Presentation on theme: "Psychopharmacology - Antipsychotic drugs"— Presentation transcript:
1Psychopharmacology - Antipsychotic drugs Dr. Subhash Gupta
2The objectives of this session 1. To understand the mechanisms of action of antipsychotic drugs used in psychiatric practice2. To understand therapeutic indications of antipsychotic drugs and their effectiveness3. To understand factors influencing drug tolerability and adverse effects
3Dopaminergic dysregulation is a core neurotransmitter abnormality in schizophrenia although other neurotransmitters are also thought to be involvedDopamineGlutamateAcetylcholineSerotoninNorepinephrine-Aminobutyric acid (GABA)Neuropeptides (eg, cholecystokinin)Others?Goff et al. Med Clin North Am. 2001;85:663.Crismon and Dorson. Pharmcotherapy: a pathophysiologic approach
4Neurotransmitters and Neuromodulators Monoamines DopamineDopamine:A neurotransmitter; one of the catecholamine.Implicated roles in movement, attention, learning, reinforcing effects of abused drugs.Synthesized from tyrosine that we obtain from our diet.
5Neurotransmitters and Neuromodulators Monoamines DopamineL-Dopa:The levorotatory form of DOPA; the precursor of the catecholamines; often used to treat Parkinson’s disease because of its as a dopamine agonist.
6Neurotransmitters and Neuromodulators Monoamines DopamineNigrostriatal system:A system of neurons originating in the substantia nigra and terminating in the neostriatum (caudate nucleus and putamen of the basal ganglia); appears to play a role in the control of movement.
7Neurotransmitters and Neuromodulators Monoamines DopamineMesolimbic system:A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus; appears to play a role in the reinforcing effects of drugs that are commonly abused.
8Neurotransmitters and Neuromodulators Monoamines DopamineMesocortical system:A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex; appears to influence formation of short-term memories, planning, and preparing strategies for problem solving.
10Neurotransmitters and Neuromodulators Monoamines DopamineParkinson’s Disease:A neurological disease characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements; caused by degeneration of the nigrostriatal system; Parkinson’s disease has been treated with L-DOPA.
11Neurotransmitters and Neuromodulators Monoamines DopamineMonoamine oxidase (MAO):A class of enzymes that destroy the monoamines; dopamine, norepinephrine, and serotonin.
12Neurotransmitters and Neuromodulators Cocaine and AmphetamineDopamine agonistsCocaine blocks DA transportersAmphetamine increase DA release and reverses transporter
19What is atypical?Unlike typical antipsychotics (neuroleptics), atypical antipsychotics decreased amphetamine induced hyperactivity in rats in doses that did not produce catalepsy (immobility).Classically, an antipsychotic is said to be atypical when it improves both positive and negative symptoms of schizophrenia but:Produces minimal or no EPSCauses minimal or no sustained prolactin elevationMany researchers have proposed greater efficacy in treating negative symptoms, mood changes and cognitive deficits, giving rise to broader definitions of atypicality.
20ClassEfficacyEPSProlactin1st generation (HPL, CPZ)Limited to positive symptomsHighElevating2nd generation (risperidone)Both positive and negative symptomsDose dependent3rd generation (clozapine, olanzapine, quetiapine)Broad spectrum (both positive and negative symptoms + mood and cognition effects)LowSparing
21Why they are atypical? Serotonin – Dopamine Hypothesis Fast-off D2 hypothesis – Low affinity and fast dissociation from D2 receptorsDopamine D4 hypothesisIn this presentation I will be covering …5 important receptors implicated in schizophreniaRefreshing our minds of the 4 dopamine pathways implicated in schizophreniaThen a brief mention about the close relationship between dopamine and serotoninFinally will put the basic science covered into a clinical context by looking at 1st, 2nd and 3rd generation antipsychotics
22Serotonin–Dopamine Hypothesis Greater affinity and antagonism at serotonin 5HT2 receptors than at D2 receptorsSo, the name Serotonin – Dopamine Antagonists (SDA) was coined.
23Contradictions to Serotonin Dopamine Hypothesis Typical antipsychotics such as loxapine and chlorpromazine show equally high 5HT2A occupancy.Amisulpride is an effective atypical antipsychotic drugs but doesn’t have 5HT2A affinity.
24Other Dopamine theories ‘Limbic Specific’Extent of D2 blockade:Antipsychotic action occurs at a D2-receptor occupancy rate of 60–70%, whereas a D2 occupancy rate greater than 80% is believed to increase the risk of EPSs without increasing efficacy.Usual doses of typical antipsychotics occupy 70–90% of D2- receptors.Clozapine, the prototypic atypical agent, occupies only 38–63% of D2-receptors at usual dosages.Olanzapine and risperidone may lose their “atypicality” at higher dosages because of increased binding affinity for D2-receptors
25Fast-off D2 hypothesisAtypical antipsychotics are loosely and transiently bound to and rapidly released from D2 receptor. They continually go on and off D2 receptors, allowing extensive access of endogenous dopamine to these receptors.Clozapine and quetiapine are most loosely bound and rapidly dissociated. This explains efficacy in controlling psychosis without worsening of motor symptoms in parkinsonismQuetiapine (Seroquel): Most atypical?
27Dopamine D4 hypothesisThis concept gained popularity based on 2 findings:Clozapine's greater D4Vs D2 affinityElevated D4 receptors in brains of schizophrenic patients.But, not applicable to other atypical antipsychotics
28Dopamine System stabilisers Prescribing information available on last slide
30Side Effects of atypicals Weight gainDyslipidemiaIncreased glucose levelsMetabolic syndromeRisk of strokeEPS, prolactin related side effects
31ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS approxPlease divide into two groups. The left hand side of the room (your left) will be Group One and right hand side of the room will be GroupTwo.Look at both clinical scenarios. I will invite each group to feedback in turn
32ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS Scenario OneA 16 year old boy has an 18 month history of self neglect, socialwithdrawal and has been very suspicious of his friends. He hascomplained of depressed mood. Two weeks ago his G.P. sent himfor urgent psychiatric assessment. He was given chlorpromazine100mg t.d.s by the doctor he saw. He has been re-referred after aserious episode of self harm (neck laceration) and complains offeeling more depressed and agitated.Discuss the appropriateness of his medication.Would you change this and if so why?
33ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS Scenario TwoA 56 year old man has a 6 month history of hearing voices in the3rd person. He has previously seen one of your colleagues andhas come for review. He complains of excessive drowsiness anddizziness and impaired short-term memory. He has gained 10kgand is more thirsty. His symptoms have been hard to control. Henow takes a range of medication (see next slide).Can his complaints be explained in terms of his current treatment?Would you wish to revise his regime and if so how?
34ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS Scenario TwoPropranolol 80mg daily*Olanzapine 35mg daily*Risperidone 12mg daily*Procyclidine 15mg daily*Lorazepam 2mg PRN 6 hourlyTemazepam 20mg nocte*All the above are in divided doses