DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 5:
Psychoses and Antipsychotic Agents Marc Imhotep Cray, M.D.
Learning Objectives:
CNS Pharmacology Lecture 5
1. The four well-defined dopamine systems in the brain as they relate to antipsychotic drug action and side effects. 2. The distinction between “typical” and “atypical” antipsychotics. 3. The difference in the mechanism(s) of action between a typical antipsychotic, an atypical anti-psychotic and the partial agonist aripiprazole. 4. The common and rare side effects associated with the use of both low potency and high potency typical antipsychotics 5. The common and rare side effects associated with the use of the second-generation atypical anti-psychotics.
Marc Imhotep Cray, M.D.
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Classification Schema: Antipsychotic Agents FIRST-GENERATION ANTIPSYCHOTIC (low potency) Chlorpromazine THORAZINE Prochlorperazine COMPAZINE Triflupromazine Thioridazine FIRST-GENERATION ANTIPSYCHOTIC (high potency) Fluphenazine PROLIXIN Haloperidol HALDOL Pimozide ORAP Thiothixene NAVANE (also called “typical” antipsychotics) Marc Imhotep Cray, M.D.
CNS Pharmacology Lecture 5
SECOND-GENERATION ANTIPSYCHOTIC Aripiprazole ABILIFY Asenapine SAPHRIS Clozapine CLOZARIL Lurasidone LATUDA Olanzapine ZYPREXA Quetiapine SEROQUEL Paliperidone INVEGA Risperidone RISPERDAL (also called “atypical” antipsychotics)
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CNS Pharmacology Lecture 5
Antipsychotic classification (2) Typical antipsychotic drugs are often sub-classified according to their oral milligram potency (high potency or low potency) High-potency drugs (piperazine phenothiazines, e.g., fluphenazine, and haloperidol) are more likely to produce extrapyramidal reactions Low-potency drugs (aliphatic phenothiazines, e.g., triflupromazine; piperidine phenothiazines, e.g., thioridazine) are less likely to produce acute extrapyramidal reactions and more likely to produce sedation and postural hypotension Atypical antipsychotic agents (e.g., risperidone, olanzapine) have generally replaced typical drugs for initial treatment of first-episode patients Clozapine is reserved for treatment-resistant patients Marc Imhotep Cray, M.D.
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Overview of antipsychotic drugs:
CNS Pharmacology Lecture 5
Antipsychotic drugs (also called neuroleptics or major tranquilizers) are used primarily to treat schizophrenia, but are also effective in other psychotic and manic states Use involves a difficult trade-off between benefit of alleviating psychotic symptoms and risk of a wide variety of troubling adverse effects Antipsychotic drugs are not curative and do not eliminate chronic thought disorders, but they often decrease intensity of hallucinations and delusions and permit person with schizophrenia to function in a supportive environment
Marc Imhotep Cray, M.D.
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Schizophrenia
CNS Pharmacology Lecture 5
Schizophrenia is a type of chronic psychosis characterized by delusions, hallucinations (often in form of voices), and thinking or speech disturbances Onset of illness is often during late adolescence or early adulthood It occurs in about 1% of population and is a chronic and disabling disorder aged 15–45 years, with a greater proportion being male
Has a strong genetic component and probably reflects some fundamental biochemical abnormality, possibly a dysfunction of mesolimbic or mesocortical dopaminergic neuronal pathways Marc Imhotep Cray, M.D.
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Symptoms and signs of schizophrenia:
CNS Pharmacology Lecture 5
Symptoms fall into two groups (positive and negative) that may have different underlying causes Positive symptoms include: Delusions – false personal beliefs held with absolute conviction Hallucinations – false perceptions in the absence of a real external stimulus; most commonly, these are auditory (hearing voices) and occur in 60–70% of schizophrenics, but they can be visual, tactile or olfactory Thought alienation and disordered thought – belief that one’s thoughts are under the control of an outside agency (e.g. aliens, government etc.) o This type of belief is common, and thought processes are often incomprehensible Marc Imhotep Cray, M.D.
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Symptoms and signs of (2)
CNS Pharmacology Lecture 5
Negative symptoms include: Poverty of speech – restriction in the amount of spontaneous speech Flattening of affect – loss of normal experience and expression of emotion Social withdrawal Anhedonia – inability to experience pleasure Apathy – reduced drive, energy, and interest Attention deficit – inattentiveness at work or on interview N.B-The distinction between the positive and negative symptoms is of importance as “first generation” neuroleptic drugs tend to have most effect on positive symptoms, whereas negative symptoms are fairly refractory to treatment and carry a worse prognosis. “Second generation” drugs have been shown to improve negative symptoms. Marc Imhotep Cray, M.D.
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Schizophrenia (2)
CNS Pharmacology Lecture 5
This patient exhibits the flat affect that is common to schizophrenia She appears to be responding to internal stimuli-perhaps attending to auditory hallucinations Alternatively, she may have significant negative symptoms including anhedonia, amotivation, and poverty of speech Finally, she may have parkinsonism secondary to anti-psychotic medication Marc Imhotep Cray, M.D.
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Neural Pathways Involved in Schizophrenia
CNS Pharmacology Lecture 5
 The therapeutic action of typical antipsychotic drugs not certain, but is correlated best with antagonist activity at postjunctional dopamine (DA) D2-receptors in mesolimbic and mesocortical areas of the CNS where DA normally inhibits adenylyl cyclase activity Marc Imhotep Cray, M.D.
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Classes of dopamine receptor: Type
2nd messenger + cellular effects
Location in CNS and postulated function
D1
cAMP increase
Mainly postsynaptic inhibition Functions unclear
D2
cAMP decrease K conductance up Ca conductance down
Mainly presynaptic inhibition of dopamine synthesis/release in nigrostriatal, mesolimbic and tuberoinfundibular systems Affinity of neuroleptics for D2 receptors correlates with antipsychotic potency
D3
Unknown
Localized mainly in limbic and cortical structures concerned with cognitive functions and emotional behavior Not clear whether antipsychotic effects of neuroleptics are mediated by the D3 type
D4
Marc Imhotep Cray, M.D.
CNS Pharmacology Lecture 5
Similar to D3 type; clozapine has particular affinity for D4 receptors
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CNS Pharmacology Lecture 5
Psychosis and Dopamine Pathways Research in dopamine, 5-HT, and Glu neurotransmitters led to most early drugs’ targeting the dopamine system, primarily as dopamine D2 receptor antagonists Typical antipsychotics (e.g., chlorpromazine, haloperidol) are better for treating positive signs than negative signs For treating negative signs, the newer (atypical) antipsychotic drugs (e.g., clozapine, risperidone) target other receptors, particularly 5-HT Neurologic (e.g., dystonia, parkinsonism), anticholinergic (e.g., blurred vision), and antiadrenergic (e.g., hypotension) adverse effects can occur Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 5
Antipsychotic Drugs (Neuroleptics) Antipsychotics are divided into first-generation (typical) and secondgeneration (atypical) agents First-generation drugs are further classified as “low potency” or “high potency” Classification does not indicate clinical effectiveness of drugs, but rather specifies affinity for dopamine D2 receptor, which, in turn, may influence the adverse effect profile of the drug
Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 5
Antipsychotic Drugs (2) Typical antipsychotics block D2-dopamine receptors in limbic system, which probably accounts for therapeutic effects of these drugs in reducing the symptoms of psychoses, hallucinations, and delusions BLOCKADE AT OTHER SITES LEADS TO SIDE EFFECTS: Blockade of D2 receptors in extrapyramidal system (basal ganglia) induces iatrogenic parkinsonism This complication can be reduced by anticholinergic drugs, such as benztropine (Cogentin) o This restores dopamine–acetylcholine balance L-Dopa should not be used to treat antipsychotic-induced extrapyramidal symptoms (Why?) Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 5
Antipsychotic Drugs (3) Blockade of D2 receptors in the pituitary enhances the release of prolactin, which induces galactorrhea and gynecomastia Blockade of histamine receptors often leads to sedation, but these drugs have little abuse potential and display no tolerance Blockade of M-cholinoceptors leads to anticholinergic symptoms Blockade of α-adrenoceptors induces hypotension and tachycardia>>arrhythmias Serotonin (5-HT) receptors are also blocked by newer atypical drugs Effect on hypothalamus shifts body temperature toward ambient temperature (poikilothermia)
Marc Imhotep Cray, M.D.
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Dopamine-blocking actions of antipsychotic drugs.
Marc Imhotep Cray, M.D.
Relative affinity of clozapine, chlorpromazine, and haloperidol at D1 and D2 dopaminergic receptors.
Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015
CNS Pharmacology Lecture 5
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Antipsychotic Drugs (5)
CNS Pharmacology Lecture 5
Antipsychotic drugs block at dopaminergic and serotonergic receptors as well as at adrenergic, cholinergic, and histamine binding receptors
Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015
Marc Imhotep Cray, M.D.
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Effect of D2 dopamine receptor blockade on dopaminergic pathways in brain
CNS Pharmacology Lecture 5
Modified from: Battista E. Crash Course Pharmacology 4e. 2012
Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 5
Typical drugs: Phenothiazines include: Chlorpromazine (Thorazine) and thioridazine (Mellaril), which are low potency phenothiazines Fluphenazine (Prolixin) which is a high-potency phenothiazine Thiothixene (Navane), pimozide (Orap), and haloperidol are also high potency antipsychotics
Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 5
Side effects of typical antipsychotics: Side effects of typical antipsychotics are related to their potency High-potency typical antipsychotics induce most extrapyramidal symptoms Low-potency typical antipsychotics induce fewer extrapyramidal symptoms, but they induce more anticholinergic effects, more hypotension, and more sedation than high-potency typical antipsychotics Evolution of EPS side effects: TI is very large • 4 hr acute dystonia (muscle At high doses, convulsions can rarely occur spasm, stiffness, oculogyric crisis) Weight gain • 4 day akathisia (restlessness) • 4 wk bradykinesia (parkinsonism) • 4 mo tardive dyskinesia
Marc Imhotep Cray, M.D.
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CNS Pharmacology Lecture 5
Side effects of typical antipsychotics (2) Tardive dyskinesia is a major complication that can develop after long-term administration of typical antipsychotics Following months or years treatment Orofacial symptoms predominate in adults
D2 blocker should be stopped, but structural changes occur and may be irreversible An atypical antipsychotic (e.g. aripiprazole) may help alleviate symptoms and should help maintain control of the schizophrenia Anticholinergics do not reduce tardive dyskinesia They aggravate symptoms
One proposed theory is that tardive dyskinesia is due to an upregulation of D2-receptors in basal ganglia possible increased sensitivity of presynaptic dopamine receptors) Marc Imhotep Cray, M.D.
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Atypical drugs:
CNS Pharmacology Lecture 5
Risperidone (Risperdal) is a newer antipsychotic with 5HT2 receptor-blocking activity and fewer extrapyramidal symptoms than the typical antipsychotics increase prolactin (causing lactation and gynecomastia) Dibenzodiazepines such as clozapine and olanzapine have a low affinity for D2 receptor and a higher affinity for D1 and D4 receptors Clozapine (Clozaril) also blocks 5HT2-receptors as well as D-receptors It induces the fewest extrapyramidal symptoms Is effective in some patients that are refractory to other antipsychotics Can cause agranulocytosis; WBC counts must be monitored Olanzapine (Zyprexa) is similar to clozapine but does not cause agranulocytosis However, it leads to metabolic syndrome, type 2 diabetes, and hyperlipidemia Weight gain is more significant with atypicals (Olanzapine/clozapine) Marc Imhotep Cray, M.D.
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Idiosyncratic reaction & pharmacokinetics: Toxicity: Neuroleptic malignant syndrome (NMS) is a rare but severe idiosyncratic reaction to antipsychotic medication (20% mortality rate) Syndrome is characterized by autonomic instability, muscle rigidity, diaphoresis, profound hyperthermia, and myoglobinuria Tx-antipsychotic should be discontinued and supportive care given along with bromocriptine to overcome DA receptor blockade, muscle relaxants such as diazepam or dantrolene to reduce muscle rigidity Pharmacokinetics: These drugs are very long acting Binding to many tissues results in a large Vd Many drug metabolites due to extensive metabolism in liver Marc Imhotep Cray, M.D.
CNS Pharmacology Lecture 5
For NMS, think FEVER: Fever Encephalopathy Vitals unstable Enzymes increase Rigidity of muscles
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Other Uses of Antipsychotic Drugs:
CNS Pharmacology Lecture 5
Manic phase in bipolar disorder Schizoaffective disorders Atypical psychotic disorders Depression with psychotic manifestations Tourette syndrome (haloperidol, pimozide [Orap] or risperidone) Severe nausea or vomiting associated with, e.g., radiation treatment and cancer chemotherapy, as well as postoperative nausea and vomiting With the exception of thioridazine, typical antipsychotic agents have strong antiemetic activity due to DA D2-receptor blockade in chemoreceptor trigger zone (CTZ) of medulla o most commonly used are phenothiazines prochlorperazine and promethazine (both are void of antipsychotic activity) Marc Imhotep Cray, M.D.
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THE END
Marc Imhotep Cray, M.D.
CNS Pharmacology Lecture 5
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Further study (SDL):
CNS Pharmacology Lecture 5
MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: Meltzer H. Ch. 29 Antipsychotic Agents & Lithium In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 501-13 Online resource center: Medical Pharmacology Cloud Folder
Lectures/discussions to follow: 6. Drugs Affecting Movement Disorders and Other Neurodegenerative Disorders 7. Analgesics 8. Anesthetics
Marc Imhotep Cray, M.D.
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