Antipsychotics

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

Psychotic Disorders

Schizophrenia Manic phase of bipolar (manic-

depressive) illness Senile Psychosis Drug induced psychosis Post surgical delirium Amphetamine intoxication Acute idiopathic psychotic illness

Schizophrenia Characterized by delusions, hallucinations

(hearing voices), thinking and speech disturbances

Often affected during adolescence Strong genetic component Characterized by 2 components;

breakdown of personalityloss of contact with reality

Considered neurodevelopmental disorder possibly overactivity of mesolimbic

dopaminergic neurons

Schizophrenia Etiology Dopamine Hypothesis

no longer considered to cover all aspects of schizophrenia

Important in understanding pos./neg. symptoms

Serotonin Hypothesis5-HT stimulation responsible for hallucinationsAtypical antipsychotics – MOA

Glutamate HypothesisHypofunction of NMDAr - decreased GABAergic

inhibitory activity

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)

Mechanism of Action of Antipsychotics

○ 5 DA receptors (D1-D5)D1 like – D1 and D5 activate adenyl cyclaseD2 like – D2, D3 and D4 inhibit adenyl cyclase involved in psychotic disordersBlockade 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 amphetamineThe Atypical antipsychotics, Clozapine has a high

affinity for the D4 receptor (low EPS)

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

Douglas L. Geenens, D.O. 2000

Dopamine Pathways

Nigrostriatal

Mesocortical / Mesolimbic

Tuberoinfundibular

Medullary-Periventricular

Incertohypothalamic

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

Major Dopamine Pathways

Nigrostriatal pathway•Part of extrapyramidal system,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 tardive dyskinesia

Tuberoinfundibular pathway•Increased neuronal activity of this pathway inhibits prolactin

release

•Blockade of D2 receptor increases prolactin release and causes:

-- galactorrhea

-- amenorrhea

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

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

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

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

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 Tardive dyskinesia Fluphenazine (Prolixin) Perphenazine (Trilafon) Trifluperazine (Stelazine)

Pharmacological Action of Phenothiazine

Basal Ganglia – blockade of D1 or D2 results in EPSCardiovascular – depressed by antipsychotics –

hypotensionChemoreceptor trigger zone (CTZ) - These

receptors are blocked by phenothiazines (anti-emetic action).

Hypothalmus - stimulate release of prolactinMisc. – no physical dependence, decrease seizure

thresholdAutonomic effects – anticholinergic action

(piperidines – strongest, piperizines – weakest)α – adrenergic antagonist - hypotension

Side Effects of Phenothiazines

Orthostatic hypotension – due to α- blockade, dose/effect response

Extrapyramidal Syndrome – increased cholinergic activity (Piperazine – highest, Piperidines – lowest)Parkinson-like SyndromeAkathesia – uncontrollable restlessness, distress, anxietyTardive Dyskinesia – 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)

Therapeutic use of Phenothiazines

Tx psychotic disordersSchizophrenia, 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

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

Thioxanthenes• very specific for D2 receptor

• very low affinity for 5-HT receptor

• very potent

• intermediate EPS

• sedative action and hypotension

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.

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)

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.

Atypical Antipsychotics

Clozapine (Clozaril)

Risperidone (Risperdal

, Quetiapine (Seroquel)

Olanzapine (Zyprexa)

Ziprasidone (Geodon)

Aripiprazole (Abilify)

Atypical Antipsychotics Admin PO QD or BID

Low or no EPS

5-HTr antagonist 5-HT2A receptor

No effect on prolactin Exception (Compared to clozapine and quetiapine)

Increase prolactin release, low risk of tardive dyskinesia

Control both positive and neg. symptoms

Atypical Antipsychotics

Low or no EPS

5-HT2A antagonist

Control both positive and neg. symptoms

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

Summary of Antipsychotics

Atypical antipsychotics can be distinguished from the classsic neuroleptics 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.

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

Treatment of Mania Lithium - Closely related to Na+ and K+ in

generating AP

MOA involves interference of second messengers inositol triphosphatase (IP3)

and diacylglycerol (DAG)neurotransission mechanisms.

○ Important in α-adrenergic and muscarinic transmission

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

Adverse Effects of Lithium

Tremors Propranolol and atenolol alleviate lithium induced tremors

Decreased thryoid function (reversible) Nephrogenic Diabetes Insipidus

Resistant to vasopressin – treated w/ Amiloridepts. should avoid dehydration

Edema Related to Na+ retention

PregnancyIncreased renal clearance during, and lowered

postpartum

Other Antimanic Mood-Stabilizing agents

Valproic Acid Shows efficacy equivalent to LithiumEffective in pts not responding to LithiumMay be used in combinationS/E – GI distress weight gain and alopecia

CarbamazepineOxcarbazepine not effectiveMay be used prophylactic therapyMay be used w/ Lithium but not Valproic

Acid