Transcript NEUROLEPTICS
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 stimuli perceptions that occur in the absence of 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 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
Introduction of Antipsychotics in the US
1950 1960 1970 1980 1990 2000 Era of “Typical Antipsychotics”
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 …) 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-HT 2A D 1 =D 2 Increases NT in caudate and nucleus accumbens Atypical High 5-HT 2A Lower D 2 Low D 1 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 V d Weak bases Highly protein bound
Antipsychotics: ADME
Extensive hepatic metabolism CYP 450 Possible CYP 450 polymorphism Significant active metabolite profile
Phenothiazine Antipsychotics
Mellaril ® Prolixin ® Serentil ® Stelazine ® Thorazine ® Trilafon ® Vesprin ® (thioridazine) (fluphenazine) (mesoridazine) (trifluoperazine) (chlorpromazine) (perphenazine) (triflupromazine)
Phenothiazines
CH 3 N CH 3 N CH 3 N S
Chlorpromazine
Cl N S
Thioridazine
S CH 3
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 • 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
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
3500 3000 2500 2000 1500 1000 500 0 19 94 19 96 19 98 20 00 chlorpromazine fluphenazine perphenazine thioridazine trifluoperazine
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 S N CH 3 S CH 3
Thioridazine: Pharmacology
V d : 18 L/kg Half-life: 26-36 hr Metabolism in the gastric mucosa and during first pass
N S
12 metabolites Pathways: Oxidation (e.g. mesoridazine*, sulforidazine*) Ring oxidation (e.g. ring sulfoxide) N-Demethylation Hydroxylation Glucuronidation
N CH 3 S CH 3
Thioridazine: Dosing
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
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
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
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
40-50 tablets (100 mg) missing the decedent’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
Haloperidol: Dosing
Single Acute 0.5 to 5 mg > 100 mg daily up 1000 mg daily Peak Plasma Oral ≤ 5 hr 10 mg: 3 μ g/L Intramuscular 20 min 2 mg: 5 μ g/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
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 Sleep -Body Temperature
6000 Emergency Department Episodes 1994-2001 Estimated From SAMSHA DAWN Data
olanzapine
5000
quetiapine
4000
risperidone
3000 2000 1000 0 1994 1995 1996 1997 1998 1999 2000 2001
Olanzapine
Chemistry (Zyprexa
®
)
Structure C 17 H 20 N 4 S 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 dementia related 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 1 st 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 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
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) Accident (11) Natural (5) Homicide (1) Undetermined (2) 400 25 – 1,600 90 25 – 190 50 25 50 180 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: trifluoropropyl methyl polysiloxane (Restek) B. RTx-50: 50% phenyl, 50% methyl polysiloxane (Restek)
Jenkins et al. J Anal Toxicol 1998
Quetiapine
G
eneral 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 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
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
Mode Suicide (22 cases) Accident (24) Natural (33) Total 79 cases* Average Quetiapine (ug/ml or ug/g) Heart Blood 6.6 (14 ) 2.3 (12) 0.65 (7) Femoral Blood 5.3 (12) 2.3 (7) 0.62 (4) Liver 76 (7) 37 (4) 5.4 (3) *Not all cases contained parent drug - metabolites only in some
D. Anderson, AAFS 2003
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 0.72-18.37 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 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
Quetiapine: 230 mg/L
Peripheral blood
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
C 23 H 27 FN 4 O 2 MW = 410.49
pKa = ??
Benzisoxazole Derivative
Risperidone Pharmacokinetics
Dosing
Initial Dose 1 mg bid Increase 1 mg bid on 2nd and 3rd day Maximum 3 mg bid Dosage adjustments at 1-week intervals
Bioavailability
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 ~ 3 hr (fast) risperidone ~ 20 hr (slow) 9-OH-risperidone ~ 21 hr (fast) 9-OH-risperidone
Elimination
~ 30 hr (slow) 70% dose recovered in urine 15% dose recovered in feces
Risperidone Pharmacokinetics
Blood/plasma ratio 0.67
Time to peak plasma concentration risperidone 9-OH-risperidone ~ 1 hr ~ 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 2 6 10 16 3.2
9.2
13 15 Recent Case WCSO – None Detected 11 34 60 98 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
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: 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 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-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 C 18 H 19 ClN 4 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 50-60% 2-7 L/kg Half-Life Metabolism 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 T herapeutic Steady State Plasma Concentrations 500 mg daily for 12 weeks 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
200-700 mg/day 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 0.51; 0.54 mg/L Adults (accidental overdose) Seizures 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 Average Blood (mg/L) 5.2
Liver (mg/kg) 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 C 21 H 21 ClN 4 OS MW = 412 If you are a mass spectrometer
Ziprasidone Pharmacology
High affinity for: D 2 , D 3 , 5HT 2A , 5HT 2C ,5HT 1A , 5HT 1D , 1 Moderate affinity for H 1 Antagonist for: D 2 , 5HT 2A , 5HT 1D Agonist for 5HT 1A High 5HT/D 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 40-80 mg BID Bioavailability 60% Vd 1.5 L/kg Half-Life 4 – 8 hrs
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
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 C 18 cartridges Detection/Quantification HPLC – UV detection LC/MS/MS
Aripiprazole (Abilify
®
)
Available since 2002 Tablets 10, 15, 20, 30 mg Oral Solution 1 mg/mL C 23 H 27 Cl 2 N 3 O 2 MW = 448.38
Aripiprazole Pharmacology
High Affinity for: D 2 , D3, 5HT1A, 5HT2A Moderate affinity for: D4, 5HT 2C , 5H T7 , 1 , H 1 , serotonin reuptake site No affinity for muscarinic receptors * Partial agonist D 2 Antagonist at 5HT 2A and 5HT 1A *
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
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 3-5 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 column switching LC/MS/MS or with UV detection
Acknowledgement
The presenter would like to thank Dr. Alphonse Poklis for the organizational concept for this presentation.