Presentation on theme: "MPHRM-512 Lec-7 V-3-Date Antipsychotics"— Presentation transcript:
1MPHRM-512 Lec-7 V-3-Date-8-11-14 Antipsychotics Psychotropic drugs are those having primary effects on Psyche (mental) and are used for treatment of psychosis.
2PsychosisSevere mental illness with serious distortion of thoughts, behaviour, capacity to recognize and of perception such as delusions and hallucinations.Psychosis can broadly categorized in to four groups:
3PsychosisAcute and Chronic organic brain syndromes (cognitive disorders) such as delirium, dementia, confusion, disorientation, defective memory and disorganized behaviour.Functional disorder: memory and orientation mostly retained by emotion; thought, reasoning and behaviour are altered.Schizophrenia (split mind): splitting of perception and interpretation from reality- hallucinations and inability to think coherently. Described in terms of positive and negative symptoms.Paranoid state: fixed delusions (false beliefs) and loss of insight.
5Environmental Factors PsychosisEnvironmental FactorsExposure to infections Toxic/Traumatic/nutritional ( in utero) InsultsALTERATIONS IN NEURODEVELOPMENTAutoimmunity Stress during gestation or early in childhood/adolescence
7Neuronal connectivity Structural changes during development and in response to environmental factorsChanges in neurotransmitter activity in response to environmental factorsNeurotrophic factors and changes in gene transcription(eg. neuroregulin-1 which regulates neuronal migration)
8NEURONAL CONNECTIVITY Functional activity in neocortex of psychotic patients may be decreased:MyelinationHormonal effects of pubertyExposure to stressorsDefective connections in midbrain, thalamus, limbic and prefrontal cortex
9What is SCHIZOPHRENIA?Schizophrenia is a neurodevelopmental disorder with complex genetics and incompletely understood pathophysiology.Mutations or polymorphisms of many genes appear to contribute to the risk for schizophrenia.
10STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA Schizophrenics show deficits in tasks involving prefrontal cortex or those requiring working memoryPrefrontal cortical thickness is reduced 5-10%, neuron size is down, but no change in neuron numberSynaptic connectivity is reducedMedial dorsal thalamus shows 30% reduction in neuron numberPrefrontal cortex receives fewer projections from the thalamus
11STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA Schizophrenia patients have increased mesolimbic DA activity related to positive symptoms.Schizophrenia patients have decreased DA D1 activity in the dorsolateral and ventromedial prefrontal cortex (PFC) that is associated with cognitive deficits and negative symptoms.
12Schizophrenia - symptoms Positive SymptomsHallucinationsDelusionsDisorganized ThoughtPerception disturbancesInappropriate emotionsNegative SymptomsBlunted emotionsAnhedoniaLack of feelingFUNCTIONMood SymptomsLoss of motivationSocial withdrawalInsightDemoralizationSuicideCognitionNew LearningMemory
13Positive/active symptoms include thought disturbances, delusions, hallucinations Negative/passive symptoms include social withdrawal, loss of drive, paucity of speech, impaired personal hygiene.
14Paranoid-type schizophrenia characterized by delusions and auditory hallucinations but relatively normal intellectual functioning and expression of affect.The delusions can often be about being some other person who is famous.exhibit anger, aloofness, anxiety, and argumentativeness.Delirium: an acutely disturbed state of mind characterized by restlessness, illusions, and incoherence/A delusion, in everyday language, is a fixed belief that is either false, fanciful, or derived from deception.14
15Negative Symptoms - A’s Affect FlatteningFound in about 2/3 of schizophrenic patientsAlogiaThe failure to respond to questions or commentsCan also take the form of slow or delayed responsesAvolitionInactivity or early loss of interest in ongoing activityAnhedonia-inability to derive pleasure
16Prevalence of Schizophrenia 1-2% of U.S. population2 million diagnosed in U.S.Median age at diagnosis = mid-20’sMen = Women prevalence
17Prognosis of Schizophrenia 10% continuous hospitalization< 30% recovery = symptom-free for 5 years60% continued problems in living/episodic periods
18Schizophrenia Pathophysiology Schizophrenia Pharmacologic Pathophysiology Profile of APDsPast Excess dopaminergic Dopamine D2-receptor activity antagonistsPresentRenewed interest in the Combined 5-HT2/D2 role of serotonin (5-HT) antagonistsFutureImbalance in cortical More selective antagonists communication and Mixed agonist/antagonists cortical-midbrain Neuropeptide analogs integration, involving multiple neurotransmitters
19DA pathways in the CNSRef: Goodman and Gilman’s Therapeutic Basis of Pharmacology19
20DA-containing pathways in the CNS There are three major DA-containing pathways in the CNS:The nigrostriatal pathway.The mesocortical pathway, where neurons in the ventral tegmental nucleus project to a variety of midbrain structures and to the frontal cortex .The tuberoinfundibular pathway, which delivers DA to cells in the anterior pituitary20
22Dopaminergic Pathways and Innervations The mesolimbic pathway is associated with reward and learned behaviors.Dysfunction in this pathway is associated with addiction, schizophrenia, and psychoses (including bipolar depression), and learning deficits.The mesocortical pathway is important for "higher-order" cognitive functions including motivation, reward, emotion, and impulse control.It is also implicated in psychoses, including schizophrenia, and in attention-deficit hyperactivity disorder.The mesolimbic and mesocortical pathways are sometimes grouped together as mesolimbocortical.22
23Dopaminergic Pathways and Innervations The nigrostriatal pathway is a key regulator of movement.Impairments in this pathway are evident in Parkinson disease and underlie detrimental movement side effects associated with dopaminergic therapy, including tardive dyskinesia.DA released in the tuberoinfundibular pathway is carried by the hypophyseal blood supply to the pituitary, where it regulates prolactin secretion23
24SchizophreniaWhat is the present Pathophysiology?24
25SchizophreniaWhat is paranoid type schizophrenia?25
26SchizophreniaParanoid type is characterized by organized system of delusions and auditory hallucination.Individual is often tense, suspicious, and guarded.26
27Schizophrenia: A case study Tony, age 21, has been diagnosed with paranoid schizophrenia. He has been socially isolated and hearing voices telling him to kill his parents. He has been admitted to the psychiatric unit from the ED.What would be the INITIAL intervention for Tony?27
28Schizophrenia: A case study Ensure a safe environment for him and othersDecrease his anxiety and increase trustAntipsychotic drugs to decrease psychotic symptoms28
29Dopamine recognized as a neurotransmitter in the 1950’s DOPAMINE RECEPTORSDopamine recognized as a neurotransmitter in the 1950’sFive dopamine receptor subtypes: D-1,-2,-3,-4,-5Schizophrenics show elevated D2 receptor numberCortex has much higher amounts of D1 than D2 receptorschronic antipsychotic drugs downregulate D1’s in the cortex and striatum
30Schizophrenia - Dopamine Hypothesis Repeated administration of stimulants like amphetamines and cocaine cause a psychosis - resembles the positive symptoms of schizophreniaStress can produce a psychotic state in recovered amphetamine addicts.Carlsson and Lindqvist (1963) first proposed that drugs such as chlorpromazine and haloperidol alleviate schizophrenic symptoms by blocking DA receptors.These antipsychotic medications have in common their ability to block dopamine D2 receptors
31Schizophrenia - Dopamine Hypothesis A strong correlation between the affinity of antipsychotic drugs for DA receptors and their clinical potencyBut no clear and consistent abnormality in DA function has been detected in schizophrenic patients.Some early studies with postmortem tissue revealed increased numbers of DA receptors (in particular D2-like) in schizophrenic patients.Reduced cortical dopamine transmission induced by long-term phencyclidine (PCP) exposure may be associated with a hyperactivity of subcortical dopamine systems
33Schizophrenia - Serotonin Hypothesis correlation between DA affinity and antipsychotic efficacy has become weaker as a result of recently developed atypical antipsychotic medications that also show substantial affinity for 5HT2 receptors.Alteration of 5-HT transmission in the brains of schizophrenics patients have been reported in post-mortem studies and serotonin-agonists challenge studies.There are widespread and complex changes in the 5-HT system in schizophrenics patients.These changes suggest that 5-HT dysfunction is involved in the pathophysiology of the disease.
34Serotonin-Dopamine Interactions Ventral Tegmental Area Prefrontal CortexDopamine (DA)Serotonin (5-HT)GABA GlutamateStriatumGABA/AChMotor OutputsLimbic SystemBlockade of D2 receptors by conventional APDs causes EPSVentral Tegmental AreaSubstantia Nigra5-HT2A antagonists release dopamine from inhibition and decrease EPSMedian RapheDorsal Raphe
35Schizophrenia - Glutamate Hypothesis Cognitive dysfunction is the greatest predictor of poor functional outcome in schizophrenia and shows limited response to antipsychotic treatment.Glutamate NMDA receptor stimulation is involved in tonic inhibition of mesolimbic DA release, but facilitates mesocortical DA release.The NMDA antagonists phencyclidine and ketamine indirectly act to stimulate DA availability by decreasing the glutamate-mediated tonic inhibition of DA release in the mesolimbic DA pathway.
36SchizophreniaSchizophrenia has at least _____ symptoms, each present for a significant portion of the time during a _________ period and continuous signs of disturbance for at least _________.
37SchizophreniaAbout half the people with schizophrenia display significant difficulties with __________ and other kinds of cognitive functioning.
38SchizophreniaWhat is the medical term for “Poverty of speech”?
39General Goals of Pharmacotherapy The immediate goal of antipsychotic treatment is to decrease in acute symptoms that induce patient distress, particularly behavioral symptoms (e.g., hostility, agitation).The dosing, route of administration, and choice of antipsychotic depend on the underlying disease state, clinical acuity, drug-drug interactions with concomitant medications, and patient sensitivity to short- or long-term adverse effects.- that may present a danger to the patient or others
40General Goals of Pharmacotherapy With the exception of clozapine's superior efficacy in treatment-refractory schizophrenia, neither the clinical presentation nor biomarkers predict the likelihood of response to a specific antipsychotic class or agent.As a result, avoidance of adverse effects based upon patient and drug characteristics, are the principal determinants for choosing initial antipsychotic therapy.- that may present a danger to the patient or others
41General Goals of Schizophrenia The immediate goals of acute antipsychotic treatment are:reduction of agitated, disorganized, or hostile behaviordecreasing the impact of hallucinations,improvement of organization of thought processes,reduction of social withdrawal.- that may present a danger to the patient or others
42General Goals of Schizophrenia Doses used are often higher than those required for maintenance treatment of stable patients.Despite considerable debate, newer atypical antipsychotic agents are not more effective in the treatment of positive symptoms than typical agents although there may be small but measurable differences in effects on negative symptoms and cognition.- that may present a danger to the patient or others
43Refractory Schizophrenia Refractory schizophrenia is defined using the Kane criteria: failed 6-week trials of two separate agents and a third trial of a high-dose typical antipsychotic agent (e.g., haloperidol or fluphenazine 20 mg/day).In this patient population, response rates to typical antipsychotic agents, defined as 20% symptom reduction using standard rating scales (e.g., Positive and Negative Syndrome Scale [PANSS].- Lack of response to adequate antipsychotic drug doses for adequate periods of time may indicate treatment-refractory illness.
44Significance of antipsychotics/neuroleptics Introduction of chlorpromazine in 1952 led by the end of the 1950’s to emptying psychiatric hospitals back into community, with mixed results.The successful treatment of a psychiatric disorder with a drug led to a search for biological mechanisms.
45ANTIPSYCHOTICS Pre-90’s Post-90’s “Typical”, conventional, traditional neuroleptics, major tranquilizorsModeled on D2 antagonismEPS/TDPost-90’s“Atypical”, novel, 2nd generationModeled on 5-HT2/D2 antagonismLess EPS, prolactin effectsWeight gain, sedation, diabetes
46Antipsychotic drugsAntipsychotic drugs are also known as neuroleptics, ataractic, major tranquilizer and anti-schizophrenic drugs.A first generation antipsychotic known as typical antipsychotic was discovered in 1950s.Most of the drugs are in the second generation, known as atypical antipsychotics, have been developed more recently.46
48Classification Typical antipsychotics Phenothiazines: a. aliphatic side chains: Chlorpromazine, Triflupromazine.b. Piperidine side chain: Thioridazinec. Piperazine side chain: Trifluoperazine, fluphenazine.2. Butyrophenones: Haloperidol, Trifluperidol.3. Thioxanthenes: Chlorprothixene, Flupenthixole
49Classification of antipsychotic drugs Atypical antipsychoticlower affinity for D2 receptors than typical antipsychotic drugs and high 5-HT2 antagonist effects.OlanzipineClozapineSertindoleRisperidone
50Goal of antipsychotic treatment The immediate goal of antipsychotic treatment:Decrease in acute symptoms that induce patient distress- e.g. behavioral symptoms that present a danger to the patient or others.The dosing, route of administration, and choice of antipsychotic depend on the underlying disease state, drug-drug interactions with concomitant medications, and patient sensitivity to short- or long-term adverse effects.Neither the clinical presentation nor biomarkers predict the likelihood of response to a specific antipsychotic class or agent.Avoidance of adverse effects based upon patient and drug characteristics, or exploitation of certain medication properties are the principal determinants for antipsychotic therapy.(e.g., hostility, agitation).With the exception of clozapine's superior efficacy in treatment-refractory schizophrenia
51MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect.DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS.DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia
52LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE: Dopamine neurons reduce activity.Postsynaptic D-2 receptor numbers increase (compensatory response).When D2 blockade is reduced, DA neurons resume firing and stimulate increased number of receptors >> hyper-dopamine state >> tardive dyskinesia
53MANAGEMENT OF EPSDystonia and parkinsonism: anticholinergic antiparkinson drugsNeuroleptic malignant syndrome: muscle relaxants, DA agonists, supportiveAkathisia: benzodiazepines, propranololTardive dyskinesia: increase neuroleptic dose; switch to clozapine
54Typical Antipsychotics: adverse Effects Sedation ‑ initially considerable; tolerance usually develops after a few weeks of therapy.Postural hypotension ‑ results primarily from adrenergic blockade; tolerance can develop.Anticholinergic effects ‑ include blurred vision, dry mouth, constipation, urinary retention; results from muscarinic cholinergic blockade.Endocrine effects ‑ increased prolactin secretion can cause galactorhea; results from antidopamine effectHypersensitivity reactions ‑ jaundice, photosensitivity, rashes, agranulocytosis can occur.Idiosyncratic reactions ‑ malignant neuroleptic syndrome (MNS).Weight gainNeurological side effects H1 blockade.
57Neurological Side Effects of antipsychotics REACTIONFEATURESTIME OF MAXIMAL RISKPROPOSED MECHANISMTREATMENTAcute dystoniaSpasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria1 to 5 daysUnknownAntiparkinsonian agents are diagnostic and curativeAkathisiaMotor restlessness; not anxiety or "agitation"5 to 60 daysReduce dose or change drug: antiparkinsonian agents,b benzodiazepines or propranololc may helpParkinsonismBradykinesia, rigidity, variable tremor, mask facies, shuffling gait5 to 30 daysAntagonism of dopamineAntiparkinsonian agents helpfulNeuroleptic malignant syndromeCatatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatalWeeks; can persist for days after stopping neurolepticAntagonism of dopamine may contributeStop neuroleptic immediately: dantrolene or bromocriptined may help: antiparkinsonian agents not effectivePerioral tremor ("rabbit" syndrome)Perioral tremor (may be a late variant of parkinsonism)After months or years of treatmentAntiparkinsonian agents often helpTardive dyskinesiaOral-facial dyskinesia; widespread choreoathetosis or dystoniaAfter months or years of treatment (worse on withdrawal)Excess function of dopamine hypothesizedPrevention crucial; treatment unsatisfactorya. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).
58Adverse Effects - EPS Parkinson-like symptoms Tardive dyskinesia Details on two main extrapyramidal disturbances (EPS):Parkinson-like symptomstremor, rigiditydirect consequence of block of nigrostriatal DA2 Rreversible upon cessation of antipsychoticsParkinsonism resembling its idiopathic form occurs when striatal D2 occupancy exceeds 78%, and often responds to dose reduction or switching to an antipsychotic with weaker D2 antagonismTardive dyskinesiainvoluntary movement of face and limbsless likely with atypical antipsychotics (AP)appears months or years after start of APresult of proliferation of DA R in striatumtreatment is generally unsuccessful
59Antipsychotic Medications (Neuroleptics) Uses:-reduce hallucinations-improve organization of thought processes-reduce preoccupations with improbable beliefs-tranquilization-anti-emesis
60Common Side effects of antipsychotics: sedationdrowsinessanergydecreased motivationslowing of thought processesdepressiondry mouthconstipationblurred visionweight gain, diabetes, hyperlipidemiaorthostatic hypotensionamenorrheagalactorrheagynecomastia
61Common Side effects of antipsychotics: rashessun sensitivitysexual dysfunctionrestlessnessrestless leg syndromeheadache (especially aripiprazole and ziprasidone)nausea and vomiting (especially risperidone and ziprasidone)
62Neurological side effects of antipsychotics Parkinsonian Side EffectsOnset generally about 7 days after beginning antipsychotic medicationsKey features:"pill-rolling" tremorincreased muscle tonestooped, shuffling gaitbradykinesiaimpaired balance
63Neurological side effects of antipsychotics AkathisiaCharacterized by extreme motor restlessness or "nervousness"People may be observed to pace, jog their legs, repeatedly sit then standWhen severe, people may not be able to sleepMay be a cause of increased aggression in people having developmental disabilitiesOnset: immediate to a few days
64Neurological side effects of antipsychotics DystoniaCharacterized by a sustained, painful contraction of one or more muscle groups.Common presentations:rigid tongue protrusionthroat "closing up" or tongue drawn backupward deviation of the eyesOnset: frequently within an hour of dosage, may be recurrentCan be lethal if airway obstruction occurs
65Neurological side effects of antipsychotics Tardive DyskinesiaCharacterized by involuntary muscle movementsOnset generally after many years of taking antipsychotic medications, but can occur within weeksCan be progressive and permanentTypical movements:chewing, lip-smacking, lip-licking, puffingfrequent blinkingtongue flickering or protrusionfoot tapping, ankle movementsshrugging, twisting of torso, reflux, vomitingProgresses to cause respiratory difficulties, aspiration pneumonia
66Serious side effects of antipsychotics neutropeniaseizuresneuroleptic malignant syndromecardiac arrhythmiashyperthermiacataractsprecipitation of glaucomadiabeteshyperlipidemia
67Phenothiazines - Side effects Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; also histamine.Sexual dysfunctionresult from NE blockadeerectile dysfunction in 23-54% of menloss of libido in men and womenSeizures - <1% for generalized grand mal
68Phenothiazines - Side effects Neuroleptic malignant syndrome (1-2% early in trt)combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up)can be fatal in 5-20% of cases if untreatedtreatment – discontinue medicines; treatments for fever and cardiac problems.
69some phenothiazines collect in skin (chlorpromazine) Sensitivity to sunsome phenothiazines collect in skin (chlorpromazine)sunlight causes pigmentation changes – grayish-purple spot.can also occur in eye and cause brown in corneaAgranulocytosis - <1%reduced white blood cell countlowered resistance to infectioncan be fatalJaundice – elevated bilirubin in liver - < ½%this produces a brownish cloud to vision and possibly permanent impairment
70Phenothiazines – Metabolism and Drug Interactions Metabolized by CYP2D6. Over 10 identified human metabolites, most inactive.Enzyme interactions with 3A4 inducers barbiturates (phenobarbital); phenytoin (Dilantin); carbamazepine (Tegretol) – reduce phenothiazine levelsco-administration must be carefully monitored to prevent toxicityenzyme competition with SSRIs increases levels and may increase side effects
71Haloperidole entered US market in 1967 more potent than phenothiazines, so doses are loweralso have long half-lifelike phenothiazines, they block dopamine and norepinephrine receptors and show the related side effectsextrapyramidal effects are worsebut blood pressure effects are lessreduced sedationno blood abnormalities or jaundice
72Haloperidole: Metabolism Multiple CYP pathways, particularly 2D6, 3A4, and minor pathway 1A2.One active metabolite, reduced haloperidol (formed by ketone reductase).Reduced haloperidol inhibits CYP2D6 and may be re-oxidized to the parent drug.Therapeutic serum levels not well defined; 5-20 ng/mL used as a target for dosing.
73Limitations Of Conventional Antipsychotics Approximately one-third of patients with schizophrenia fail to respondLimited efficacy againstNegative symptomsAffective symptomsCognitive deficitsHigh proportion of patients relapseSide effects and compliance issuesSome safety issues are prominent
74Antipsychotic Drugs – New Generations “atypical” About 40-60% do not respond to phenothiazines or cannot handle side effectsQuestions remain about the efficacy of phenothiazines and haloperidole for negative symptomsDrugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative
75Antipsychotic Drugs – New Generations “atypical” clozapinerisperidoneolanzapinesertindolequetiapine etc.
77Clozapine (1989)Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathwayAlso blocks NEMore strongly blocks 5-HT2 receptors in cortex which then acts to modulate some dopamine activityAmong non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine
78Clozapine Extrapyramidal side effects are minimal May help treat tarditive dyskinesiashows orthostatic hypotension effects, sedation, weight gain, increased heart rateIncreased risk for seizures (2-3%)Agranulocytosis in 1%Agranulocytosis risks increase when co-administered with carbamazepineInteractions with SSRIs and valproic acid increase Clozapine levels and risks
79Risperidone (1994) Fewer side effects than Clozapine Marketed as first line approach to treatmentBlocks selective D2 and 5-HT2Argued as effective for positive and negative symptoms (controversial)Extrapyramidal side effects low (but are shown at high doses) - controversialShares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactinNo agranulocytosis risksMay cause anxiety/agitation (possible OCD)
80Risperidone (Risperdal) Research designs clearly stacked in favor of Risperidone showing better profile for extrapyramidal side effects and for symptom reductionAdvantages unclear other than agranulocytosis issue
81Olanzipine - Zyprexa – 1996Same poorly supported arguments about improved negative symptom reductionArgued to be better than risperidone in extrapyramidal issuesDoes not cause prolactin elevationSame claim to fame reduced agranulocytosis risks
82Sertindole – Serlect – 1995Some poorly supported arguments about improved negative symptom reductionLow risk for extrapyramidal side effects – major advantageNo sedation and very mild prolactin elevation– major advantagesShares orthostatic hypotension, tachycardia, and weight gainCommon side effects are rhinitis and reduced ejaculatory volume (not associated with disturbed function)concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998
83Quetiapine – Seroquel - 1997 No increased risks for extrapyramidal symptomsShares sedation, orthostatic hypotension, weight gainDoes cause anticholinergic side effects (like older and Clozapine) – dry mouth, constipationDoes not elevate prolactinZiprasidoneSimilar to advantages of others, but argued not to cause weight gain
84StatusLimited evidence to support arguments about improved treatment of negative symptomsclearly do have reduced extrapyramidal side effects, reduced sedation, and do not cause prolactin elevationWeight gain issue – is ziprasidone better?Wetterling Evaluation of published data from varying designs, etc:Clozapine – 1.7 kg/month Risperidone – 1 kg/monthOlanzipine – 2.3 kg/month Ziprasidone – 0.8 kg/monthQuetiapine kg/month
85Pharmacological effects Effects on dopamine systemsi. Mesolimbic/ mesocorticalii. Nigrostriataliii. TuberoinfundibularDopamine receptors and their effectsi. D1/D5ii. D2/D3/D4 family
86Dopamine partial agonist no clinically available effective antipsychotic is devoid of D2 antagonistic activity.This reduction in dopaminergic neurotransmission is presently achieved through one of two mechanisms: D2 antagonism or partial D2 agonism,Of which aripiprazole is the only current example.Emerging data indicate that stimulation of glutamate or muscarinic receptors confer antipsychotic properties
87AntipsychoticsAripiprazole has an affinity for D2 receptors intrinsic activity is ~25% that of dopamine.In the absence of DA, aripiprazole produces a maximal level of D2 activity ~25% that of DA.The potent D2 antagonist haloperidol is capable of reducing dopamine's effect to zero, but when DA is incubated with increasing concentrations of aripiprazole, maximal inhibition of D2 activity did not exceed 25% of the DA response, that is, the level of agonism provided by aripiprazole.
89AntipsychoticsAripiprazole's capacity to stimulate D2 receptors in brain areas where synaptic DA levels are limited (e.g., PFC neurons) or decrease dopaminergic activity when dopamine concentrations are high (e.g., mesolimbic cortex) is thought to be the basis for its clinical effects in schizophrenia.FDA approval.The potent D2 antagonist haloperidol is capable of reducing dopamine's effect to zero, but when DA is incubated with increasing concentrations of aripiprazole, maximal inhibition of D2 activity did not exceed 25% of the DA response, that is, the level of agonism provided by aripiprazole.
90Metabolism2D6 and 3A4 convert aripiprazole to active metabolite dehydro-aripiprazole. Metabolite has longer t1/2 (75 vs. 94 hours).
91CLOZAPINE: AN EXAMPLE OF AN ATYPICAL NEUROLEPTIC Clozapine (sold as Clozaril, Leponex, Fazaclo; Gen-Clozapine in Canada) was the first of the atypical antipsychotics to be developed. It was approved by the United States Food and Drug Administration (FDA) in 1989 and is the only FDA-approved medication indicated for treatment-resistant schizophrenia and for reducing the risk of suicidal behaviour in patients with schizophrenia. [dubious – discuss]Clozapine has been shown to be superior in efficacy in treating schizophrenia. Were it not for its side effects it would be first line treatment; however the rare but potentially lethal side effects of agranulocytosis and myocarditis relegate it to third-line use. Furthermore it may rarely lower seizure threshold, cause hepatic dysfunction, weight gain and be associated with type II diabetes. More common side effects are predominantly anticholinergic in nature, with dry mouth, sedation and constipation. It is also a strong antagonist at different subtypes of adrenergic, cholinergic, histaminergic and serotonergic receptors.Safer use of clozapine requires weekly blood monitoring for around five months followed by four weekly testing thereafter. Echocardiograms are recommended every 6 months to exclude cardiac damage.
92.There is now ample evidence to suggest that neuroleptics (aka. anti-psychotics and major tranquillizers) are dangerous drugs, and patients’ exposure to them should be minimized wherever possible. This clinical imperative applies whether neuroleptics are of the traditional type or atypical variety, albeit for different reasons since the traditional agents are neurotoxic while atypicals are mainly metabolic poisons. Usage of traditional neuroleptics seems indeed to be declining progressively, but the opposite seems to be happening for ‘atypicals’, and new indications for these drugs are being promoted. Yet the atypical neuroleptics are a category of pharmaceuticals which are close to being un-necessary since there are safer, cheaper and pleasanter substitutes such as benzodiazepines and the sedative antihistamines (eg. promethazine).“In terms of therapeutic value, it therefore seems likely that 'atypicals' are merely an unusually dangerous way of sedating patients. In therapeutic terms these drugs therefore represent a significant backward step. Rationally, the atypicals should now be dropped and replaced with safer sedatives. Potential neuroleptic-substitutes which already exist would include benzodiazepines and sedative antihistamines such as promethazine [4,8].”
93Atypicals have less tendency to produce motor side effects Clozapine is generally referred to as an "atypical" neuroleptic. What is the difference between "atypical" and "typical" neuroleptics (such as haloperidol)?There is no rigorous line between typical and atypical neuroleptics…butAtypicals have less tendency to produce motor side effectsAtypicals produce effects on negative symptoms of schizophreniaMay have effects in therapy-resistant patients
94Parkinson's diseaseParkinson's disease (PD also known as idiopathic or primary parkinsonism) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. Parkinson's disease is more common in the elderly, with most cases occurring after the age of 50
95Parkinson's diseaseThe four primary symptoms of PD are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50. Early symptoms of PD are subtle and occur gradually.
96Clinical features of PD Three cardinal symptoms:® resting tremor® bradykinesia (generalized slowness of movements)® muscle rigidityClinically, PD is characterized by three cardinal symptoms: resting tremor, bradykinesia (generalized slowness of movements) and muscle rigidity.
97Clinical features of PD Resting tremor: Most common first symptom, usually asymmetric and most evident in one hand with the arm at rest.Bradykinesia: Difficulty with daily activities such as writing, shaving, using a knife and fork, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing.Rigidity: Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture, anteroflexed head, and flexed knees and elbows.The most common first symptom is resting tremor, which is usually asymmetric and most evident in one hand with the arm at rest. It is the most easily recognized sign of the disease. The frequency of parkinsonian tremor is low, typically in the 3-6 Hz range. The alternating contraction of agonist and antagonist muscles of the forearm results in a "pill-rolling" tremor. Bradykinesia is the central motor abnormality in PD. Difficulties with daily activities such as writing, shaving, cutting food with a knife and fork and opening or buttoning buttons, as well as decreased blinking, masked facies, slowed chewing and swallowing and drooling reflect bradykinesia. Muscle tone is increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints (a "cog-wheel" rigidity can be felt during passive movements of joints). Rigidity underlies the chracteristic stooped posture, anteroflexed head, and flexed knees and elbows in the patients. The symptoms typically start asymmetrically from one side spreading from one affected limb on one side to the other limb on the same side (e.g. from hand to leg), and later also to contralateral side.Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001
98Additional clinical features of PD Postural instability: Due to loss of postural reflexes.Dysfunction of the autonomic nervous system: Impairedgastrointestinal motility, bladder dysfunction, sialorrhea, excessive head and neck sweating, and orthostatic hypotension.Depression: Mild to moderate depression in 50 % of patients.Cognitive impairment: Mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks, and impaired concentration in most patients; at least 1/3 become demented during the course of the disease.In addition to these three cardinal features, postural instability, dysfunction of the autonomic nervous system, depression and cognitive impairment are common. Loss of postural reflexes causes balance difficulties and the body can move or fall into the direction of the center of gravity. Therefore, turning or bending forward may be associated with involuntary steps. Autonomic dysfunction can result into impaired gastrointestinal motility causing sense of fulness and constipation. Furthermore, bladder dysfunction (urinary frequency, urgency and urge incontinence), sialorrhea (due to excessive saliva production and decreased frequency of swallowing), excessive head and neck sweating (resulting from altered thermoregulation), and orthostatic hypotension result from autonomic dysfunction. Approximately 50 % of patients show mild to moderate depression. Many patients show mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks and impaired concentration. At least 1/3 of the patients become demented during the course of the disease.Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001
99Functional neuroanatomy of PD Substantia nigra: The major origin of the dopaminergic innervation of the striatum.Part of extrapyramidal system which processes information coming from the cortex to the striatum, returning it back to the cortex through the thalamus.One major function of the striatum is the regulation of posture and muscle tonus.Substantia nigra is the major origin of the dopaminergic innervation of the striatum and is part of so called extrapyramidal system which processes information coming from the cortex to the striatum, and returns it back to the cortex through the thalamus. One major function of the striatum, which is under the control of substantia nigra, is the regulation of posture and muscle tonus.Source: Marsden, C. D. Parkinson's disease. Lancet 335, , 1990
100Dopamine pathways in human brain The ventral tegmental area (VTA) cells project to limbic (mesolimbic projection) and cortical (mesocortical projection) areas. Neurons of the substantia nigra project to the striatum (nigrostriatal projection). In PD, dopaminergic nerve cells in the substantia nigra develop nerve cell loss, and its degeneration and the resulting striatal dopamine depletion are responsible for most of the motor abnormalities.
101Neurochemistry of PDPD symptoms become manifest when about % of the DA-containing neurons in the substantia nigra and % of striatal DA are lost.The ventral tegmental area (VTA) cells project to limbic (mesolimbic projection) and cortical (mesocortical projection) areas. Neurons of the substantia nigra project to the striatum (nigrostriatal projection). In PD, dopaminergic nerve cells in the substantia nigra develop nerve cell loss, and its degeneration and the resulting striatal dopamine depletion are responsible for most of the motor abnormalitiesIn late 1950s, it was shown that dopamine is present in mammalian brain, and that the levels are highest within the striatum. In 1960, Ehringer and Hornykiewicz showed that the levels of dopamine are severely reduced in the striatum of patients with PD. Degeneration of the nigrostriatal dopaminergic neurons causes symptoms of PD: symptoms become manifest when about % of the dopamine-containing neurons in the substantia nigra and % of striatal dopamine are lost.Carlsson, A. The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol. Rev. 11, , 1959Sano, I. et al. Distribution of catechol compounds in human brain. Biochim. Biophys. Acta 32, , 1959Ehringer, H. & Hornykiewicz, O. Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Ekrankungen des extrapyramidalen Systems. Klin. Wschr. 38, (1960)Marsden, C. D. Parkinson's disease. Lancet 335, , 1990Forno, L. S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, , 1996Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp , 2001.
102Dopamine synthesisDopamine is synthesized from tyrosine, which is first catalysed to L-DOPA by tyrosine hyroxylase. L-DOPA is then decarboxylated to dopamine by dopadecarboxylase, and stored in the vesicles. When released into synaptic cleft, dopamine binds to receptors (D1-D5 in the figure), which activates different second messenger systems inside the cell causing changes in excitability, metabolism and gene expression. Reuptake of dopamine is by dopamine transporter. If unstored in the cytosol, dopamine is oxidized by monoamine oxidase (MAO).
103Therapy of PD: levodopa Late 1950s: L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of DA that crosses the blood-brain barrier, could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine).First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements; took years before it become an established and succesfull treatment.Still today, levodopa cornerstone of PD treatment; virtually all the patients benefit.In late 1950´s, it was shown that L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of dopamine that crosses the blood-brain-barrier, could restore brain dopamine levels and motor functions in animals treated with catecholamine depleting drug, reserpine. The observations about the striatal dopamine depletion in PD were followed by attempts to alleviate the symptoms through the administration of levodopa. First attempts resulted in dramatic but short-term improvements. It took years before this treatment become an established and succesfull treatment for PD. Still today, it continues to be the cornerstone of PD treatment. Virtually all PD patients benefit from levopoda treatment.Cotzias, G. C. et al. Modification of parkinsonism: chronic treatment with L-DOPA. N. Engl. J. Med. 280, , 1969.Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp
104Therapy of PD: limitations of levodopa Efficacy tends to decrease as the disease progresses.Chronic treatment associated with adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems).Levodopa therapy has, however, its limitations. The efficacy of the therapy is greatest during the early stages of the disease, and tends to decrease as the disease progresses. Chronic levodopa treatment is also associated with the development of adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems) in the majority of patients.
105Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of PD symptoms.Catechol-O-methyl-transferase (COMT) inhibitors, like entacapone, which increase the bioavailability of levodopa by inhibiting COMT enzyme peripherally and thus slow down the breakdown of levodopa, can be used as adjunctive therapy to levodopa to reduce some of the adverse effects related to long-term levodopa treatment (results in smoother levodopa plasma levels, and a decrease in motor fluctuations in patients).
106Therapy of PD: limitations of levodopa Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic.Levodopa does not however prevent the continuing degeneration of nerve cells in the substantia nigra, the treatment being therefore symptomatic.Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp
107Therapy of PD: Other treatments DA receptor agonists (bromocriptine, pergolide, pramipexole, ropinirole, cabergoline)AmantadineAnticholinergicsIn addition to levopoda, other drugs increasing dopaminergic activity can be used as symptomatic treatments. These include e.g. dopamine receptor agonists (e.g. bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) which directly stimulate striatal dopamine receptors, and are thus independent of the degenerating dopaminergic projections of the substantia nigra for their mechanism of action. Amantadine is an antiviral agent which also increases dopamine release, blocks dopamine reuptake, and stimulates dopamine receptors. It is also a non-competitive NMDA receptors antagonist. However its mechanism of action at therapeutic doses in PD is still under discussion.Normally there is a balance between dopaminergic and cholinergic neurotransmission in the striatum, which is disrupted in PD due to dopamine depletion resulting in a state of relative cholinergic sensitivity, so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms. Anticholinergics can be used in younger PD patients and are useful for treating resting tremor, but adverse effects (such as memory impairments, acute confusion and hallucinations, as well as peripheral side effects) are common are limit their use.Koller, WC and Minagan, A. Treatment strategies for the management of Parkinson’s disease. In: Parkinson’s disease management guide, Medical economics Company Inc. at Montvale NJ, pp
108What is Alzheimer’s ?Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer’s is the most common form of dementia.This incurable, degenerative, terminal disease was first described by a German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.Alzheimer's disease (AD) is a slowly progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, planning, language, and perception.Many scientists believe that Alzheimer's disease results from an increase in the production or accumulation of a specific protein (beta-amyloid protein) in the brain that leads to nerve cell death.
109Generally, it is diagnosed in people over 65 years of age, although the less-prevalent early onset of Alzheimer’s can occur much earlier.In 2006, there were 26.6 million sufferers worldwide.Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.Alzheimer’s disease
111Symptoms of Developing A.D 1) Early StageThis is considered as a mild/early stage and the duration period is 2-4 years.Frequent recent memory loss, particularly of recent conversations and events.Repeated questions, some problems expressing and understanding language.Writing and using objects become difficult and depression and apathy can occur.Need reminders for daily activities and difficulties with sequencing impact driving early in this stage.
112Continued 2) Second stage This is considered as a middle/moderate stage and the duration is 2-10 years. Pervasive and persistent memory loss impacts life across settings.Rambling speech, unusual reasoning, confusion about current events, time, and place. Slowness, rigidity, tremors, and gait problems impact mobility and coordination. Need structure, reminders, and assistance with activities of daily living.
113Continued Increased memory loss and confusion. 3) Moderate stageIncreased memory loss and confusion.Problems recognizing family and friends.Inability to learn new things.Difficulty carrying out tasks that involve multiple steps (such as getting dressed).Problems coping with new situations.Delusions and paranoia.Impulsive behavior.In moderate AD, damage occurs in areas of the brain that control language, reasoning, sensory processing, and conscious thought
114Continued4) Last stageThis is considered as the severe stage and the duration is 1-3 years.Confused about past and present. Loss of recognition of familiar people and placesGenerally incapacitated with severe to total loss of verbal skills.Unable to care for self. Immobility likely.Patients need total support and care, and often die from infections or pneumonia
115Diagnosis of Alzheimer’s Disease Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computer tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia.The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.
116Causes of Alzheimer’s Disease Scientists don’t yet fully understand what causes AD. It is likely that the causes include genetic, environmental, and lifestyle factors.Some drug therapies propose that AD is caused by reduced synthesis of the neurotransmitter acetylcholine.Alzheimer's disease is characterized by a build-up of proteins in the brain. Though this cannot be measured in a living person, extensive autopsy studies have revealed this phenomenon. The build-up manifests in two ways:Plaques– deposits of the protein beta-amyloid that accumulate in the spaces between nerve cellsTangles – deposits of the protein tau that accumulate inside of nerve cells
117NeuropathologyAlzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.Plaques are dense, mostly insoluble deposits of amyloid – beta peptides and cellular material outside and around neurons.Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves.
118TreatmentAlthough there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management.Mild/Moderate AD:Cholinesterase inhibitors increase the levels of acetylcholine in the brain, which plays a key role in memory and learning. This kind of drug postpones the worsening of symptoms for 6 to 12 months in about half of the people who take it. Cholinesterase inhibitors most commonly prescribed for mild to moderate Alzheimer's disease include Aricept (donezepil HCL), Exelon (rivastigmine), and Razadyne (galantamine).
119Continued Moderate/Severe AD: Namenda (memantine) regulates glutamate in the brain, which plays a key role in processing information. This drug is used to treat moderate to severe Alzheimer's disease and may delay the worsening of symptoms in some people. It may allow patients to maintain certain daily functions a little longer than they would without the medication.
120ContinuedExelon is a cholinesterase inhibitor that prevents the breakdown of acetylcholine and butyrylcholine in the brain by blocking the activity of two different enzymes. Acetylcholine and butyrylcholine play a key role in memory and learning.When given orally, bioavailability is about 40% in the 3 mg dose. The compound can cross the blood-brain barrier.
121Continued Aricept (Donepizel) One of the most widely used drugs to treat the symptoms of Alzheimer's disease. Aricept is FDA-approved for mild, moderate, and severe stages of the disease.
122ContinuedAricept is available in tablet form or an orally disintegrating tablet form, and is commonly started at 5 mg a day.Can cross the blood-brain barrier.
123Continued Namenda (Memantine) Namenda is an N-methyl D-aspartate (NMDA) antagonist that regulates the activity of glutamate in the brain. Glutamate plays a key role in memory and learning, but excess glutamate can lead to the disruption of nerve cell communication or nerve cell death.
124ContinuedStudies involving Namenda have shown that the drug can slow the rate of decline in thinking and the ability to perform daily activities in individuals who have moderate to severe Alzheimer's diseaseA dysfunction of glutamatergic neurotransmission is thought to be involved in the etiology of AD.Namenda is available in generic form (memantine HCL).
125Adverse pharmacological effects Behavioural Effects (pseudodepression, akinesia, confusion)Neurological Effects (parkinsonism, akathisia, dystonia, tardive dyskinesia)Autonomic Effects (orthostatic hypotension, impaired ejaculation)Metabolic and Endocrine Effects (weight gain, hyperprolactinemia, loss of libedo, impotence)Toxic or allergic effects (agranulocytosis, choleostatic jaundice, clozapine)
129Drug CombinationsCombining antipsychotic drugs confounds evaluation of the efficacy of the drugs being used. Use of combinations, however, is widespread, with more emerging experimental data supporting it.Tricyclic antidepressants or, more often, SSRIs may be used with antipsychotics for clear symptoms of depression complicating schizophrenia.Lithium or valproic acid is sometimes added to antipsychotic agents with benefit to patients who do not respond to the latter drugs alone. Clozapine plus lamotrigine developed here in Psychiatry. It is uncertain whether such instances represent misdiagnosed cases of mania or schizoaffective disorder. Sedative drugs may be added for relief of anxiety or insomnia not controlled by antipsychotics.