Various Names for These Drugs. Antipsychotic Drugs. Schizophrenia

Transcription

1 Various Names for These Drugs Antipsychotic Drugs William H. Anderson, Ph.D. Washoe County Sheriff s s Office Reno, NV 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 Negative symptoms: Schizophrenia Alogia-Poverty of speech and low initiative Avolition-lack lack of will Anhedonia-absence absence of pleasure Affective flattening-lack lack of emotional expression Mood symptoms: Depression, Anxiety, Hopelessness, etc. Social or occupational dysfunction DMS-IV 1

2 Schizophrenia Common onset 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 t know how they work but they act upon many receptors D 1, D 2, D 4, D 5, 5HT 2, 5HT 6, 5HT 7, alpha 1 - adrenergic, H 1, 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-alpha 1 -adrenergic 2

3 Introduction of Antipsychotics in the US Chlorpromazine 54 Fluphenazine 59 Thioridazine 59 Haloperidol 67 Clozapine 90 Risperidone 94 Olanzapine Era of Typical Antipsychotics Quetiapine 97 Ziprasidone 01 Terms used to categorize antipsychotics Typical Conventional Classic Standard 1 st Generation vs. vs. vs. vs. vs. Atypical Novel New Modern 2 nd Generation Classes of Antipsychotic Medications Typical (e.g. CPZ) Block D2 receptors Produce neurological effects (neuroleptics( 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 D 2 Low 5-HT5 2A D 1 =D 2 Increases NT in caudate and nucleus accumbens Atypical High 5-HT5 2A Lower D 2 Low D 1 Increases NT in nucleus accumbens only 3

4 Antipsychotics: : ADME Large interindividual variation in bioavailability GI absorption tends to be incomplete High degree of first pass metabolism Large to very large V d Weak bases Highly protein bound Antipsychotics: ADME Extensive hepatic metabolism CYP 450 Possible CYP 450 polymorphism Significant active metabolite profile Phenothiazine Antipsychotics Phenothiazines Mellaril Prolixin Serentil Stelazine Thorazine Trilafon Vesprin (thioridazine) (fluphenazine) (mesoridazine) (trifluoperazine) (chlorpromazine) (perphenazine) (triflupromazine) CH 3 N N S Chlorpromazine CH 3 Cl N N S Thioridazine CH 3 S CH 3 4

5 ADDITIONAL CLASSICAL ANITPSYCHOTICS Haldol (haloperidol), Haldol Decanoate Loxitane (loxapine) Moban (molindone) Navane (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 These result in torticallis, facial grimacing 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 may result in joint dislocation Laryngeal dystonia: can impair respiration Pseudo-Parkinsonism Parkinsonism bradykinesia slowing of movement pill rolling mask-like faces hyper salivation (drooling) resting tremor rigidity shuffling gait cog wheeling stooped posture 5

6 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) 6

7 Phenothiazine Lethality Emergency Department Episodes Estimated From SAMSHA DAWN Data 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 chlorpromazine fluphenazine perphenazine thioridazine trifluoperazine Thioridazine (Mellaril ) Thioridazine: Pharmacology 1959 Formulations: Tablets ( mg) Liquid ( mg/ml) Initial dose 25 mg po t.i.d. Maximum: 800 mg/day Titrate down to maintenance dose N S N CH 3 S CH 3 V d : 18 L/kg Half-life: life: hr Metabolism in the gastric mucosa and during first pass 12 metabolites Pathways: Oxidation (e.g. mesoridazine*, sulforidazine*) Ring oxidation (e.g. ring sulfoxide) N-Demethylation Hydroxylation Glucuronidation N S N CH 3 S CH 3 7

8 Thioridazine: Dosing Liver Establishes Overdose Single Acute Oral Average serum 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 N CH 3 S CH 3 A. Poklis, Chap 31, Casarett & Doull s Toxicology: the Basic Science of Poisoning. C.D. Klaassen, ed 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 living room couch last contact 10 days prior no evidence of disturbance or struggle ME case unknown/ possible natural cause autopsy ordered two letters with wording indicating suicidal intent 8

9 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 tablets (100 mg) missing the decedent s s estranged husband had committed suicide four weeks prior cause of death chlorpromazine toxicity manner of death suicide RE Winecker Amer Acad Forensic Sci, 2003 Single Acute 0.5 to 5 mg > 100 mg daily up 1000 mg daily Peak Plasma Oral Haloperidol: Dosing 5 hr 10 mg: 3 µg/l Intramuscular 20 min 2 mg: 5 µg/l F F O CCH 2 CH 2 CH 2 N OH N OH OH Cl Cl 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 9

10 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 6000 Emergency Department Episodes Estimated From SAMSHA DAWN Data olanzapine Olanzapine Chemistry (Zyprexa ) quetiapine risperidone Structure C 17 H 20 N 4 S MW = pka = 5.0, 7.4 Thienobenzodiazepine Derivative Organic base 10

11 Olanzapine General Information Olanzapine Adverse Effects FDA Approval in late 1996 Tablets as free base 2.5, 5, 7.5, and 10-mg doses Daily doses range from mg a day Drowsiness Dry mouth Hypotension Parasthesias CNS Depression Tachycardia Increased mortality in elderly with dementia- related psychosis Life-threatening hyperglycemia Alteration of blood lipids Elongated Q-T Q T intervals Possible weight problems Gain and loss Constipation Olanzapine Pharmacokinetics Absorption Well absorbed Extensive 1 st pass metabolism - 40 % Distribution Vd L/kg T 1/ hours Protein Binding 93 % Olanzapine Pharmacokinetics Metabolism P450 CYP 1A2 & 2D6 N-desmethyl & 2 Hydroxymethylolanzapine Glucuronidation Elimination 57 % dose recovered in urine 7 % as unchanged drug 11

12 Olanzapine Analytical Considerations Thio group very unstable In-vitro 16 % in extraction 40 % during 1 week at 4 O C 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 Olanzapine, ng/ml ~26 Aravagiri et al. Therap Drug Monitor, 1997 Olanzapine Blood Concentrations 1653 Clinical Specimens Olanzapine (ng/ml) Range Mean 36 +/- 40 Median % of the cases Range: Robertson et al. J Forensic Sci, Postmortem Specimens Olanzapine (ng/ml) Range 10 5,000 Mean 358 +/- 758 Median % less than 30O 86 % less than

13 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) ,600 Accident (11) Natural (5) Homicide (1) 50 Undetermined (2) 10; 1,200 D. Anderson, AAFS deaths Olanzapine Postmortem Redistribution 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

14 Quetiapine General Information Quetiapine Chemistry Developed in 1993 FDA approval in Sept Manufactured by Zeneca Pharmaceuticals Tablets as a fumarate salt (Seroquel ) 25, 100 & 200 mg dose Daily doses range from mg Structure C 21 H 25 N 3 O 2 S MW =383.6 pka=3.3, 6.8 Dibenzothiazepine, organic base Structurally related to Clozapine Quetiapine Adverse Effects Quetiapine Pharmacokinetics Dizziness Somnolence, sedation Constipation Dry mouth Dyspepsia Tachycardia Hypotension Hyperglycemia Diabetes Headache Absorption Rapidly and completely absorbed after oral administration. Distribution Vd T 1/2 2.7 Protein Binding 83 % 10 L/kg hours 83 % 14

15 Quetiapine Pharmacokinetics Metabolism CYP3A4 Sulfoxidation - Inactive Oxidation - Inactive Active Metabolite : 7-Hydroxyquetiapine7 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: 25 mg bid Day 2-3: mg bid or tid Target: mg a day Quetiapine Therapeutic Concentrations 75 mg oral dose mean, 279 ng/ml range, ng/ml 450 mg daily dose mean, 402 ng/ml range, ng/ml Quetiapine Average Quetiapine (ug/ml or ug/g) Mode Heart Blood Femoral Blood Liver Suicide (22 cases) 6.6 (14 ) 5.3 (12) 76 (7) Accident (24) 2.3 (12) 2.3 (7) 37 (4) Natural (33) 0.65 (7) 0.62 (4) 5.4 (3) Total 79 cases* *Not all cases contained parent drug - metabolites only in some D. Anderson, AAFS

16 Toxic Quetiapine Concentrations Parker and McIntyre, JAT, 2005 (21 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 Wise and Jenkins, JFS, 2005 (3 cases) Heart blood mg/l Langman, Kaliciak, Carlyle, JAT, 2004 (3 cases) 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 reacts with TCA Immunoassays Emit & CEDIA, not Triage cross-reacts 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 reactivity related to metabolites Hendrickson & Morocco, J Clin Toxicol 2003 Capillary HP-5 5 NPD A. 7-Hydroxyquetiapine C. quetiapine metabolite B. quetiapine metabolite D. quetiapine Anderson & Fritz J Anal Toxicol

17 Quetiapine GC/MS Quetiapine: 210, 239, 144, 253, 321 Major Metabolite: 227, 210, 209, & 251 Minor Metabolites: 210, 239, 209, , 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 Quetiapine: 230 mg/l Peripheral blood Quetiapine: 43 mg/l Liver Quetiapine: 200 mg/kg 17

18 Suicide via Quetiapine Disposition of death cause - quetiapine toxicity manner - suicide Risperidone General Information Available since 1993 Tablets 0.25, 0.5, 1, 2, 3, 4-mg4 Solution 1 mg/ml RE Winecker Amer Acad Forensic Sci, 2003 Risperidone Chemistry Risperidone Pharmacokinetics FN 4 O 2 MW = C 23 H 27 FN pka =?? Benzisoxazole Derivative Dosing Initial Dose 1 mg bid Increase 1 mg bid on 2nd and 3rd day Maximum 3 mg bid Dosage adjustments at 1-week 1 intervals Bioavailability % Distribution Vd L/kg 18

19 Risperidone Pharmacokinetics Metabolism Hydroxylation 9-Hydroxyrisperidone (9-OH OH-R) Active - equivalent to risperidone CYP2D6 polymorphism ~ 6-10% 6 caucasians ~ 1% Asian Oxidative N-dealkylationN inactive Risperidone Pharmacokinetics Plasma half-life life risperidone ~ 3 hr (fast) risperidone ~ 20 hr (slow) 9-OH-risperidone ~ 21 hr (fast) 9-OH-risperidone ~ 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 Steady- State Plasma Concentrations, ng/ml Dose, mg Risperidone 9-hydroxyrisperidone 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,

20 Dizziness Somnolence Nausea Hypotension Anxiety Headache Risperidone Adverse Effects Tachycardia EKG changes Confusion Lethargy Drooling Sudden death in elderly with dementia Risperidone Overdose Cases 8 cases: 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 R f 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 OH-R) R)-Admission Blood 74/50 ng/ml - 48 hours post ingestion Suicidal Ingestion 1,8001,800 ng/ml Blood 14,40014,400 ng/ml Urine Lee et al., J. Clin., Psychopharm., 1997 Springfield & Bodiford, J Anal Toxicol,

21 Available since 1989 Tablets 25, 100 mg C 18 H 19 ClN 4 MW = pka = 3.7, 7.6 Tricyclic dibenzodiazepine derivative Clozapine General Information Clozapine Pharmacokinetics Dosing Initial 12.5 mg once or twice per day Increase to mg/day after two weeks Bioavailability 50-60% Vd 2-77 L/kg Half-Life 6-17 hrs. Metabolism N-demethylation,, N-oxidation, N oxidation of chlorine-containing 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: hrs Clozapine Therapeutic Steady State Plasma Concentrations 500 mg daily for 12 weeks Clozapine mg/l Norclozapine mg/l in those who responded to treatment Clozapine mg/l Norclozapine mg/l in those unresponsive to treatment Threshold for response mg/l but adverse effects over twice as high at or greater as compared to below mg/day mg/l All studies show wide variations in concentrations as a function of dose 21

22 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 N reduction to clozapine HPLC UV, electrochemical detection, MS Clozapine Concentrations in Non-Lethal Overdose Cases Pediatric patients Confusion, ataxia, hyper-hypo hypo tonic disorders 0.51; 0.54 mg/l Adults (accidental overdose) Seizures 1.3; 2.2 ; 3.8 mg/l Adults (intentional overdose 7 cases) mg/l 22

23 Clozapine Concentrations in Fatal Overdose Cases Average Range Blood (mg/l) Liver (mg/kg) Baselt, Disposition of Toxic Drugs and Chemical in Man, Seventh Ed., 2004 Available since 1992 Capsules 20,40,60,80 mg Solution for injection 20 mg/ml ml C 21 H 21 ClN 4 OS MW = 412 If you are a mass spectrometer Ziprasidone (Geodon ) Ziprasidone Pharmacology High affinity for: D 2, D 3, 5HT 2A, 5HT 2C,5HT 1A, 5HT 1D, α 1 Moderate affinity for H 1 Antagonist for: D, 2 5HT 2A, 5HT 1D High 5HT/D Agonist for 5HT 1A Inhibits serotonin and norepinephrine reuptake No affinity for muscarinic receptor Ziprasidone Pharmacokinetics Dosing Schizophrenia Initial 20 mg BID with food If necessary, may increase slowly to 80 mg BID Bipolar mania 40 mg BID with food Increase to 60 or 80 mg BID on second day Adjust dose efficacy and tolerance to mg BID Bioavailability 60% Vd 1.5 L/kg Half-Life 4 8 hrs 23

24 Ziprasidone Pharmacokinetics Metabolism 12 known metabolites Therapeutic affect primarily due to parent drug Major circulating metabolites are: Benzisothiazole (BITP) sulphoxide BITP-sulphone Ziprasidone sulphoxide S-methyl-dihydroziprasidone Metabolism mediated by P450 CYP3A4 CYP1A2 to a much lesser extent Elimination 20% in urine Ziprasidone Pharmacokinetics Only trace amounts of unchanged drug 66% in feces Time to peak plasma concentration 2 6 hrs During Therapy Sedation Headache Postural hypotension NMS Ziprasidone Adverse Affects 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 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, ng/ml 24

25 Ziprasidone Analytical Consideratioins Extraction Liquid-liquid C18 cartridges Detection/Quantification HPLC UV detection LC/MS/MS Available since 2002 Tablets 10, 15, 20, 30 mg Oral Solution 1 mg/ml ml C 23 H 27 Cl 2 N 3 O 2 MW = Aripiprazole (Abilify ) Aripiprazole Pharmacology High Affinity for: D 2, D3, 5HT1A, 5HT2A Moderate affinity for: D4, 5HT 2C, 5H T7, α 1, H 1, serotonin s reuptake site No affinity for muscarinic receptors * Partial agonist D 2 and 5HT 1A * Antagonist at 5HT 2A Aripiprazole Pharmacokinetics Dosing 10 or 15 mg qd Bioavailability Tablets 87% Solution near 100% Vd = 4.9 L/kg Half-Life Aripiprazole 75 hrs EM 146 hrs PM Dehydroariprazole 94 hrs 25

26 Aripiprazole Pharmacokinetics Metabolism Dehydrogenation and hydroxylation CYP3A4 and CYP2D6 N-dealkylation 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 Less than 1% excreted unchanged 55% excreted in feces Time to peak plasma concentration 3-55 hrs Steady state attained within 14 days for both active moieties Aripiprazole Adverse Affects Schizophrenia and Overdose Bipolar Disorder Nausea, vomiting, Headache, Nausea asthenia, diarrhea, Vomiting, Constipation somnolence Anxiety, agitation Tachycardia, EPS Insomnia, sleepiness CNS depression Dizziness Akathisia,, EPS Drug Interactions Somnolence, transient loss of consciousness, CNS effects for 2 weeks Aripiprazole Concentration in Blood 27-year 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 ng/ml (metabolite not measured) Not aware of a death case doesn t t mean there isn t t one Analysis Clean up by direct injection of diluted sample and column- switching LC/MS/MS or with UV detection 26

27 Acknowledgement The presenter would like to thank Dr. Alphonse Poklis for the organizational concept for this presentation. 27