Antipsychotics and Lithium PDF

Antipsychotics and Lithium Dru Riddle Advanced Pharmacology STUDENT PERFORMANCE OBJECTIVES: 1. List typical and atypical antipsychotics and discuss advantages and disadvantages of each 2. Describe mechanisms of action for typical and atypical antipsychotics 3. Describe the drugs used to treat bipo...

Antipsychotics and Lithium Dru Riddle Advanced Pharmacology STUDENT PERFORMANCE OBJECTIVES: 1. List typical and atypical antipsychotics and discuss advantages and disadvantages of each 2. Describe mechanisms of action for typical and atypical antipsychotics 3. Describe the drugs used to treat bipolar (manicdepressive) disorder 4. Describe the major side effects commonly encountered for each of the major drug classes Drug List: Typical Antipsychotics • Typical Antipsychotics (low potency) – Chlorpromazine (Thorazine) – Prochlorperazine (Compazine) – Thioridazine (Mellaril) • Typical Antipsychotics (high potency) – Fluphenazine (Prolixin, others) – Haloperidol (Haldol) – Pimozide (Orap) – Thiothixene (Navane) – Trifluoperazine (Stelazine) Drug List: Atypical Antipsychotics • • • • • • Aripiprazole (Abilify) Clozapine (Clozaril) Olanzapine (Zyprexa) Quetiapine (Seroquel) Risperidone (Risperdal) Ziprasidone (Geodon) Drug List: Mood Stabilizers (Treatment of Bipolar Disorder) • • • • • • Lithium carbonate (Li+) (Eskalith) Valproic Acid (Depakene) Divalproex (Depakote) Carbamazepine (Tegretol) Lamotrigine (Lamictal) Atypical antipsychotics + combos – – – – – Olanzapine (Zyprexa) Aripiprazole (Abilify) Quetiapine (Seroquel) Risperidone (Risperdal) Olanzapine + fluoxetine (Zyprexa + Prozac = Symbyax) Introduction: Psychosis and Schizophrenia • Psychosis – Delusions, hallucinations – Grossly disorganized thinking • Schizophrenia is a type of psychosis – Disorder of thought, perception and mood • Three Classes of Symptoms – Positive • Delusions • Hallucinations – Negative • Affective flattening • Anhedonia • Avolition (inability to make choices) – Cognitive symptoms • Disorganized speech and behavior, poor attention Positive Symptoms of Schizophrenia Negative Symptoms Sexual Dysfunction SEROTONIN General Effects of Antipsychotics (sometime called neuroleptics) Control bizarre behavior and calm agitation – Cause psychomotor slowing • Decreased agitation, aggression, impulsivity – Produce emotional quieting Antipsychotics can induce these effects in anyone if the dose is high enough Additional Effects of Antipsychotics in Schizophrenics • Core thought disorders improve in about 50-70% of schizophrenics. • Negative symptoms are particularly resistant to pharmacotherapy – atypical antipsychotics are better for treating negative symptoms Other Uses of Antipsychotics • Tourette’s Syndrome • Hiccups – Brainstem • Nausea – Chemoreceptor trigger zone in the floor of the fourth ventricle – D2 receptors Dopamine and Schizophrenia • Pharmacologic studies of Dopamine Receptor Subtypes – Two major subtypes: • D1-like – D1, D5 • D2-like – D2, D3, D4 • D1 and D2 receptors highest concentration – Basal ganglia of the brain in the caudate • Extrapyramidal motor functions • Parkinson’s disease due to atrophy of dopamine neurons in this region Extrapyramidal symptoms (EPS) Dopamine and Thought Disorders • Ventral tegmental area (VTA) – Contains cell bodies, dopamine neurons • Mesolimbic system releases dopamine in nucleus accumbens • Mesocortical system releases dopamine in prefrontal cortex • Likely mediators of: – Natural reinforcerment – Euphoria from drugs of abuse – Psychosis Dopamine and Positive Symptoms of Schizophrenia • Excess dopamine in mesolimbic system • Likely site for causing positive symptoms in schizophrenia Dopamine and Negative Symptoms of Schizophrenia • Decreased dopamine in PFC and mesolimbic system – Like cause of negative symptoms in schizophrenia • Serotonin may also be involved • “Burnt out schizophrenics” Dopamine Hypothesis of Schizophrenia • There is an imbalance in the brain that leads to over stimulation of postsynaptic dopamine receptors • Receptor over-stimulation can be attenuated by dopamine receptor antagonists. • The extrapyramidal effects of antipsychotics are mediated by the basal ganglia • The antipsychotic effects are mediated by the mesolimbic and prefrontal cortex systems. Evidence in favor of the dopamine hypothesis • Antipsychotics are high affinity, and often selective, antagonists for D2 receptors • Administration of dopaminergic agonists can initiate psychotic episodes in normal and psychotic individuals. • Drugs that block the dopamine up-take site (transporters), such as amphetamines, PCP or cocaine, can initiate psychotic episodes. Affinity of drugs for D2 receptor Katzung-15E, fig 29-3 Evidence against the dopamine hypothesis • Therapeutic effects on delusional thought requires time (3-6 weeks) before drugs are effective, whereas binding to DA receptors occurs immediately. • Many schizophrenics get no help from antipsychotics. This implies a heterogeneity of the illness. • Several laboratories have studied the expression of D2 receptors in normal and schizophrenic individuals. The reports are conflicting whether there are differences in the expression of D1 or D2 receptors in these populations. • There is an emerging role for 5-HT2 receptors Mechanism of Action of Antipsychotics • All of these drugs block dopamine receptors, particularly the D2 receptor. – Clinical efficacy against positive symptoms correlates with D2 antagonism – Many side-effects correlate with D2 antagonism Typical Antipsychotics • Two broad classes: – Phenothiazines • Chlorpromazine (Thorazine) – original prototype • Fluphenazine (Prolixin) a depot form; used i.m. for long duration action in non-cooperative patients) • Prochlorperazine and promethazine (antiemetic) – Butyrophenones • Haloperidol • Droperidol (Inapsine) (antiemetic) • Amisulpride (Barhemsys) (antiemetic) – Brand new, introduced in anesthesia in 2020/21 Critical Points for Typical Antipsychotics • High affinity D2 receptor antagonists – Clinical potency highly correlated with affinity for D2 receptors • Most of these drugs are very messy in their pharmacology – Antagonists at dopamine, alpha1, muscarinic and histamine receptors. Receptor Blocking Properties of Antipsychotic Drugs Butyrophenones • Haloperidol (Haldol) • Haloperidol ester – Haldol Decanoate – injectable depot preparation form • Droperidol (Inapsine) – Antiemetic, prevent PONV – QT prolongation led to “Black Box” warning by FDA – Not used as antipsychotic • Amisulpride (Barhemsys) – Antiemetic, better at treatment or rescue – No QT prolongation – Used at very high doses orally as antipsychotic (10mg IV versus 400-800mg PO) Haloperidol: (standard against which older and newer drugs are judged) • Relatively “clean” D2 antagonist – Some 5HT2 antagonism – Some alpha1 antagonism • Half-life of approximately 20 hours • Highly effective against positive symptoms – Some effect against negative symptoms • Greater potential for extrapyramidal motor side-effects than many typical (and all atypical) antipsychotics Rapidly Occurring Neurologic Side Effects: Extrapyramidal Symptoms • Direct Result of Blocking DA Receptors in the Basal Ganglia – Dystonias – Parkinsonism – Neuroleptic Malignant Syndrome Dystonias I • Defined by body region affected – Torticollis - muscle contractions leading to twisting of the neck with an unnatural position of the head – Facial distortion – Tongue protrusion – Dysarthria (imperfect articulation of speech) Dystonias II • • • • Opisthotonus -- whole body spasm Scoliosis -- bending of the spine Oculogyric crisis -- rapid eye movements Akathisia – Inability to sit; patient is constantly pacing, restlessness. – Most common after about a week of treatment. Parkinson’s-like Syndrome • Iatrogenic Parkinson’s diseases caused by antipsychotics blocking dopamine receptors in the basal ganglia. – Rigidity or tremor (3 per second) at rest – Facial “mask” – Bradykinesia or akinesia Treatment of Extrapyramidal Symptoms • Reduce dose • Do NOT give dopamine agents (ie do not administer L-DOPA) • Use anticholinergics Neuroleptic Malignant Syndrome • This syndrome occurs in 0.5-1.0% of patients. • Resembles a severe form of Parkinsonism – Muscle rigidity, catatonia, tremors – and instability of the autonomic system • alterations in blood pressure and pulse rate, cardiac arrhythmias • Altered mental status • In severe cases impairment of sweating, and high fever can ensue with a 10% mortality rate • Potentially fatal Neuroleptic Malignant Syndrome: Treatment • • • • • Stop antipsychotic and anticholinergics Antipyretics Dopamine agonist (e.g. bromocriptine) Diazepam (muscle relaxant) Dantrolene Side Effects Antipsychotics • Dysphoria • Endocrine – Increased secretion of prolactin (hyperprolactinemia) – D2 receptor block in pituitary • Release of prolactin is under negative regulation by dopamine secreted from cells in the tuberoinfundibular system of the hypothalamus. – Females • Galactorrhea, excessive or spontaneous production of milk – Males • Gynecomastia Other Side Effects • Sexuality – Loss of sex drive – impotence in males Side Effects II • • • • Weight gain Akathisia Hypotension (alpha1-blocking effect) Poikilothermia – failure to regulate body temperature Long Term Neurologic Side Effects • Tardive dyskinesia is the major long-term side effect of chronic treatment with antipsychotics. – tardive = belated or delayed – dyskinesia = impairment of voluntary movement Tardive Dyskinesia • Late appearing – occurs after chronic treatment with neuroleptics (> 10 years) – 15-20% of institutionalized patients on typical antipsychotics will develop syndrome – more prevalent in older patients Tardive Dyskinesia • Motor dysfunction – stereotypical, repetitive, involuntary movements • • • • Lateral jaw movements Lip smacking Twisting and protrusion of the tongue Purposeless movements of the extremities Tardive Dyskinesia: Mechanism • Perhaps up-regulated striatal dopamine receptors – Up regulation of DA receptors occurs – However, poor correlation between upregulation of DA receptors and onset of tardive phenomena Therapy for Tardive Dyskinesia • Decrease the dose of the antipsychotic – Initially the dyskinesia will get worse – Over the next several weeks it may improve • Increasing the dose of the antipsychotic drug will temporarily suppress the dyskinesia – Contraindicated – At some point the dyskinesia will reappear, and it will be worse The “Cocktail” • To control acutely agitated patient on psych ward • Chemical restraint, IM injection – Haldol (haloperidol) = 10mg – Ativan (lorazepam)= 2 mg – Benadryl (diphenhydramine) = 50mg Atypical Antipsychotics • • • • • • clozapine (Clozaril) risperidone (Risperdal) olanzapine (Zyprexa) ziprasidone (Geodon) quetiapine (Seroquel) aripiprazole (Abilify) SEROTONIN Critical Points for Atypical Antipsychotics • High affinity for – 5HT2 receptors>>>D2 receptors • Efficacious for positive and negative symptoms • Tardive dyskinesia – All atypical antipsychotics are less prone than typical antipsychotics in causing TD – Some may be free of causing TD at all Summarizing Atypical Antipsychotics • Atypical antipsychotics are better than typical antipsychotics – Greater efficacy for negative symptoms – Less likely to cause tardive dyskinesia Clozapine (Clozaril) • Original atypical antipsychotic – Appears to be more efficacious than other antipsychotics, but most dangerous – Essentially devoid of extrapyramidal motor side-effects – Causes blood dyscrasias (agranulocytosis) in about 2% of patients • Monitor blood, weekly at first • Because of this side effect other agents are used first – Other side effects are strong sedation, weight gain, Type II DM, anticholinergic effects (dry mouth, urinary retention), and hypotensive effects – Because of adverse effects, reserved for refractory patients – Most useful for treatment-resistant schizophrenia or suicidal ideation Olanzapine (Zyprexa) • Rapidly becoming the standard against which other atypical antipsychotics are judged – Side effect profile more acceptable – Weight gain significant SE – Somnolence significant SE – Metabolic syndrome • All atypical antipsychotics use results in metabolic syndrome à Type II DM • Aripiprazole lacks metabolic effects (see later slide) – Remarkable efficacy for schizophrenia and depression Risperidone (Risperdal) • Pharmacodynamics – High affinity for 5HT2 and D2 receptors – Little affinity for muscarinic receptors – Compared to other atypical antipsychotics, risperidone has greater potential • EPS • Hyperprolactinemia • Weight gain Quetiapine (Seroquel) • Binds D2 and 5HT2 with modest affinity • Antipsychotic activity against positive and negative symptoms • Some alpha1 binding (orthostatic hypotension) • Minimal extrapyramidal effects • Limited weight gain and hyperglycemia can occur Aripiprazole (Abilify) • Partial dopamine agonist – Effective treating schizophrenia—weak D2 partial agonist, blocks full agonist dopamine – Effective treating depression—partial DA agonist provides therapeutic efficacy • Partial 5HT1a agonist (~buspirone) • Partial 5HT2a antagonist • Efficacious in treating – Positive symptoms – Negative symptoms – Depression Aripiprazole (Abilify) • Remarkably low incidence of side-effects, including less weight gain than olanzapine • No incidence of metabolic syndrome or hyperprolactinemia PART II MOOD STABILIZERS: DRUGS TO TREAT BIPOLAR DISORDER STUDENT PERFORMANCE OBJECTIVES: 1. List typical and atypical antipsychotics and discuss advantages and disadvantages of each 2. Describe mechanisms of action for typical and atypical antipsychotics 3. Describe the drugs used to treat bipolar (manicdepressive) disorder 4. Describe the major side effects commonly encountered for each of the major drug classes Lithium: A Mood Stabilizing Drug Typically administered as Li2CO3 Lithium Carbonate Lithium: Multiple & Variable Effects • Effects on electrolytes (substitutes for Na+) • Effects on neurotransmitter systems – DA – 5HT – ACh • Many of these effects are seen acutely, yet lithium must be taken for 2-3 weeks before clinical effects are seen Katzung, 15th ed, figure 29.4 Lithium: Effects on Phosphoinositide Signaling • inhibits phosphatase enzyme primarily responsible for the conversion of IP2 to IP1and IP1 to inositol • With chronic lithium treatment there is a depletion of phosphatidylinositol-4,5bisphosphate (PIP2)-- the source of the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG) Lithium: PI3 Signaling • A depletion of PIP2 may lead to a decreased responsiveness to synaptic transmission receptors that utilize phosphoinositide second messenger signaling (e.g. muscarinic receptors). • A depletion of PIP2 sufficient enough to produce decreased responsiveness may not occur until lithium has been administered for 2-3 weeks, a time course consistent with the latency to clinical improvement. Lithium: Adverse Effects • • • • • • • • Tremor hypothyroidism renal dysfunction (polydipsia & polyuria) cardiac conduction problems gastric distress mild cognitive impairment edema weight gain Lithium has a narrow therapeutic window • acute ~1-1.4 meq/L • maintenance ~0.6 - 1.4 meq/L • toxic levels ~ 2.0 meq/L • plasma drug levels must be monitored NOTE: 20-40% of bipolar patients do not respond to lithium Other Mood Stabilizing Drugs: Anticonvulsant Drugs • Valproic Acid + Sodium Valproate = Divalproex Sodium • Carbamazepine • Lamotrigene Anticonvulsant Drugs Used As Mood Stabilizers • Valproic Acid + Sodium Valproate = Divalproex Sodium (combo of the two - less GI distress) • Wider therapeutic window and faster onset than lithium (4-5 days) • May act through increasing GABA levels • GI (N&V) & hepatic problems • Congenital neural tube defects • Alopecia (hair loss) Anticonvulsant Drugs Used As Mood Stabilizers • Carbamazepine • Most probably act through blockade of voltage dependent sodium channels • Aplastic anemia and agranulocytosis (more with carbamazepine) • pharmacokinetic tolerance through autoinduction of metabolism • hyponatremia (~3%), diplopia, ataxia, GI upset, sedation, wt gain Anticonvulsant Drugs Used As Mood Stabilizers • Lamotrigene Not effective in acute mania, used for maintenance therapy Blocks sodium and/or calcium channels. can be used as a potentiating agent for antidepressants. Helps prevent switches to mania in bipolar patients treated with antidepressants • dizziness,headache diplopia, GI upset, somnolence, skin rash • valproic acid doubles concentration of lamotrigene • carbamazepine halves concentration of lamotrigene • • • • Other mood stabilizers for treating manic bipolar state • Start with atypical antipsychotics – Aripiprazole, olanzapine, quetiapine, risperidone and ziprasideone – Olanzepine followed by fluoxetine • Control acute mania then possibly add BZD and lithium • Sedative drugs such as benzodiazepines may be given to sedate a manic individual. Other Drugs in Bipolar Antidepressants • Start mood stabilizer before antidepressants • TCA & venlafaxine most likely to cause switch to mania • Bupropion, escitalopram and paroxetine have a low probability of a switch to mania Summary • • • • • • • Schizophrenia is a type of psychosis with positive, negative, and cognitive symptoms Antipsychotics control bizarre behavior, calm agitation, improve thought disorders Typical antipsychotics more effective with positive symptoms; atypical antipsychotics effective for positive and negative symptoms Dopamine imbalance likely cause of schizophrenia symptoms Dopamine hypothesis has evidence to support and evidence to refute—review points Typical antipsychotics interact with many receptors; many side effects Typical antipsychotics can induce extrapyramidal symptoms – Seen as dystonias, Parkinson’s-like syndrome, neuroleptic malignant syndrome • • Many side effects, some evident in short term, some appear after years of therapy Atypical antipsychotics have less propensity to induce tardive dyskinesia • Lithium is a mood stabilizer that depletes DAG, IP3 second messenger signaling; results in reduced synaptic transmission – However, have another set of significant side effects – Significant side effects • Newer mood stabilizers are more common, fewer side effects