Pharmacology of Schizophrenia

Typical Antipsychotic Drugs MOA o The behavioral effects and time-course of the antipsychotic response correlates with the D2 receptor blockade includes:

Calming of the psychomotor agitation Decreased hostility Decreased social isolation Hallucinations

o Chlorpromazine Uses ___ ___ ___ ___

Psychosis Mania Intractable hiccups Nausea

o While distinction between typical and atypical antipsychotics are not clearly defined, their pharmacological profiles depend on:

Receptor activity profile Incidence of extrapyramidal side effects (less in atypical group) Efficacy in 'treatment-resistant' group of patients Efficacy against negative symptoms

Risperidone Uses ___,___

Schizophrenia Mood disorders

Aripiprazole Uses ___, __,__

Schizophrenia Tourette's disorder Mood disorders

Haloperidol: ___ ___ ___

-Psychosis -Tourette's disorder (characterized by tics - repetitive involuntary movement or vocalization) -Short-term treatment of hyperactivity in children refractory to psychotherapy other medications

Extrapyramidal symptoms (EPS): Acute dystonia (spasms of muscles of the tongue, face, neck and back): ____ Akathisia (inability to remain seated due to motor restlessness): ___ Parkinsonism (bradykinesia, rigidity and tremor): ___

1-5 days 5-60 days 5-30 days

Pathophysiology o Incidence: Affects individuals in the teen to early ___ Occurs in the ___ proportion of males and females About 4.75 million individuals have this disease in the U.S. 100,000 to 150,000 new cases are diagnosed annually both ___ and environmental factors may account for the disease

20's same genetic

Aripiprazole o Partial agonist at D2 and ___receptors o A ____ antagonist o Active ___ o Metabolized by ___ and ___

5-HT1A 5-HT2A orally CYP2D6 3A4

o ____ actions: some antipsychotic drugs such as chlorpromazine and thioridazine can block muscarinic receptors

Anticholinergic

o _____ actions: due to the blockade of D2-receptors in the chemoreceptor trigger zone of the medulla

Antiemetic

Second-generation (atypical antipsychotics) o ______

Aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone

Although these drugs are approved for the treatment of schizophrenia, they have also been employed in the therapy of psychosis associated with Parkinson's disease and dementia

Atypical Antipsychotic Drugs

Pharmacokinetics: o Metabolism is by the liver: Chlorpromazine: metabolized by ___; also an ___ Haloperidol: metabolized by multiple CYP pathways, especially ___. ___. ___

CYP2D6 inducer 2D6, 3A4, and 1A2

a-adrenergic receptor ____

Chlorpromazine

Clozapine - High affinity for ____ receptors

D1

Quetiapine: binds to ____

D1, D2, 5-HT1, 5-HT2, 1, 2, H1

Olanzapine: binds to ___

D1-D4, 5-HT2, 1, H1, M

Clozapine: binds to ____

D1-D5, 5-HT2, 1, H1, M

Typical Antipsychotic Drugs MOA o Blockade of ___ receptors in the limbic system which are important in mediating the positive symptoms of the disease o Data from imaging studies suggest that the therapeutic effects requires about ___ occupancy of D2 receptors

D2 80%

Ziprasidone: binds to ___

D2, 5-HT1, 5-HT2, 1, H1

Risperidone o Binds to _______-receptors o Active _____ o Metabolized by ___

D2, 5-HT2, a1, a2 and H1 orally or parenterally CYP2D6

Side effects o Extrapyramidal symptoms (EPS): due to alteration of the balance between inhibitory action of ___ and the excitatory effects of ___in the striatum. The appearance of EPS is time and dose-dependent:

DA Ach

o ____ effects: dystonia (sustained muscle contraction), Parkinson-like symptoms, akathisia (moto restlessness) and tardive dyskinesia (involuntary movement of the tongue, lips, neck and trunk) are associated with chronic therapy

Extrapyramidal

Schizophrenia Pharmacology o ___-generation or typical antipsychotic drugs are also referred to as neuroleptics. The term neuroleptic is associated with the neurological action of these drugs that are displayed as extrapyramidal side effects (due to blockade of DA receptors in the basal ganglia)

First

Dopamine Receptor All, but particularly

Haloperidol Fluphenazine Thiothixene

_____ system: neurons originate in the ventral tegmental area and project to regions of the cerebral cortex (especially the prefrontal cortex)

Mesocortical

Neuronal pathways of DA: _____ system: neurons originate in the ventral tegmental area and projects to the nucleus accumbens in the ventral striatum, parts of the amygdala and hippocampus and other parts of the limbic system

Mesolimbic

o ____ syndrome: resembles a severe form of parkinsonism, with signs of: Autonomic instability (hyperthermia, unstable blood pressure and respiratory rate) Muscle rigidity Myoglobinemia

Neuroleptic malignant

Serotonin Receptors __.___

Risperidone Clozapine

o ____: characterized by involuntary, repetitive body movements: Quick choreiform (tic-like) movement of the face, eyelids (blinks or spasm), mouth (grimaces) Tongue sticking out Rapid jerking movements or slow writhing movements • Hypothesized to be due to an ____ in DA receptor supersensitivity and ____ as a compensatory mechanism to prolonged D2-receptor blockade

Tardive dyskinesia increased, upregulation

Cholinergic Muscarinic receptors ___,___

Thioridazine Chlorpromazine

Other actions: Orthostatic hypotension (due to blockade of ______ ) ____ (a condition in which body temperature varies with the environment) due to an effect on temperature regulating mechanisms in the hypothalamus Sedation (due to blockade of_____ ____ (blockade of the pituitary actions of the tuberoinfundibular dopaminergic neuron that delivers DA to the anterior pituitary)

a-adrenoceptors Poikilothermia Histamine H1-receptors) Hyperprolactinemia

Haloperidol: CNS depression potentiated with ___ and other depressants May be potentiated by CYP3A4 ___/substrates (e.g., venlafaxine, buspirone, alprazolam) May be antagonized by CYP3A4 ____ (e.g. rifampin, carbamazepine) May increase intraocular pressure with ___

alcohol inhibitors inducers anticholinergics

Risperidone Drug Interaction May potentiate ___ May antagonize____, dopamine agonists May be potentiated by ___ and ranitidine

anti-hypertensives levodopa cimetidine

Aripiprazole drug interaction Potentiates ___ Levels reduced by CYP3A4 ___ (e.g. ____) Levels may be increased by CYP3A$ ___ (e.g. ___) Levels may be increased with CYP2D6 inhibitors (e.g. ______)

anti-hypertensives inducers carbamazepine inhibitors ketoconazole quinidine, fluoxetine

o Binding of these drugs to D2 receptors in the _____(nigrostriatal pathway) and ___ accounts for most of their observed adverse effects

basal ganglia pituitary gland

First generation (typical antipsychotics) o Low potency: ___,____

chlorpromazine thioridazine

Mesolimbic system • Involved in the development of ___ and ___ • ____ of this system is hypothesized to account for the positive symptoms of schizophrenia

emotion memory Hyperactivity

o Both therapeutic efficacy and the ____ side effects of these drugs correlate directly with their affinity for D2 receptors

extrapyramidal

First generation (typical antipsychotics) o High potency: __________ (8)

fluphenazine, haloperidol, loxapine, perphenazine, pimozide, prochlorperazine, thiothixene, trifluroperazine

Aripiprazole o Side effects CNS: headache, anxiety, ___, somnolence, sedation, dizziness, restlessness, EPS, ___ dyskinesia, neuroleptic malignant syndrome CVS: ____ GI: nausea, vomiting, ___, salivary hypersecretion Metabolic: hyperglycemia, dyslipidemia ____ gain

insomnia tardive orthostatic hypotension constipation Weight

Atypical Antipsychotic Drugs MOA o These drugs tend to have a ___ affinity for D2-receptors

low

Mesocortical system • Involved in ____ behavior, ___ and ___ • Hypothesized to be responsible for the ___ symptoms of schizophrenia

motivated attention planning negative

o These drugs are less effective against the ____ symptoms of the disease which correlate with hypo-activity of the mesocortical neurons

negative

Atypical Antipsychotic Drugs o These drugs are more effective than typical antipsychotic drugs in treating the ____ symptoms of schizophrenia o These drugs produce ___ extrapyramidal symptoms than typical antipsychotics o These drugs have a much higher incidence of metabolic side effects such as _____, ___,___

negative milder diabetes, hypercholesterolemia and weight gain

Pathophysiology o A particular type of psychosis (a mental illness characterized by a distorted ____

nonexistent sense of reality

Efficacy against negative symptoms Typical Antipsychotic Drugs • Two most prominent classes are:

o Phenothiazines: chlorpromazine o Butyrophenones: haloperidol

Pharmacokinetics: o Active ___ o Prone to ____ metabolism o Exhibit ___ degree of binding to plasma proteins

orally and parenterally (IM) high first-pass high

Others: Sedation, ____(due to blockade 1-receptors) ___ and galactorrhea in women and ____ and impotence in men (due to blockade of DA receptors in the pituitary gland) ____ effects (dry mouth, constipation and difficulty in urination)

orthostatic hypotension Amenorrhea gynecomastia Anticholinergic

Risperidone Side effects CNS: headache, _____, dizziness, fatigue, ____, agitation, depression, anxiety, tardive dyskinesia, neuroleptic malignant syndrome CVS: ____, blood disorders GI: dry mouth, ___ Metabolic: hyperprolactinemia ___, priapism

parkinsonism sedation orthostatic hypotension constipation Weight gain

Pathophysiology o Patients may display disorders of ____

perception, thinking, speech, emotion and/or physical activity

Drug interactions: o Chlorpromazine: Potentiates ____, alcohol and other CNS depressants Potentiated by ___ Antagonized by ___

phenytoin propranolol anticholinergics

Pharmacological actions: o Antipsychotic: reduction of the hallucinations and delusions associated with schizophrenia (___ symptoms)

positive

Atypical Antipsychotic Drugs • These drugs include _____

risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole, asenapine, paliperidone, lurisadone and iloperidone

o _____ -generation antipsychotic drugs that are also referred to as atypical antipsychotics owe their pharmacological actions largely to the blockade of serotonin and DA receptors

second

Negative symptoms: involve the reduction or loss of normal functions such as:

• Affective flattening (decrease in the range or intensity of emotional expression) • Alogia (decrease in the fluency of speech) • Avolition (decrease in the initiation of goal-directed behavior)

Schizophrenia can be divided into two broad categories: Positive symptoms: involve the developmental of abnormal function such as:

• Delusions (distorted or false beliefs and misinterpretation of perceptions) • Hallucinations (especially auditory) • Disorganized speech • Catatonic behavior (muscular rigidity and lack of response to environment)