Antipsychotics

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  • Why do you care? The issue is that everybody wants to get rid of positive symptoms. For a long time, that was what the conventional antipsychotics did, and that was enough. But if positive symptoms go away, we don't cure patients -- they don't go back to work, and they're not in remission -- so that's not enough. You can even get rid of some aggressive symptoms with just D2 blockade. What the addition of serotonin 2A antagonism did was not to interfere with that property.
  • Which Receptor Properties of Second-Generation Atypical Antipsychotics Are "Class" Actions? Which receptor properties of the so-called "second-generation" drugs (which I just showed) are class actions? The answer is that they are all serotonin 2A and D2 dopamine antagonists. They all substantially block D2 receptors at therapeutic doses. If you don't dose them right, then they don't work. But, if you dose them right, they work right. What's wrong with the brain is that it's out of tune. It is not quite clear whether the neurotransmitters are too high and some pathways are too low -- that's kind of an old fashioned way of looking at it -- but they're basically not correct and need to be tuned. This is why you have to titrate the dose of the drug to the patient in order to get the right amount of action at that particular person's receptor sites. From what we can tell, if you don't block a substantial number of their D2 receptors -- however you do it -- patients don't benefit much. We found that all of these drugs have comparable or even greater functional blockade of the other receptor, called the serotonin 2A receptor, if you do it enough.
  • These problems are not just with typical drugs.
  • The atypical antipsychotics started with clozapine, and then went to the 5 first-line drugs -- risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. They all have this property; there is no known antipsychotic that doesn't dance on a dopamine (D)2 receptor. Some of them dance and go away fast, called rapid dissociation or "hit and run," and some of them are partial agonists; but, every effective antipsychotic has some D2 action -- even the old drugs. What's new about the new drugs is this 5-hydroxytryptamine 2A receptor (5HT2A) action. They're all, in some ways, dancing upon the serotonin 2A receptor -- that makes them different as a class.
  • What's So Great About Serotonin 2A Antagonism? What's so great about it is that -- at least in the pathway that's thought to moderate and mediate the delusions, hallucinations, and thought disorders (the positive symptoms) -- this serotonin 2A property doesn't confound that. Every study seems to suggest that they're just as good for positive symptoms. So there may not be an advantage here. Part of a good pharmacologist's repertoire is to understand that the mesolimbic system is where we think the positive symptoms live. What really made these drugs different was their ability to block a little of the dopamine actions in the nigrostriatal pathway. When you block enough receptors in the striatum, you get parkinsonism; if you just pull back from the edge a couple of percentages, you don't. These new drugs were able to reduce enough D2 binding so that they became quite clearly special -- and were coined, by Dr. Meltzer, "atypical antipsychotics." What does that mean? Some people would say his original definition was that it's a drug that has positive symptom reduction without extrapyramidal symptoms (EPS). Others would say other things, but the issue is that they don't have the EPS for every pound of antipsychotic action. We've learned more; being on the market now for several years, we found that there's a third pathway. In the cortex, this serotonin 2A property increases dopamine release -- yes, I said increases. Now wait, I thought it decreased dopamine in the mesolimbic area. It does, but it actually causes a lot of dopamine release in the cortex. Wouldn't that be self-defeating? The answer is no -- because God didn't put D2 receptors in very big concentrations in the front of the brain. So if the receptor is not there, you can't block it. If you increase dopamine in the cortex, the D2 property is moot because you want to stimulate D1 receptors. What is very interesting about this is that you do not interfere with the dopamine blockade in the mesolimbic area. You interfere just a little bit with it in the striatum, so you don't get EPS. And then you overwhelm the cortex with so much dopamine that it actually stimulates D1 receptors in the brain at the same time. Can you imagine if they had actually tried to do that on purpose? It was an accident, but we're sure glad.
  • What's So Great About Serotonin 2A Antagonism? What's so great about it is that -- at least in the pathway that's thought to moderate and mediate the delusions, hallucinations, and thought disorders (the positive symptoms) -- this serotonin 2A property doesn't confound that. Every study seems to suggest that they're just as good for positive symptoms. So there may not be an advantage here. Part of a good pharmacologist's repertoire is to understand that the mesolimbic system is where we think the positive symptoms live. What really made these drugs different was their ability to block a little of the dopamine actions in the nigrostriatal pathway. When you block enough receptors in the striatum, you get parkinsonism; if you just pull back from the edge a couple of percentages, you don't. These new drugs were able to reduce enough D2 binding so that they became quite clearly special -- and were coined, by Dr. Meltzer, "atypical antipsychotics." What does that mean? Some people would say his original definition was that it's a drug that has positive symptom reduction without extrapyramidal symptoms (EPS). Others would say other things, but the issue is that they don't have the EPS for every pound of antipsychotic action. We've learned more; being on the market now for several years, we found that there's a third pathway. In the cortex, this serotonin 2A property increases dopamine release -- yes, I said increases. Now wait, I thought it decreased dopamine in the mesolimbic area. It does, but it actually causes a lot of dopamine release in the cortex. Wouldn't that be self-defeating? The answer is no -- because God didn't put D2 receptors in very big concentrations in the front of the brain. So if the receptor is not there, you can't block it. If you increase dopamine in the cortex, the D2 property is moot because you want to stimulate D1 receptors. What is very interesting about this is that you do not interfere with the dopamine blockade in the mesolimbic area. You interfere just a little bit with it in the striatum, so you don't get EPS. And then you overwhelm the cortex with so much dopamine that it actually stimulates D1 receptors in the brain at the same time. Can you imagine if they had actually tried to do that on purpose? It was an accident, but we're sure glad.
  • What's So Great About Serotonin 2A Antagonism? What's so great about it is that -- at least in the pathway that's thought to moderate and mediate the delusions, hallucinations, and thought disorders (the positive symptoms) -- this serotonin 2A property doesn't confound that. Every study seems to suggest that they're just as good for positive symptoms. So there may not be an advantage here. Part of a good pharmacologist's repertoire is to understand that the mesolimbic system is where we think the positive symptoms live. What really made these drugs different was their ability to block a little of the dopamine actions in the nigrostriatal pathway. When you block enough receptors in the striatum, you get parkinsonism; if you just pull back from the edge a couple of percentages, you don't. These new drugs were able to reduce enough D2 binding so that they became quite clearly special -- and were coined, by Dr. Meltzer, "atypical antipsychotics." What does that mean? Some people would say his original definition was that it's a drug that has positive symptom reduction without extrapyramidal symptoms (EPS). Others would say other things, but the issue is that they don't have the EPS for every pound of antipsychotic action. We've learned more; being on the market now for several years, we found that there's a third pathway. In the cortex, this serotonin 2A property increases dopamine release -- yes, I said increases. Now wait, I thought it decreased dopamine in the mesolimbic area. It does, but it actually causes a lot of dopamine release in the cortex. Wouldn't that be self-defeating? The answer is no -- because God didn't put D2 receptors in very big concentrations in the front of the brain. So if the receptor is not there, you can't block it. If you increase dopamine in the cortex, the D2 property is moot because you want to stimulate D1 receptors. What is very interesting about this is that you do not interfere with the dopamine blockade in the mesolimbic area. You interfere just a little bit with it in the striatum, so you don't get EPS. And then you overwhelm the cortex with so much dopamine that it actually stimulates D1 receptors in the brain at the same time. Can you imagine if they had actually tried to do that on purpose? It was an accident, but we're sure glad.
  • Antipsychotics

    1. 1. PSYCHOPHARMACOLOGY
    2. 2. DOPAMINE RECEPTORS
    3. 3. OUTLINE•Functions of Dopamine•Dopamine ReceptorsTypes•Regulation of Dopamine
    4. 4. Roles of Dopamine•Role in movement•Role in pleasure andmotivation•Controls the flow ofinformation from otherareas of the brain
    5. 5. Dopamine Receptors•There are five types of dopamine receptors.D1,D2,D3,D4,D5.•We can categorize dopamine receptors in two main subtypes:•D1 like receptor family: the Gs protein is involved and adenylylcyclase would be activated. The action of the enzyme causes theconversion of adenosine triphosphate to cyclic adenosinemonophosphate (cAMP).•D2 like receptor family: which is the receptor combining with theGi protein and its activated alpha-subunit then inhibits adenylylcyclase so that the concentration of cAMP is reduced.
    6. 6. Effectors Pathways Associated with G-Protein-Coupled DOPA MINE Efficacy Receptors D1-D5 • PN08060.JPG D2-D3-D4 Dr. Mejía 2004Ziprasidone binds with high affinity to D2 receptors (Ki=3.1nM), (Ki=7.2 nM) to the D3, moderateaffinity (Ki=32 nM) to D4,Low affinity (Ki=130 nM) to the D1 and D5
    7. 7. Dopamine Receptors•Five subtypes of dopamine receptor have been cloned.TheD1 andD5 receptors are closely related, and couple toGsAlpha and stimulate adenylylcyclase activity. In contrast,theD2, D3 andD4 receptors couple to GiAlpha and inhibit the formation of cAMP.
    8. 8. • D1 receptorsD Most abundant receptor in the central nervous systems Highly expressed in basal gangliaH Stimulate AC
    9. 9. D5•50% homology with D1•Expression in nucleus of thalamus ;suggesting that role inpain stimuli•Stimulate AC
    10. 10. D2•Inhibti AC, phospoinositide turnover•Activation of potassium channel potentiation ofarachidonic acid releaseTwo isoforms;D2L and D2s by alternative splicing.•Similar profiles in terms of affinity but different inregulation.•Highly expressed in basal ganglia, septi, ventraltegmental area
    11. 11. D3•As a functional receptor remains uncertain•Similarity to D2 and the expression areasRecent study shows it might mediate positive regulatoryinfluences on production of neurotension.
    12. 12. D4•Homology with D2 and D3 41% and 39%•Hippocampus and frontal cerebral cortex
    13. 13. Dopamine 1 (DA1) Receptor agonists•Fenoldopam•Piribedil•Ibopamine•SKF 3893•Apomorphine
    14. 14. Therapeutic uses of DA1 Receptor Agonists•Decreases peripheral resistance•Inducing lowering of arteriel blood pressure-increases inheart rate and increases in sympathetic tone•Increases in activity of the reninaldosterone system
    15. 15. Dopamine 2 (DA 2) ReceptorAgonists•Bromocriptine•Pergolid•Lisuride•Guinpirole•Carmoxirole
    16. 16. Theraputicuses of DA2 receptoragonists•Used for treating Parkinson’sdisease•Inhibits prolactin release (whichdecreases tumor size)
    17. 17. DA 1 Receptor Antagonists•Clozapine( used for treating schizophrenia
    18. 18. SEROTONIN RECEPTORS Introduction DefinitionChemistry of serotonin and synthesis Pharmacokinetics Receptors classification Mechanism of action Pharmacological actions Specific agonists and antagonists
    19. 19. INTRODUCTION 5-HT is an amine autocoid.The Autocoid is derived from a Greek word; where, autos means self and akos means healing or remedy or medicinal substance. These autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures & pharmacological activities.
    20. 20. They generally act on the tissues which produce them at the site of synthesis & are hence called as local hormones.Prostaglandins, histamines & serotonin belongs to the group ofautocoids. Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted. It was chemically identified as 5- hydroxytryptamine. It was found in GIT and CNS, and was observed to be functioning as a neurotransmitter and as local hormone in peripheral vascular system.
    21. 21. Chemistry and Synthesis : Serotonin is synthesized in biologic systems from the aminoacids L- TRYPTOPHAN by HYDROXYLATION of Indole ring.After synthesis, the free amines undergoes inactivation by the action of MAO (Mono Amine Oxidase).
    22. 22. 2. 5-HT1 RECEPTOR Occurs mainly in brain and its subtypes are 5-HT1 A, B, D,E,F . And are distinguished based on their distribution and pharmacological specificity. All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood and behavior, migraine and used to treat acute attacks. Moreover they activates potassium channels and inhibits calcium channels. 5-HT1D receptors inhibit noradrenaline. 2. 5-HT2 RECEPTOR :There are 3 subtypes A, B and C. These are linked to phospholipase C . It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors. 5-HT2C receptor present on endothelium produces vasodilation.
    23. 23. 3. 5-HT3 RECEPTOR These occur mainly in the peripheral nervoussystem, mainly on autonomic and enteric neurons. These are of 2types 5HT3A & 5HT3B These receptors have reflex effects on:Somatic and autonomic nerve endings; shows pain, itch and othervisceral effects. Nerve endings in myenteric plexus; increase ofperistalsis, emetic reflex. Region of medulla; nausea, vomiting.4. 5-HT4 RECEPTOR These are present in brain and peripheralorgans such as GIT, bladder and heart. In GIT they producesneuronal excitation and mediate the effect of 5-HT in stimulatingperistalsis Ex; Cisapride, Renzapride.
    24. 24. PHARMACOLOGICAL ACTIONSCardiovascular system: Arteries are constricted (by the actionon smooth muscles) as well as dilated (through EDRF release) In microcirculation 5HT dilates the arterioles and constrictsvenules. Smooth muscles: 5-HT is a potent stimulation of g.i.t., both by direct action as well as through enteric plexus. Peristalsis is increased and diarrhoea can occur.
    25. 25. 5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS: Methysergide Pharmacological effects On central nervoussystem it exerts mild CNS stimulation. On smooth muscles it shows vasoconstriction and oxytocic effect. In migraine it is used only as a prophylactic agent. MOA It stimulates the receptors located in the brain. Adverse effects such as : Nausea, vertigo, drowsiness. G.I.irritation, bradycardia, insomnia.
    26. 26. THERAPEUTIC USES: It is used as a prophylactic agent in migraine. Other antagonist drugs are: Pizofen It showsantihistaminic and antidepressant effect Causes drowsiness,urine retention and weight gain. Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-HT2C receptors.
    27. 27. 2. 5-HT2A ANTAGONIST : Ketanserin It is the prototype for the drugs having 5-HT2receptor blocking activity. It produces antihypertensive activity.It acts on platelets and prevents its aggregation. It also causes bronchocostriction. Adverse effects are nausea, dryness of mouth, tiredness. Clinical use: as a prophylactic agent inReynauds disease. Cyproheptadine. It has anticholinergic and ca2+ channel blocking effect. It shows mild CNS depressantactivity and causes sedation. It improves appetite by acting on hypothalamus. Used in curing Cushing’s syndrome and allergies.
    28. 28. • 5-HT3 ANTAGONISTS• Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy. It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain. Adverse effects are headache, constipation, diarrhoea, abdomen pain etc. Used as prophylaxis and postoperative nausea and vomiting. Granisetron It is 15 times more potent than Ondansetron. It is similar to Ondansetron. Adverse effects fever, dizziness, anxiety etc.•
    29. 29. OTHER DRUGS AFFECTING 5-HT SYSTEMChlorophenylalanine: it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT.Tricyclic antidepressants: inhibit 5-HT uptake along with noradrenaline.Reserpine: blocks the uptake of 5-HT into storage granules.Ergot alkaloids: they exert their effect through 5-HT, adrenoreceptors or dopamine receptors. Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors. Adverse effects are muscle cramps, weakness, nausea, vomiting etc
    30. 30. schizophrenia positive negative symptoms symptomsanx/dep aggressive symptoms cognitive symptoms
    31. 31. Mechanism of Action of Antipsychotic Drugs Dopaminergic Pathways Goals: Presynaptic Dopaminergic Neuron To quiet hyperactive DAneurons that mediatepsychosis Autoreceptor To trigger underactive DAneurons that mediate Antipsychotic drugnegative and cognitivesymptoms Postsynaptic receptor To preserve physiologicfunction in DA neurons thatregulate movement and Postsynaptic neuronprolactin secretion
    32. 32. Conventional AntipsychoticsPositive symptom efficacy??Can aggravate negative and cognitive symptomsHigh incidence of EPSHigh non-compliance rates H1 D2 D2 α 1 M
    33. 33. The Dopamine Hypothesis of Schizophrenia• All conventional antipsychotics block the dopamine D2 receptor• Conventional antipsychotic potency is directly proportional to dopamine receptor binding• Dopamine enhancing drugs can induce psychosis (e.g., chronic amphetamine use)
    34. 34. “Typical” antipsychotic medications (aka first-generation, conventional, neuroleptics, major tranquilizers) • High Potency (2-20 mg/day) (haloperidol, fluphenazine) • Mid Potency (10-100 mg/day) (loxapine, perphenazine) • Low Potency (300-800+ mg/day) (chlorpromazine, thioridizine)
    35. 35. Dopamine blockade effects• Limbic and frontal cortical regions: antipsychotic effect• Basal ganglia: Extrapyramidal side effects (EPS)• Hypothalamic-pituitary axis: hyperprolactinemia
    36. 36. Typical Antipsychotic limitation:Extrapyramidal side effects (EPS)• Parkinsonism• Akathisia• Dystonia• Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
    37. 37. Typical Antipsychotic limitation:• Anticholinergic side effects: dry mouth, constipation, blurry vision, tachycardia• Orthostatic hypotension (adrenergic)• Sedation (antihistamine effect)• Weight gain
    38. 38. Typical Antipsychotic limitation: Treatment Resistance• Poor treatment response in 30% of treated patients• Incomplete treatment response in an additional 30% or more
    39. 39. The First “Atypical” Antipsychotic: Clozapine • FDA approved 1990 • For treatment-resistant schizophrenia • 30% response rate in severely ill, treatment-resistant patients (vs. 4% with chlorpromazine/Thorazine) • Receptor differences: Less D2 affinity, more 5-HT 10
    40. 40. Clozapine: pros and cons• Superior efficacy for positive symptoms• Possible advantages for negative symptoms• Virtually no EPS or TD• Advantages in reducing hostility, suicidality• Associated with agranulocytosis (1-2%) – WBC count monitoring required• Seizure risk (3-5%)• Warning for myocarditis• Significant weight gain, sedation, orthostasis, tachycardia, sialorrhea, constipation• Costly• Fair acceptability by patients
    41. 41. Atypical antipsychotics (aka second-generation, novel)FDA approval Generic Name (Brand Name)• 1990 clozapine (Clozaril)• 1994 risperidone (Risperdal)• 1996 olanzapine (Zyprexa)• 1997 quetiapine (Seroquel)• 2001 ziprasidone (Geodon)• 2002 aripiprazole (Abilify)• 2003 risperidone MS (Consta)
    42. 42. Defining “atypical” antipsychoticRelative to conventional drugs:• Lower ratio of D2 and 5-HT2A receptor antagonism• Lower propensity to cause EPS (extrapyramidal side effects)
    43. 43. Atypical Antipsychotics: Efficacy• Effective for positive symptoms • (equal or better than typical antipsychotics)• Clozapine is more effective than conventional antipsychotics in treatment- resistant patients• Atypicals may be better than conventionals for negative symptoms
    44. 44. Atypical Antipsychotics: Efficacy for Cognitive and Mood Symptoms• Atypical antipsychotics may improve cognitive and mood symptoms (Typical antipsychotics tend to worsen cognitive function)• Dysphoric mood may be more common with typical antipsychotics
    45. 45. Atypical Antipsychotics: Side Effects• Atypical antipsychotics tend to have better subjective tolerability (except clozapine)• Atypical antipsychotics much less likely to cause EPS and TD, but may cause more: • Weight gain • Metabolic problems (lipids, glucose) • ECG changes
    46. 46. Ideal Antipsychotic Broad efficacy Amelioration of cognitive dysfunction andaffective symptoms Earlier and more globally these manifestationsare arrested, the better the long-term prospects. Overall safety D2 ↓↓EPS ↓↓Hyperprolactinemia Metabolically neutral 5-HT2
    47. 47. Current consensus on antipsychotics• Atypical antipsychotics (other than clozapine) are first choice drugs: -superiority on EPS and TD -at least equal efficacy on + and – symptoms -possible advantages on mood and cognition• BUT: -long-term consequences of weight gain and metabolic effects may alter recommendation -atypicals are very expensive
    48. 48. mesolimbic overactivity =positive symptoms ofpsychosis
    49. 49. primary dopamine deficiency D2 receptor blockad e increase in negative and secondary cognitive dopamine symptoms deficiency mesocortical pathway10-11 Stahl S M, Essential Psychopharmacology (2000
    50. 50. Binding to Dopamine Receptors Z ip r a s id o n e
    51. 51. Aspects of tight and loose antipsychoticbinding at Dopamine D2 receptors Tight Loose Dosage Low High EPS Yes No Prolactin High Normal TD High risk Low risk Less lipophilic
    52. 52. dopamine neuron dopamine Substantia 5HT2A nigra receptor serotonin 5HT2A receptor serotonin neuronRaphe
    53. 53. dopamine neuron dopamine Substantia 5HT2A nigra receptor serotonin 5HT2A receptor serotonin neuronRaphe
    54. 54. dopamine neuron Substantia 5HT2A nigra receptor serotonin neuronRaphe
    55. 55. Differences among Antipsychotic Drugs• All effective antipsychotic drugs block D2 receptors• Chlorpromazine and thioridazine – block α1 adrenoceptors more potently than D2 receptors – block serotonin 5-HT2 receptors relatively strongly – affinity for D1 receptors is relatively weak• Haloperidol – acts mainly on D2 receptors – some effect on 5-HT2 and α1 receptors – negligible effects on D1 receptors• Pimozide and amisulpride† – act almost exclusively on D2 receptors
    56. 56. Differences among Antipsychotic Drugs• Clozapine – binds more to D4, 5-HT2, α1, and histamine H1 receptors than to either D2 or D1 receptors• Risperidone – about equally potent in blocking D2 and 5-HT2 receptors• Olanzapine – more potent as an antagonist of 5-HT2 receptors – lesser potency at D1, D2, and α1 receptors• Quetiapine – lower-potency compound with relatively similar antagonism of 5-HT2, D2, α1, and α2 receptors
    57. 57. Differences among Antipsychotic Drugs• Clozapine, olanzapine and quetiapine – potent inhibitors of H1 histamine receptors – consistent with their sedative properties• Aripiprazole – partial agonist effects at D2 and 5-HT1A receptors
    58. 58. Differences among Antipsychotic Drugs• Chlorpromazine: α1 = 5-HT2 > D2 > D1• Haloperidol: D2 > D1 = D4 > α1 > 5-HT2• Clozapine: D4 = α1 > 5-HT2 > D2 = D1
    59. 59. Thank you

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