Antipsychotics

1. Antipsychotics

2. Psychosis • a state in which a person’s mental capacity to recognize reality, communicate, and relate to others is impaired • delusions, hallucinations (auditory, visual, tactile, olfactory), grossly disorganized thinking in a sensible manner • thus interfering with the capacity to deal with life’s normal everyday demands

3. Psychotic Disorders • Schizophrenia • Manic phase of bipolar (manic-depressive) illness • Senile Psychosis • Drug induced psychosis • Post surgical delirium • Amphetamine intoxication • Acute idiopathic psychotic illness

4. Schizophrenia • Characterized by delusions, hallucinations (hearing voices), thinking and speech disturbances • Often affected during adolescence • Strong genetic component • Characterized by 2 components; • breakdown of personality • loss of contact with reality • Considered neurodevelopmental disorder • possibly overactivity of mesolimbicdopaminergic neurons

5. Schizophrenia Etiology • Dopamine Hypothesis • no longer considered to cover all aspects of schizophrenia • Important in understanding pos./neg. symptoms • Serotonin Hypothesis • 5-HT stimulation responsible for hallucinations • Atypical antipsychotics – MOA • Glutamate Hypothesis • Hypofunction of NMDAr - decreased GABAergic inhibitory activity

6. Manic Phase of Bipolar Disorder • two phases that cycle back and forth -- mania and depression. • cyclic attacks of mania induce paranoid schizophrenia (grandiosity, bellicosity, paranoia, and overactivity)

7. Mechanism of Action of Antipsychotics • 5 DA receptors (D1-D5) • D1 like – D1 and D5 activate adenylcyclase • D2 like – D2, D3 and D4 inhibit adenylcyclase • involved in psychotic disorders • Blockade of D2 receptor is antipsychotic action • Efficacy of the typical neuroleptic drugs correlate to their ability to block D2 receptors in the mesolimbic system. (high EPS) • Antagonized by levodopa and amphetamine • The Atypical antipsychotics, Clozapine has a high affinity for the D4 receptor (low EPS)

8. Dopaminergic Systems • Until 1959, DA was not recognized as a NT in CNS, but a precursor to NE. • Neurons that secrete dopamine are primarily located in three discreet regions of the brain

9. Dopamine Pathways • Nigrostriatal • Mesocortical / Mesolimbic • Tuberoinfundibular • Medullary-Periventricular • Incertohypothalamic Douglas L. Geenens, D.O. 2000

11. Major Dopamine Pathways Mesolimbic pathway •Hyperactivity on this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway •Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia

12. Major Dopamine Pathways Nigrostriatal pathway •Part of extrapyramidalsystem,controls motor movement •Blockade of D2 receptors causes: -- deficiency in dopamine in this pathway and thus movement disorder such as Parkinson’s disease -- hyperkinetic movement such as tardivedyskinesia Tuberoinfundibular pathway •Increased neuronal activity of this pathway inhibits prolactin release •Blockade of D2 receptor increases prolactin release and causes: -- galactorrhea -- amenorrhea

13. Antipsychotic Actions • positive symptoms reduced by typical neuroleptics • Negative symptoms not as responsive to typical, but respond to atypical. • All have a calming effect, reduce spontaneous physical movement. • Onset of action of Antipsychotic – 2 weeks

14. Positive and Negative Symptoms of Schizophrenia • Positive symptoms - symptoms that most individuals do not normally experience but are “added” in schizophrenia. • Negative symptoms - symptoms that reflect the loss or absence of normal traits or abilities (motivation). feelings that are "taken away" such as motivation

15. Antipsychotics • Referred to as antischizophrenic, antipsychotic or major tranquilizers • Typical (neurolelptics) properties due to dopamine receptor antagonism • first generation, 1950’s, D2 • High EPS • Atypical properties due to Serotonin and DA receptor antagonism • Second generation • Not curative, does not eliminate thinking disorder, but allow patient to function in supportive environment

16. Antipsychotics • Reserpine and chlorpromazine were first drugs used for schizophrenia/psychosis • Typical antipsychotics are divided into 5 major classifications based on structure. Side chains have significant effect on potencies • Typical (neuroleptics) • 1. Phenothiazines - Chlorpromazine (Thorazine) • 2. Butyrophenones – Haloperidol (Haldol) • 3. Thioxanthenes – Thiothixene (Navane) • 4. Dibenzoxazepines – Loxapine (Loxapac) • Atypical • Clozapine (Clozaril), Risperidone (Risperdal), Quetiapine (Seroquel), Olanzapine (Zyprexa), Ziprasidone (Geodon) • Aripiprazole (Abilify) • Proper management of psychotic disorder can be determined by familiarity of side effects of drugs in each class

17. Phenothiazine( Typical Antipsychotics) • 1.Aliphatic – least potent, intermediate, EPS, intermediate anticholinergic action, high sedative action • Chlorpromazine (Thorazine) • 2. Piperidine – least potent, lower incidence of EPS, high incidence of anticholinergic action • Thioridazine (Mellaril) • 3. Piperazine – most potent, selective and effective, increased incidence of Tardivedyskinesia • Fluphenazine (Prolixin) • Perphenazine (Trilafon) • Trifluperazine (Stelazine)

18. Pharmacological Action of Phenothiazine • Basal Ganglia – blockade of D1 or D2 results in EPS • Cardiovascular – depressed by antipsychotics – hypotension • Chemoreceptor trigger zone (CTZ) - These receptors are blocked by phenothiazines (anti-emetic action). • Hypothalmus - stimulate release of prolactin • Misc. – no physical dependence, decrease seizure threshold • Autonomic effects – anticholinergic action (piperidines – strongest, piperizines – weakest) • α – adrenergic antagonist - hypotension

19. Side Effects of Phenothiazines • Orthostatic hypotension – due to α- blockade, dose/effect response • Extrapyramidal Syndrome – increased cholinergic activity (Piperazine – highest, Piperidines – lowest) • Parkinson-like Syndrome • Akathesia – uncontrollable restlessness, distress, anxiety • TardiveDyskinesia– develops late in antipsychotic therapy, usually at high doses x 6 months, rhythmic motions of head, face and shoulders, may be irreversible • Do not use DA or Levo-Dopa, use diphenhydramine (Benadryl), benztropine (Cogentin) or trihexephenidyl (Artane)

20. Therapeutic use of Phenothiazines • Tx psychotic disorders • Schizophrenia, senile dementia, extreme paranoia, manic phase of manic depressive syndrome • Anti-emetics – radiation toxicity, anticancer meds, opioids, gastroenteritis • Phenothiazines • Control positive symptoms – Hallucinations, delusions, hostility, hyperactivity • Not negative symptoms – social withdrawal, lack of expression, decrease in speech patterns

21. Butyrophenone • Haloperidol (Haldol) • alleviates positive symptoms • manic phase of bipolar disorder • severe EPS, < α - adrenergic blockade • < sedation than phenothiazines • Used in Huntington’s Chorea, Tourette’s Syndrome

22. Thioxanthenes • very specific for D2 receptor • very low affinity for 5-HT receptor • very potent • intermediate EPS • sedative action and hypotension

23. Atypical Antipsychotics • In the last decade new "atypical" antipsychotics have been introduced • More effective, less side effects • appear to be equally effective for helping reduce the positive symptoms like hallucinations and delusions • but may be better than the older medications at relieving the negative symptoms of the illness, such as withdrawal, thinking problems, and lack of energy.

24. Mechanism of Action of Atypical Antipsychotics • Blockade of DA2 (weak) and / or 5-HT receptors. Many also block cholinergic, adrenergic, and histamine receptors – variety of side effects (low D2) • DA receptor antagonism in brain (typical and atypical antipsychotics) • Neuroleptics are antagonized by agents that increase DA concentration (L-dopa and amphetamines) • Serotonin receptor antagonism in brain (atypical)

25. NEUROBIOLOGY OF CLOZAPINE Here you can see that Clozapine will not bind to any Dopamine receptor, it is selective, it has an affinity for the D4 receptor subtype.

26. Atypical Antipsychotics • Clozapine (Clozaril) • Risperidone (Risperdal • , Quetiapine (Seroquel) • Olanzapine (Zyprexa) • Ziprasidone(Geodon) • Aripiprazole (Abilify)

27. Atypical Antipsychotics • Admin PO QD or BID • Low or no EPS • 5-HTr antagonist • 5-HT2Areceptor • No effect on prolactin • Exception (Compared to clozapine and quetiapine) Increase prolactin release, low risk of tardivedyskinesia • Control both positive and neg. symptoms

28. Atypical Antipsychotics • Low or no EPS • 5-HT2A antagonist • Control both positive and neg. symptoms

29. Atypical Antipsychotics(second generation) • Clozapine (prototype) • little to no EPS, high incidence of agranulocytosis (regular CBC’s), high incidence of siezures, blood dyscrasia, weight gain • Olanzapine (Zyprexa) • sedation, weight gain, no agranulocytosis, low incidence of siezures • Quetiapine (Seroquel) • sedation, low incidence of all side effects

30. Summary of Antipsychotics • Atypical antipsychotics can be distinguished from the classsicneuroleptics by three main characteristics; • Less likely to induce EPS • More effective against negative symptoms of schizophrenia • Able to effectively treat patients unresponsive to classic neuroleptics.

31. Treatment of Bipolar Disorder • Manic Phase • many symptoms of paranoid schizophrenia (grandiosity, excitement, impulsivity, disinhibition, aggression, diminished need for sleep, paranoid thoughts and overactivity) • Decrease in activity of DA and NE relieve mania • Depressive Phase • Similar to major depression, depressed mood, sleep disturbance, anxiety, and sometimes psychotic symptoms • Mixed manic and depressive symptoms are sometimes seen, high risk of suicide • Strong genetic component, no effect on normal individuals

32. Treatment of Mania • Lithium - Closely related to Na+ and K+ in generating AP • MOA involves interference of • second messengers inositoltriphosphatase (IP3) and diacylglycerol (DAG) • neurotransissionmechanisms. • Important in α-adrenergic and muscarinic transmission

33. Lithium Drug Interactions • Diuretics - renal clearance is reduced by 25%, dose may need to be reduced. • Same w/ some anti-inflammatory drugs that block prostaglandin synthesis. • Neuroleptics (typical) – produce more EPS when combined w/ Lithium

34. Adverse Effects of Lithium • Tremors • Propranolol and atenolol alleviate lithium induced tremors • Decreased thryoid function (reversible) • Nephrogenic Diabetes Insipidus • Resistant to vasopressin – treated w/ Amiloride • pts. should avoid dehydration • Edema • Related to Na+ retention • Pregnancy • Increased renal clearance during, and lowered postpartum

35. Other Antimanic Mood-Stabilizing agents • Valproic Acid • Shows efficacy equivalent to Lithium • Effective in pts not responding to Lithium • May be used in combination • S/E – GI distress weight gain and alopecia • Carbamazepine • Oxcarbazepine not effective • May be used prophylactic therapy • May be used w/ Lithium but not Valproic Acid