Pharmacology of Antipsychotics Douglas L. Geenens, D.O. University Of Health Sciences College of Osteopathic Medicine Downloaded from

Dopamine Hypothesis Drugs that increase dopamine will enhance or produce positive psychotic symptoms –E.G. Cocaine, amphetamine

Downloaded from All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors –Esp..D-2 receptors Dopamine Hypothesis

Downloaded from Dopamine Pathways Mesolimbic Nigrostriatal Mesocortical Tuberoinfundibular

Downloaded from Dopamine Pathways Mesolimbic Projects from brainstem to limbic areas. Overactivity produces delusions and hallucinations.

Downloaded from Dopamine Pathways Nigrostriatal Projects from the substania nigra to the basal ganglia –A part of the extrapyramidal system –Thus side effects are called “extrapyramidal”

Downloaded from Dopamine Pathways Nigrostriatal Controls movements The term “neuroleptics” refers to: –Antipsychotics ability to “quiet the neurological system” – To their neurological side effects

Downloaded from Dopamine Pathways Nigrostriatal Types of movement disorders caused by this pathway include: –Akathisia –Dystonia –Tremor, rigidity, bradykinesia Drug-induced Parkinsonism

Downloaded from Dopamine Pathways Nigrostriatal Chronic blockade can cause –Potentially irreversible movement disorder “ Tardive Dyskinesia” Role is undetermined

Downloaded from 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”

Downloaded from Dopamine Pathways Tuberoinfundibular Blockade produces galactorrhea Dopamine=PIF

Downloaded from 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

Downloaded from

Antipsychotics Phenothiazines (piperidines) –Mesoridazine Serentil –Thioridazine Mellaril Phenothiazines (Aliphatic) –Chlorpromazine Thorazine

Downloaded from Antipsychotics Phenothiazines (piperazines) Perphenazine –Trilafon Trifluoperazine –Stelazine Fluphenazine –Prolixin

Downloaded from Antipsychotics Thioxanthenes –Navane Dibenzazepines –Clozapine Clozaril –Ioxapine Loxitane

Downloaded from Antipsychotics Butyrophenones –Haloperidol Haldol Diphenylbutylpiperidines –Pimozide Orap

Downloaded from

Antipsychotics Indoles –Molindone Moban Rauwolfia –Reserpine Serpasil

Downloaded from Antipsychotics Benzisoxazole –Risperidone Risperdal Thienobenzodiazepines –Olanzapine Zyprexa

Downloaded from 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”

Downloaded from Antipsychotics Efficacy Newer agents –e.g. Clozaril –Have significant activity at the D-1 receptor; –Risperdal and Zyprexa have significant 5- HT2 activity

Downloaded from Antipsychotics Potency Potency is an important variable in terms of pharmacodynamic properties of these medicines. Potency determines the predictable side effects of the antipsychotics.

Downloaded from Antipsychotics Potency Low potency medications cause more: –sedation –Anti-ACH –Orthostatic hypotension High potency medications cause more: –EPS

Downloaded from Dopaminergic D2 Blockade Possible Clinical Consequences Extrapyramidal movement disorders Endocrine changes Sexual dysfunction

Downloaded from Antipsychotics Relative potencies (mg equivalents)

Downloaded from Histamine H1 Blockade Possible Clinical Consequences Sedation, drowsiness Weight gain Hypotension

Downloaded from Antipsychotics Potency for H-1 blockade

Downloaded from Alpha-1 receptor blockade Possible clinical consequences Postural hypotension Reflex tachycardia Dizziness

Downloaded from Antipsychotics Potency for alpha-1 blockade

Downloaded from Muscarinic receptor blockade Possible clinical consequences Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction

Downloaded from Antipsychotics Potency for muscarinic blockade

Downloaded from

Clozaril Clozapine “Atypical” antipsychotic More effective in person’s who fail typical antipsychotic therapy At least nine different receptor affinities

Downloaded from Clozaril Clozapine One of the most complicated medications in psychopharmacology Can cause death via agranulocytosis Cost is typically $10, per year

Downloaded from Extrapyramidal Symptoms Dopamine Vs Acetylcholine Dopamine and Acetylcholine have a reciprocal relationship in the Nigrostriatal pathway. A delicate balance allows for normal movement.

Downloaded from 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

Downloaded from Extrapyramidal Symptoms Dopamine Vs Acetylcholine When high potency antipsychotics are chosen, we often prescribe anti-ACH medication like –Cogentin, diphenhydramine, or Artane

Downloaded from Tardive Dyskinesia Associated with long-term use of antipsychotics –(chronic dopamine blockade) Potentially irreversible involuntary movements around the buccal-lingual- oral area

Downloaded from Tardive Dyskinesia Attempt of decrease dose –will initially exacerbate the movements Increasing the dose will initially decrease the movements

Downloaded from 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

Downloaded from Neurological Side Effects: Tremors: –Fine movement (shaking) of the extremities Akathisia: –Restlessness –Pacing May result in insomnia Tardive Dyskinesia: –Buccolinguo-masticalory syndrome –Choreoathetoid movements

Downloaded from Neurological Side Effects of Neuroleptics

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. Downloaded from

Extrapyramidal Effects TypeOnsetRisk Group Clinical Course Treatment DystoniasAcute (within 5 days) Young maleAcute, painful, spasmodic Oculogyria may be recurrent I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used AkathisiaInsidious to acute (within 10 days) 12-45% on neuroleptics May continue though out treatment I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used PseudoparkinsonismInsidious to acute (within 30 days) 12-45% on neuroleptics May continue through treatment Oral antiparkinsonian drug. Reduce or change neuroleptic Downloaded from

Neuroleptic Malignant Syndrome An idiosyncratic, life-threatening illness associated with antipsychotic therapy Clinical manifestations include –hyperpyrexia –autonomic instability, –“board-like” rigidity

Downloaded from Neuroleptic Malignant Syndrome Resembles malignant hyperthermia associated with anesthesia Treatment involves –Immediate discontinuation of antipsychotic –Hydration –Maintain vital functions –Prescribe bromocriptine and dantrolene

Downloaded from