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)