Pharmacology of Antipsychotics Dr Andrew P Mallon

Douglas L. Geenens, D.O. 2000

Dopamine Hypothesis Drugs that increase dopamine will enhance or produce positive psychotic symptoms E.G. Cocaine, amphetamine Douglas L. Geenens, D.O. 2000

Dopamine Hypothesis All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors Esp..D-2 receptors Douglas L. Geenens, D.O. 2000

Dopamine Pathways Mesolimbic Nigrostriatal Mesocortical Tuberoinfundibular Douglas L. Geenens, D.O. 2000

Dopamine Pathways Mesolimbic Projects from brainstem to limbic areas. Overactivity produces delusions and hallucinations. Douglas L. Geenens, D.O. 2000

Dopamine Pathways Nigrostriatal Projects from the substania nigra to the basal ganglia A part of the extrapyramidal system Thus side effects are called “extrapyramidal” Douglas L. Geenens, D.O. 2000

Dopamine Pathways Nigrostriatal Controls movements The term “neuroleptics” refers to: Antipsychotics ability to “quiet the neurological system” To their neurological side effects Douglas L. Geenens, D.O. 2000

Dopamine Pathways Nigrostriatal Types of movement disorders caused by this pathway include: Akathisia Dystonia Tremor, rigidity, bradykinesia Drug-induced Parkinsonism Douglas L. Geenens, D.O. 2000

Dopamine Pathways Nigrostriatal Chronic blockade can cause Potentially irreversible movement disorder “Tardive Dyskinesia” Role is undetermined Douglas L. Geenens, D.O. 2000

Dopamine Pathways Mesocortical May be associated with both positive and negative symptoms Blockade may help reduce negative symptoms of schizophrenia May be involved in the cognitive side effects of antipsychotics “mind dulling” Douglas L. Geenens, D.O. 2000

Dopamine Pathways Tuberoinfundibular Blockade produces galactorrhea Dopamine=PIF Douglas L. Geenens, D.O. 2000

Dopamine Pathways Summary Four dopamine pathways Appears that blocking dopamine receptors in only one of them is useful Blocking dopamine receptors in the other three may be harmful Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

Antipsychotics Phenothiazines (piperidines) Phenothiazines (Aliphatic) Mesoridazine Serentil Thioridazine Mellaril Phenothiazines (Aliphatic) Chlorpromazine Thorazine Douglas L. Geenens, D.O. 2000

Antipsychotics Phenothiazines (piperazines) Perphenazine Trilafon Trifluoperazine Stelazine Fluphenazine Prolixin Douglas L. Geenens, D.O. 2000

Antipsychotics Thioxanthenes Dibenzazepines Navane Clozapine Ioxapine Clozaril Ioxapine Loxitane Douglas L. Geenens, D.O. 2000

Antipsychotics Butyrophenones Diphenylbutylpiperidines Haloperidol Haldol Diphenylbutylpiperidines Pimozide Orap Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

Antipsychotics Indoles Rauwolfia Molindone Reserpine Moban Serpasil Douglas L. Geenens, D.O. 2000

Antipsychotics Benzisoxazole Thienobenzodiazepines Risperidone Risperdal Thienobenzodiazepines Olanzapine Zyprexa Douglas L. Geenens, D.O. 2000

Antipsychotics Efficacy All antipsychotics are considered equally effective Rationale for determining which medication to use is based on side effect profile Primary mechanism of action is Postsynaptic blockade of the D-2 receptor “D-2, me too” Douglas L. Geenens, D.O. 2000

Antipsychotics Efficacy Newer agents e.g. Clozaril Have significant activity at the D-1 receptor; Risperdal and Zyprexa have significant 5-HT2 activity Douglas L. Geenens, D.O. 2000

Antipsychotics Potency Potency is an important variable in terms of pharmacodynamic properties of these medicines. Potency determines the predictable side effects of the antipsychotics. Douglas L. Geenens, D.O. 2000

Antipsychotics Potency Low potency medications cause more: sedation Anti-ACH Orthostatic hypotension High potency medications cause more: EPS Douglas L. Geenens, D.O. 2000

Dopaminergic D2 Blockade Possible Clinical Consequences Extrapyramidal movement disorders Endocrine changes Sexual dysfunction Douglas L. Geenens, D.O. 2000

Antipsychotics Relative potencies (mg equivalents) Douglas L. Geenens, D.O. 2000

Histamine H1 Blockade Possible Clinical Consequences Sedation, drowsiness Weight gain Hypotension Douglas L. Geenens, D.O. 2000

Antipsychotics Potency for H-1 blockade Douglas L. Geenens, D.O. 2000

Alpha-1 receptor blockade Possible clinical consequences Postural hypotension Reflex tachycardia Dizziness Douglas L. Geenens, D.O. 2000

Antipsychotics Potency for alpha-1 blockade Douglas L. Geenens, D.O. 2000

Muscarinic receptor blockade Possible clinical consequences Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction Douglas L. Geenens, D.O. 2000

Antipsychotics Potency for muscarinic blockade Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

Clozaril Clozapine “Atypical” antipsychotic More effective in person’s who fail typical antipsychotic therapy At least nine different receptor affinities Douglas L. Geenens, D.O. 2000

Clozaril Clozapine One of the most complicated medications in psychopharmacology Can cause death via agranulocytosis Cost is typically $10,000.00 per year Douglas L. Geenens, D.O. 2000

Extrapyramidal Symptoms Dopamine Vs Acetylcholine Dopamine and Acetylcholine have a reciprocal relationship in the Nigrostriatal pathway. A delicate balance allows for normal movement. Douglas L. Geenens, D.O. 2000

Extrapyramidal Symptoms Dopamine Vs Acetylcholine Dopamine blockade: A relative increase in cholinergic activity causing EPS Those antipsychotics that have significant anti-ACH activity are therefore less likely to cause EPS Douglas L. Geenens, D.O. 2000

Extrapyramidal Symptoms Dopamine Vs Acetylcholine When high potency antipsychotics are chosen, we often prescribe anti-ACH medication like Cogentin, diphenhydramine, or Artane Douglas L. Geenens, D.O. 2000

Tardive Dyskinesia Associated with long-term use of antipsychotics (chronic dopamine blockade) Potentially irreversible involuntary movements around the buccal-lingual-oral area Douglas L. Geenens, D.O. 2000

Tardive Dyskinesia Attempt of decrease dose will initially exacerbate the movements Increasing the dose will initially decrease the movements Douglas L. Geenens, D.O. 2000

Neurological Side Effects: Dystonic Reactions: Uncoordinated spastic movements of muscle groups Trunk, tongue, face Akinesia: Decreased muscular movements Rigidity: Coarse muscular movement Loss of facial expression Douglas L. Geenens, D.O. 2000

Neurological Side Effects: Tremors: Fine movement (shaking) of the extremities Akathisia: Restlessness Pacing May result in insomnia Tardive Dyskinesia: Buccolinguo-masticalory syndrome Choreoathetoid movements Douglas L. Geenens, D.O. 2000

Neurological Side Effects of Neuroleptics Douglas L. Geenens, D.O. 2000

Neurological Effects Neurological Effects Tardive Dyskinesia Onset   Neurological Effects Tardive Dyskinesia Onset Acute or insidious Within 1 – 30 days After months or years of treatment, especially if drug dose decreased or discontinued Proposed Mechanism Due to decreased dopamine Supersensitivity of postsynaptic dopamine receptors induced by long term neuroleptic blockade Treatment Respond to antiparkinsonian drugs Generally worsen Tardive Dyskinesia Other treatments unsatisfactory; some aimed at balancing Dopaminergic and cholinergic systems. Can mask symptoms by further suppressing dopamine with neuroleptics. Pimozide or loxapine may least aggravate Tardive Dyskinesia.

Extrapyramidal Effects Type Onset Risk Group Clinical Course Treatment Dystonias Acute (within 5 days) Young male Acute, painful, spasmodic Oculogyria may be recurrent I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used Akathisia Insidious to acute (within 10 days) 12-45% on neuroleptics May continue though out treatment Pseudoparkinsonism Insidious to acute (within 30 days) May continue through treatment Oral antiparkinsonian drug. Reduce or change neuroleptic

Neuroleptic Malignant Syndrome An idiosyncratic, life-threatening illness associated with antipsychotic therapy Clinical manifestations include hyperpyrexia autonomic instability, “board-like” rigidity Douglas L. Geenens, D.O. 2000

Neuroleptic Malignant Syndrome Resembles malignant hyperthermia associated with anesthesia Treatment involves Immediate discontinuation of antipsychotic Hydration Maintain vital functions Prescribe bromocriptine and dantrolene Douglas L. Geenens, D.O. 2000

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