving in simulated driving tests Disinhibition/violence – more uncommon than presumed Depression
- 85. Pregnancy risk “D” level due to oral cleft, except clonazepam C Most recent studies show they are fairly safe but old studies suggested cleft palate
- 86. 5HT1a partial agonist No sedating, muscle-relaxant, sexual, or anticonvulsant effects No abuse potential Used mainly for generalized anxiety disorder Does not suppress respiration so is useful for anxiety in COPD patients No impairment of cognition or motor coordination
- 87. Has some efficacy in depression at 40 mg/d (STAR*D) Side effects: headache, insomnia, jitteriness, and nausea.
- 88. Propranolol 30 minutes prior to the event. Try test doses before Side effects: hypotension, bradycardia, dizziness, asthma, fatigue. Evidence contradicts idea that betablockers mask hypoglycemia symptoms. (Chalon, 1999) Half-life 3-6 hours Lipophilic so crosses into brain Not useful for social phobia, generalized type
- 89. Anticonvulsants e.g. gabapentin, valproate, lamotrigine, topiramate Pregabalin (Lyrica) – got “non-approvable” letter from FDA in 2004 for GAD but approved in Europe in 2006. Tiagabine (Gabatril)– didn’t separate from placebo in unpublished studies. MAOIs Antihistamines e.g. hydroxyzine, diphenhydramine Prazosin and terazosin (Alpha-1 antagonists)
- 90. Benzos Non-benzo – benzos Ramelteon Antihistamines
- 91. Chemically unrelated to benzodiazepines Zolpidem - Works on BZ1 receptor Eszopiclone – works on GABA a receptor Used for insomnia Intended for short term use or PRN
- 92. Works as “melatonin” for sleep Does not work immediately