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Antipsychotic Drugs William H. Anderson, Ph.D. Washoe County Sheriff’s Office Reno, NV Various Names for These Drugs ANTIPSYCHOTICS MAJOR TRANQUILIZERS NEUROLEPTICS PSYCHOTROPIC AGENTS Schizophrenia Disturbance lasting at least 6 months & including at least 1 month of 2 or more of the following positive symptoms: Positive symptoms include Delusions- beliefs that are contrary to reality & can involve control, grandeur, or persecution Hallucinations- perceptions that occur in the absence of stimuli often auditory and/or olfactory Disorganized speech Grossly disorganized or catatonic behavior Negative symptoms DMS-IV Schizophrenia Negative symptoms: Alogia-Poverty of speech and low initiative Avolition-lack of will Anhedonia-absence of pleasure Affective flattening-lack of emotional expression Mood symptoms: Depression, Anxiety, Hopelessness, etc. Social or occupational dysfunction DMS-IV Schizophrenia Common onset 15-25 years of age 1% general population develops at some point in their lives Common major mental illness in 65+ years Smoking: 3 times more likely in schizophrenia than general population Excessive mortality 20% shorter life expectancy 10% suicide rate Antipsychotic Medications Antipsychotic medications diminish the thought disorder evident in schizophrenia AP medications have similar efficacy (mostly act on positive symptoms) AP medications require weeks to take effect Antipsychotic Medications We don’t know how they work but they act upon many receptors D1, D2, D4, D5, 5HT2, 5HT6, 5HT7, alpha1adrenergic, H1, cholinergic - muscarinic, nicotinic They have many side effects and serious toxicities We are not sure of their therapeutic range There is overlap between therapeutic and toxic blood concentrations for some - many are difficult to analyze - they are ubiquitous Antipsychotic Medications Receptor Oriented Side Effects Sedation – Antihistaminic Weight gain – Antiserotonergic EPS, prolactin release – Antidopaminergic Urinary retention, dry mouth, blurred vision, constipation, sinus tachcardia, cognitionand memory effects – Anticholinergic Orthostatic hypotension, reflex tachycardia – Anti-alpha1-adrenergic Introduction of Antipsychotics in the US 1950 1960 1970 1980 Era of “Typical Antipsychotics” 1990 2000 Terms used to categorize antipsychotics Typical Conventional Classic Standard 1st Generation vs. vs. vs. vs. vs. Atypical Novel New Modern 2nd Generation Classes of Antipsychotic Medications Typical (e.g. CPZ) Block D2 receptors Produce neurological effects (neuroleptics…) Atypical Greater separation between AP action and extrapyramidal activity Block D4 receptors: Clozapine acts on D4 receptors in the accumbens (but not in the striatum) Less risk of extrapyramidal (EP) effects Negative symptoms may respond to atypical AP medications (e.g. risperdal) Typical vs. Atypical Typical High D2 Low 5-HT2A D1=D2 Increases NT in caudate and nucleus accumbens Atypical High 5-HT2A Lower D2 Low D1 Increases NT in nucleus accumbens only Antipsychotics: ADME Large interindividual variation in bioavailability GI absorption tends to be incomplete High degree of first pass metabolism Large to very large Vd Weak bases Highly protein bound Antipsychotics: ADME Extensive hepatic metabolism CYP 450 Possible CYP 450 polymorphism Significant active metabolite profile Phenothiazine Antipsychotics Mellaril® Prolixin® (thioridazine) (fluphenazine) Serentil® Stelazine® Thorazine® Trilafon® Vesprin® (mesoridazine) (trifluoperazine) (chlorpromazine) (perphenazine) (triflupromazine) Phenothiazines CH3 N N CH3 N Cl CH3 N S CH3 S Chlorpromazine S Thioridazine ADDITIONAL CLASSICAL ANITPSYCHOTICS Haldol® Loxitane® Moban® Navane® (haloperidol), Haldol Decanoate (loxapine) (molindone) (thiothixene) Extrapyramidal Symptoms Clinical Symptoms Tremor Dystonic reactions Pseudo parkinsonism Akathisia Therapy to Prevent EPS Treat EPS with benztropine (Cogentin), trihexyphenidyl (Artane ), biperiden (Akineton ) or diphenhydramine Tardive dyskinesias Potentially irreversible Acute Dystonia (First week to month) Severe spasm of the muscles of the tongue, neck or back • Oculogyric Crisis: involuntary upward deviation of the eyes Opisthotonus: tetanic spasm of the back muscles causing the trunk to arch forward while head and lower limbs are thrust backward. • These result in torticallis, facial grimacing These may result in joint dislocation Laryngeal dystonia: can impair respiration Pseudo-Parkinsonism bradykinesia slowing of movement pill rolling mask-like faces hyper salivation (drooling) resting tremor rigidity shuffling gait cog wheeling stooped posture Akathisia Inability to sit or remain quiet characterized by pacing squirming the need to be in motion profound sense of restlessness Tardive Dyskinesia Involuntary choreoathetiod movements of tongue and face choreoathetiod: twisting, writhing worm-like movements lip smacking tongue flicking motions may also produce movements of limbs, toes, fingers Risk increases with length of time on medication and dosage of medication. These symptoms are non-reversible for most patients. There is no effective treatment for TD Sudden Death Syndrome Phenothiazines Large daily doses (>1000 mg) Mechanism: Asphyxiation seizure ventricular fibrillation CV collapse during hypotensive crisis Some atypical drugs also cause sudden death Neuroleptic Malignant Syndrome Loss of thermal regulation Contributing Factors: ambient heat & dehydration underlying brain damage & dementia high neuroleptic dose (genetic vulnerability?) Treatment neuroleptic withdrawal intensive supportive care (hydration, temp. reg.) medications (dantrolene or pergolide) Phenothiazine Lethality Phenothiazines are generally safe drugs even when taken in overdose. Their therapeutic indices ~200. Deaths due to overdose have been reported, but these are rare. Emergency Department Episodes 1994-2001 Estimated From SAMSHA DAWN Data chlorpromazine fluphenazine perphenazine thioridazine 20 00 19 98 trifluoperazine 19 96 19 94 3500 3000 2500 2000 1500 1000 500 0 Thioridazine (Mellaril) 1959 Formulations: Tablets (10-100 mg) Liquid (30-100 mg/mL) Initial dose 25 mg po t.i.d. Maximum: 800 mg/day Titrate down to maintenance dose N CH3 N S CH3 S Thioridazine: Pharmacology Vd: 18 L/kg Half-life: N 26-36 hr Metabolism CH3 N CH3 S in the gastric mucosa and during first pass 12 metabolites Pathways: S Oxidation (e.g. mesoridazine*, sulforidazine*) Ring oxidation (e.g. ring sulfoxide) N-Demethylation Hydroxylation Glucuronidation Thioridazine: Dosing N Single Acute Oral Average serum CH3 4 hr 25 mg: 0.05 mg/L parent 0.17 mg/L mesoridazine 0.05 mg/L sulforidazine Peak plasma 100 mg: 0.24 mg/L thioridazine (1.7 hr) 0.32 mg/L mesoridazine (4 hr) 0.08 mg/L sulforidazine (6.9 hr) N S CH3 S Liver Establishes Overdose A. Poklis, Chap 31, Casarett & Doull’s Toxicology: the Basic Science of Poisoning. C.D. Klaassen, ed. 2001 Suicide via Chlorpromazine Subject 62 year old white female assisted living complex private apartment history schizophrenia paranoia reclusive tobacco use Suicide via Chlorpromazine Investigation found by apartment manager last contact 10 days prior no evidence of disturbance or struggle ME case living room couch unknown/ possible natural cause autopsy ordered two letters with wording indicating suicidal intent Suicide via Chlorpromazine Autopsy Pulmonary emphysema, moderate diffuse Probable colloid goiter, thyroid gland Postmortem decomposition, severe Toxicology Central “blood” chlorpromazine: positive (qns for quantification) alprazolam: 0.17 mg/L ethanol: 40 mg/dL Liver chlorpromazine: 550 mg/kg Suicide via Chlorpromazine Disposition further investigation revealed: a recent chlorpromazine prescription the decedent’s estranged husband had committed suicide four weeks prior cause of death 40-50 tablets (100 mg) missing chlorpromazine toxicity manner of death suicide RE Winecker Amer Acad Forensic Sci, 2003 Haloperidol: Dosing O Single Acute 0.5 to 5 mg > 100 mg daily CCH2CH2CH2 N OH F Cl up 1000 mg daily Peak Plasma Oral OH ≤ 5 hr 10 mg: 3 μg/L OH N Intramuscular 20 min 2 mg: 5 μg/L Cl F Phenothiazines: BioAnalytical Considerations Absorption to glassware Interference (artifacts and mtb’S) Loss of drug in plasma: PROTEIN BINDING Liver important for PM interpretation (10 mg/kg) Postmortem re-distribution (8x) Drug/metabolite stability Phenothiazines: BioAnalytical Considerations Spot tests Detection in Routine Screens Liquid/Liquid or Solid Phase Extraction of bases TLC GC-NPD, GC-ECD HPLC Quantitative Analysis GC/MS LOD- 1 to 5 ng/mL Atypical Antipsychotics Serotonin & Dopamine Antagonists Treats both positive & negative symptoms with fewer side effects. Much Less Extrapyramidal Symptoms Controls Mood & Behavior -Physical Coordination Appetite -Body Temperature Sleep Emergency Department Episodes 1994-2001 Estimated From SAMSHA DAWN Data 6000 olanzapine 5000 quetiapine 4000 risperidone 3000 2000 1000 0 1994 1995 1996 1997 1998 1999 2000 2001 Olanzapine Chemistry (Zyprexa®) Structure C17H20N4S MW = 312.44 pKa = 5.0, 7.4 Thienobenzodiazepine Derivative Organic base Olanzapine General Information FDA Approval in late 1996 Tablets as free base 2.5, 5, 7.5, and 10-mg doses Daily doses range from 10-20 mg a day Olanzapine Adverse Effects Drowsiness Dry mouth Hypotension Parasthesias CNS Depression Tachycardia Increased mortality in elderly with dementiarelated psychosis Life-threatening hyperglycemia Alteration of blood lipids Elongated Q-T intervals Possible weight problems Gain and loss Constipation Olanzapine Pharmacokinetics Absorption Well absorbed Extensive 1st pass metabolism - 40 % Distribution Vd T 1/2 Protein Binding 10 -20 L/kg 21 - 54 hours 93 % Olanzapine Pharmacokinetics Metabolism P450 CYP 1A2 & 2D6 N-desmethyl & 2 Hydroxymethylolanzapine Glucuronidation Elimination 57 % dose recovered in urine 7 % as unchanged drug Olanzapine Analytical Considerations Thio group very unstable In-vitro 16 % in extraction 40 % during 1 week at 4OC Possibly stabilize with 0.25 % ascorbic acid Olanzapine Analytical Methods TLC HPLC GLC GC/MS Internal standards: promazine, ethylmorphine ethyl-olanzapine (Lilly Co) Olanzapine Therapeutic Steady- State Trough Concentrations Daily Dose 5 10 15 20 Olanzapine, ng/mL 7 9-14 19-21 ~26 Aravagiri et al. Therap Drug Monitor, 1997 Olanzapine Blood Concentrations 1653 Clinical Specimens Olanzapine (ng/mL) Range 3 - 390 Mean 36 +/- 40 Median 26 86 % of the cases Range: 5-75 58 Postmortem Specimens Olanzapine (ng/mL) Range 10 – 5,000 Mean 358 +/- 758 Median 130 75 % less than 30O 86 % less than 500 Robertson et al. J Forensic Sci, 1999 Olanzapine Blood Concentrations Suggested that toxicity should be considered at conc above 100 ng/mL One death due primarily to olanzapine at 160 ng/mL Robertson et al. J Forensic Sci, 1999 Other studies showed postmortem toxicity often above 1000 ng/mL Literature reports of death at 237, 675, 400 heart (270 carotid) ng/mL Olanzapine Postmortem Femoral Blood Concentrations Mode of Death Olanzapine, ng/mL mean range Suicides (5) 400 25 – 1,600 Accident (11) 90 25 – 190 Natural (5) 50 25 - 180 Homicide (1) 50 Undetermined (2) 10; 1,200 D. Anderson, AAFS 2003 Olanzapine Postmortem Redistribution 16 deaths – Heart/femoral ratio averaged 4.9 (0.7-23) D. Anderson, SOFT 1998 Dual Column NPD Olanzapine Promazine (IS) A. RTx-200: trifluoropropylmethyl polysiloxane (Restek) B. RTx-50: 50% phenyl, 50% methyl polysiloxane (Restek) Jenkins et al. J Anal Toxicol 1998 Quetiapine General Information Developed in 1993 FDA approval in Sept. 1997 Manufactured by Zeneca Pharmaceuticals Tablets as a fumarate salt (Seroquel®) 25, 100 & 200 mg dose Daily doses range from 150-750 mg Quetiapine Chemistry Structure C21H25N3O2S MW =383.6 pKa=3.3, 6.8 Dibenzothiazepine, organic base Structurally related to Clozapine Quetiapine Adverse Effects Dizziness Somnolence, sedation Constipation Dry mouth Dyspepsia Tachycardia Hypotension Hyperglycemia Diabetes Headache Quetiapine Pharmacokinetics Absorption Rapidly and completely absorbed after oral administration. Distribution Vd T 1/2 Protein Binding 10 L/kg 2.7-9.3 hours 83 % Quetiapine Pharmacokinetics Metabolism CYP3A4 Sulfoxidation - Inactive Oxidation - Inactive Active Metabolite : 7-Hydroxyquetiapine Elimination 73 % dose recovered in urine Less 1% as unchanged drug Quetiapine Dosage Regimen Peak Plasma conc within 1.5 hours Steady state within 2 days of dosing Dosing Day 1: Day 2-3: Target: 25 mg bid 25-50 mg bid or tid 300-400 mg a day Quetiapine Therapeutic Concentrations 75 mg oral dose mean, 279 ng/mL range, 140 – 365 ng/mL 450 mg daily dose mean, 402 ng/mL range, 195 – 632 ng/mL Quetiapine Average Quetiapine (ug/ml or ug/g) Heart Blood Femoral Blood Liver 6.6 (14 ) 5.3 (12) 76 (7) 2.3 (12) 2.3 (7) 37 (4) 0.65 (7) 0.62 (4) 5.4 (3) Mode Suicide (22 cases) Accident (24) Natural (33) Total 79 cases* *Not all cases contained parent drug - metabolites only in some D. Anderson, AAFS 2003 Toxic Quetiapine Concentrations Parker and McIntyre, JAT, 2005 (21 cases) Wise and Jenkins, JFS, 2005 (3 cases) Heart blood 0.72-18.37 mg/L Langman, Kaliciak, Carlyle, JAT, 2004 (3 cases) > than 1 mg/L in peripheral and central blood > than 0.5 mg/L in vitreous > than 5 mg/kg in liver – especially helpful Blood: 7.2, 16, 5.9 mg/L Liver: 120 mg/kg (only data reported) Similar reports in literature Quetiapine Analytical Considerations Basic Drug L/L extractions-Various TLC GC/NPD HPLC GC/MS Metabolite Pattern Quetiapine Cross-reacts with TCA Immunoassays Emit & CEDIA, not Triage cross-reacts at 100 ug/mL parent drug in urine Normal therapeutic urine <1.0 ug/mL parent drug Patient urine following therapy & overdose, positive yield TCA results Cross-reactivity related to metabolites Hendrickson & Morocco, J Clin Toxicol 2003 Capillary HP-5 NPD A. 7-Hydroxyquetiapine B. quetiapine metabolite C. quetiapine metabolite D. quetiapine Anderson & Fritz J Anal Toxicol 2000 Quetiapine GC/MS Quetiapine: Major Metabolite: Minor Metabolites: 210, 239, 144, 253, 321 227, 210, 209, & 251 210, 239, 209, 251 210, 209, 239, 251, 322 Suicide via Quetiapine Subject 44 year old white female - homemaker History - depression medications bupropion fluoxetine dextroamphetamine quetiapine Suicide via Quetiapine Investigation found by neighbors 3 p.m. last seen alive 9:30 a.m. no evidence of disturbance or struggle body in bedroom an autopsy ordered a letter addressed to “my dear husband” - wording indicating suicide a bottle of quetiapine - 70 pills missing Suicide via Quetiapine Autopsy Mild pulmonary congestion and edema Healing contusions of abdomen and thigh Granular material in stomach Toxicology Central blood Trace: bupropion, detromethorphan, doxylamine Fluoxetine: 0.7 mg/L Norfluoxetine: 1.1 mg/L Peripheral blood Quetiapine: 230 mg/L Quetiapine: 43 mg/L Liver Quetiapine: 200 mg/kg Suicide via Quetiapine Disposition of death cause - quetiapine toxicity manner - suicide RE Winecker Amer Acad Forensic Sci, 2003 Risperidone General Information Available since 1993 Tablets 0.25, 0.5, 1, 2, 3, 4-mg Solution 1 mg/ml Risperidone Chemistry C23H27FN4O2 MW = 410.49 pKa = ?? Benzisoxazole Derivative Risperidone Pharmacokinetics Dosing Initial Dose Increase 1 mg bid on 2nd and 3rd day Maximum 3 mg bid Dosage adjustments at 1-week intervals Bioavailability 1 mg bid 68-82 % Distribution Vd 0.7-2.1 L/kg Risperidone Pharmacokinetics Metabolism Hydroxylation 9-Hydroxyrisperidone (9-OH-R) Active - equivalent to risperidone CYP2D6 polymorphism ~ 6-10% caucasians ~ 1% Asian Oxidative N-dealkylation inactive Risperidone Pharmacokinetics Plasma half-life risperidone risperidone 9-OH-risperidone 9-OH-risperidone ~ 3 hr (fast) ~ 20 hr (slow) ~ 21 hr (fast) ~ 30 hr (slow) Elimination 70% dose recovered in urine 15% dose recovered in feces Risperidone Pharmacokinetics Blood/plasma ratio 0.67 Time to peak plasma concentration risperidone ~ 1 hr 9-OH-risperidone ~ 3 hr (fast) ~ 17 hr (slow) Time to steady state risperidone 9-OH-risperidone ~ 1 day (fast -EM) ~ 5 day (slow-PM) ~ 5 days (fast) Risperidone Therapeutic SteadyState Plasma Concentrations, ng/mL Dose, mg Risperidone 2 6 10 16 3.2 9.2 13 15 9-hydroxyrisperidone 11 34 60 98 Recent Case WCSO – None Detected Long Term Care Facility – Dose to patient 0.5 mg/day Were they providing adequate care and giving prescribed dose? National Medical Services, Toxi-News,2001 Risperidone Adverse Effects Dizziness Somnolence Nausea Hypotension Anxiety Headache Tachycardia EKG changes Confusion Lethargy Drooling Sudden death in elderly with dementia Risperidone Overdose Cases 8 cases: 20 - 300 mg ingested No fatalities Drowsiness & sedation Tachycardia & hypotension Extrapyramidal symptoms MM McMullin, AAFS 1995 Risperidone Analytical Considerations Large MW & Polar molecule Low Therapeutic Concentrations RIA (Janssen) ToxiLab Rf 0.25 Ris/9-OH, brown stage IV Liquid-liquid extraction GC: Thermal degradation HPLC: diode-array or MS Risperidone Toxic & Lethal Concentrations 100 mg ingestion 1,070/100 ng/ml (Ris/9-OH-R)-Admission Blood 74/50 ng/ml - 48 hours post ingestion Suicidal Ingestion 1,800 ng/ml Blood 14,400 ng/ml Urine Lee et al., J. Clin., Psychopharm., 1997 Springfield & Bodiford, J Anal Toxicol, 1996 Clozapine General Information Available since 1989 Tablets 25, 100 mg C18H19ClN4 MW = 326.83 pKa = 3.7, 7.6 Tricyclic dibenzodiazepine derivative Clozapine Pharmacokinetics Dosing Initial 12.5 mg once or twice per day Increase to 300-450 mg/day after two weeks Bioavailability Vd Half-Life Metabolism 50-60% 2-7 L/kg 6-17 hrs. N-demethylation, N-oxidation, oxidation of chlorine-containing ring, and thiomethyl conjugation. N-desmethylclozapine has very little activity; others inactive Metabolized by P450 CYP1A2 Clozapine Pharmacokinetics Elimination 50% dose excreted in urine 30% dose excreted in feces Trace amounts of unchanged drug excreted in urine in therapeutic dosing Blood/plasma ratio 0.80 Time to peak plasma concentration 3 hrs Range: 1-6.3 hrs Clozapine Therapeutic Steady State Plasma Concentrations 500 mg daily for 12 weeks 200-700 mg/day Clozapine 0.472 mg/L Norclozapine 0.201 mg/L in those who responded to treatment Clozapine 0.328 mg/L Norclozapine 0.156 mg/L in those unresponsive to treatment Threshold for response 0.350–0.400 mg/L but adverse effects over twice as high at 0.350 or greater as compared to below 0.350 0.03-1.016 mg/L All studies show wide variations in concentrations as a function of dose Clozapine Adverse Affects Agranulocytosis Risk so high that drug should be reserved for use in Severely ill patients who show inadequate response to conventional antipsychotics Reducing the risk of recurrent suicidal behavior Patients must have a baseline WBC and ANC before initiation of therapy as well as regular WBC and ANC during treatment and for a least 4 weeks after discontinuation of treatment. Seizures Greater chance at higher dose Clozapine Adverse Affects Myocarditis – Potentially fatal especially in first month of therapy Orthostatic hypotension Increased mortality in elerdly patients with dementia-related physhosis Hyperglycemia NMS – Neuroleptic Malignant Syndrone Anticholinergic toxicity Clozapine Analytical Considerations Not a difficult drug to assay Gas Chromatography FID, NPD, MS Concern over N-oxide reduction to clozapine HPLC UV, electrochemical detection, MS Clozapine Concentrations in Non-Lethal Overdose Cases Pediatric patients Confusion, ataxia, hyper-hypo tonic disorders Adults (accidental overdose) Seizures 0.51; 0.54 mg/L 1.3; 2.2 ; 3.8 mg/L Adults (intentional overdose – 7 cases) 2.9 – 9.5 mg/L Clozapine Concentrations in Fatal Overdose Cases Blood (mg/L) Liver (mg/kg) Average 5.2 46 Range 1.2 - 13 19 - 85 Baselt, Disposition of Toxic Drugs and Chemical in Man, Seventh Ed., 2004 Ziprasidone (Geodon®) Available since 1992 Capsules 20,40,60,80 mg Solution for injection 20 mg/mL C21H21ClN4OS MW = 412 If you are a mass spectrometer Ziprasidone Pharmacology High affinity for: Moderate affinity for H1 Antagonist for: D2, D3, 5HT2A, 5HT2C,5HT1A, 5HT1D, 1 D2, 5HT2A, 5HT1D High 5HT/D Agonist for 5HT1A Inhibits serotonin and norepinephrine reuptake No affinity for muscarinic receptor Ziprasidone Pharmacokinetics Dosing Schizophrenia Bipolar mania Initial 20 mg BID with food If necessary, may increase slowly to 80 mg BID 40 mg BID with food Increase to 60 or 80 mg BID on second day Adjust dose efficacy and tolerance to 40-80 mg BID Bioavailability Vd Half-Life 60% 1.5 L/kg 4 – 8 hrs Ziprasidone Pharmacokinetics Metabolism 12 known metabolites Major circulating metabolites are: Therapeutic affect primarily due to parent drug Benzisothiazole (BITP) sulphoxide BITP-sulphone Ziprasidone sulphoxide S-methyl-dihydroziprasidone Metabolism mediated by P450 CYP3A4 CYP1A2 to a much lesser extent Ziprasidone Pharmacokinetics Elimination 20% in urine Only trace amounts of unchanged drug 66% in feces Time to peak plasma concentration 2 – 6 hrs Ziprasidone Adverse Affects During Therapy Sedation Headache Postural hypotension NMS Tardive dyskensia Prolongation of QT interval Less weight gain than other atypicals Dizziness Overdose Several cases all non-fatal QT changes (minimal) Delerium Hemodynamic instability Diarrhea Urinary retention No EPS If you have a fatal case, let me know! Ziprasidone Blood Concentrations 4 healthy males administered 20 mg Ziprasidone for 11 days Mean plasma concentration 45.4 ng/mL with a range of 28.8-62 ng/mL 39 males administered fixed doses of 10, 40, and 40 escalated to 80, and 40 escalated to 120 mg On day 18, peak plasma concentrations were 14.8, 44.6, 118.6, 139.4 ng/mL Ziprasidone Analytical Consideratioins Extraction Liquid-liquid C18 cartridges Detection/Quantification HPLC – UV detection LC/MS/MS Aripiprazole (Abilify®) Available since 2002 Tablets Oral Solution 10, 15, 20, 30 mg 1 mg/mL C23H27Cl2N3O2 MW = 448.38 Aripiprazole Pharmacology High Affinity for: Moderate affinity for: D2, D3, 5HT1A, 5HT2A D4, 5HT2C, 5HT7, 1, H1, serotonin reuptake site No affinity for muscarinic receptors * Partial agonist D2 and 5HT1A * Antagonist at 5HT2A Aripiprazole Pharmacokinetics Dosing Bioavailability 10 or 15 mg qd Tablets 87% Solution near 100% Vd = 4.9 L/kg Half-Life Aripiprazole 75 hrs EM 146 hrs PM Dehydroariprazole 94 hrs Aripiprazole Pharmacokinetics Metabolism Dehydrogenation and hydroxylation N-dealkylation CYP3A4 and CYP2D6 CYP3A4 Active metabolite Dehydroaripiprazole Approximately = parent About 40% of parent in EM Measure total active moiety Aripiprazole Pharmacokinetics Elimination 25% of dose excreted in urine 55% excreted in feces Time to peak plasma concentration Less than 1% excreted unchanged 3-5 hrs Steady state attained within 14 days for both active moieties Aripiprazole Adverse Affects Schizophrenia and Bipolar Disorder Headache, Nausea Vomiting, Constipation Anxiety, agitation Insomnia, sleepiness Dizziness Akathisia, EPS Drug Interactions Overdose Nausea, vomiting, asthenia, diarrhea, somnolence Tachycardia, EPS CNS depression Somnolence, transient loss of consciousness, CNS effects for 2 weeks Aripiprazole Concentration in Blood 27-year-old female Ingested 330 mg of aripiprazole Total active moiety of 716 ng/mL According to manufacture = ~ 6X upper limit of therapeutic dosing One clinical study suggest range for aripiprazole of 146-254 ng/mL (metabolite not measured) Not aware of a death case – doesn’t mean there isn’t one Analysis Clean up by direct injection of diluted sample and columnswitching LC/MS/MS or with UV detection Acknowledgement The presenter would like to thank Dr. Alphonse Poklis for the organizational concept for this presentation.