Download NEUROLEPTICS

Antipsychotic Drugs
William H. Anderson, Ph.D.
Washoe County Sheriff’s Office
Reno, NV
Various Names for These Drugs
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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
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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
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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
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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
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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

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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)
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Block D2 receptors
Produce neurological effects (neuroleptics…)
Atypical
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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
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High D2
Low 5-HT2A
D1=D2
Increases NT in caudate and nucleus accumbens
Atypical
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High 5-HT2A
Lower D2
Low D1
Increases NT in nucleus accumbens only
Antipsychotics: ADME
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Large interindividual variation in
bioavailability
GI absorption tends to be incomplete
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High degree of first pass metabolism
Large to very large Vd
Weak bases
Highly protein bound
Antipsychotics: ADME
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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
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Clinical Symptoms
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Tremor Dystonic reactions
Pseudo parkinsonism
Akathisia
Therapy to Prevent EPS
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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
•
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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.
•
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These result in torticallis, facial grimacing
These may result in joint dislocation
Laryngeal dystonia: can impair respiration
Pseudo-Parkinsonism
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bradykinesia
 slowing of movement
pill rolling
mask-like faces
hyper salivation (drooling)
resting tremor
rigidity
shuffling gait
cog wheeling
stooped posture
Akathisia
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Inability to sit or remain quiet

characterized by
pacing
 squirming
 the need to be in motion
 profound sense of restlessness
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Tardive Dyskinesia
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Involuntary choreoathetiod movements of tongue and
face
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choreoathetiod: twisting, writhing worm-like movements
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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
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Phenothiazines
Large daily doses (>1000 mg)
Mechanism:
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Asphyxiation
seizure
 ventricular fibrillation
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CV collapse during hypotensive crisis
Some atypical drugs also cause sudden
death
Neuroleptic Malignant Syndrome
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Loss of thermal regulation
Contributing Factors:
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ambient heat & dehydration
underlying brain damage & dementia
high neuroleptic dose (genetic vulnerability?)
Treatment
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neuroleptic withdrawal
intensive supportive care (hydration, temp. reg.)
medications (dantrolene or pergolide)
Phenothiazine Lethality
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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)
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1959 Formulations:

Tablets (10-100 mg)
 Liquid (30-100 mg/mL)
Initial dose
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25 mg po t.i.d.
Maximum: 800 mg/day
Titrate down to maintenance dose
N
CH3
N
S
CH3
S
Thioridazine: Pharmacology
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Vd: 18 L/kg
Half-life:
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N
26-36 hr
Metabolism
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CH3
N
CH3
S
in the gastric mucosa and during first pass
12 metabolites
Pathways:
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S
Oxidation (e.g. mesoridazine*, sulforidazine*)
Ring oxidation (e.g. ring sulfoxide)
N-Demethylation
Hydroxylation
Glucuronidation
Thioridazine: Dosing
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N
Single Acute Oral
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Average serum
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CH3
4 hr
25 mg: 0.05 mg/L parent
0.17 mg/L mesoridazine
0.05 mg/L sulforidazine
Peak plasma
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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
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Subject
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62 year old white female
assisted living complex
 private apartment
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history
schizophrenia
 paranoia
 reclusive
 tobacco use
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Suicide via
Chlorpromazine
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Investigation
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found by apartment manager
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last contact 10 days prior
no evidence of disturbance or struggle
ME case
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living room couch
unknown/ possible natural cause
autopsy ordered
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two letters with wording indicating suicidal intent
Suicide via
Chlorpromazine
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Autopsy
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Pulmonary emphysema, moderate diffuse
Probable colloid goiter, thyroid gland
Postmortem decomposition, severe
Toxicology
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Central “blood”
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chlorpromazine: positive (qns for quantification)
alprazolam: 0.17 mg/L
ethanol: 40 mg/dL
Liver
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chlorpromazine: 550 mg/kg
Suicide via
Chlorpromazine
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Disposition

further investigation revealed:
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a recent chlorpromazine prescription
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the decedent’s estranged husband had committed
suicide four weeks prior
cause of death
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40-50 tablets (100 mg) missing
chlorpromazine toxicity
manner of death
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suicide
RE Winecker Amer Acad Forensic Sci, 2003
Haloperidol: Dosing
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O
Single Acute
0.5 to 5 mg
> 100 mg daily
CCH2CH2CH2 N
OH
F
Cl
up 1000 mg daily
Peak Plasma
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Oral
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OH
≤ 5 hr
10 mg: 3 μg/L
OH
N
Intramuscular
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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
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Spot tests
Detection in Routine Screens
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Liquid/Liquid or Solid Phase Extraction of bases
TLC
GC-NPD, GC-ECD
HPLC
Quantitative Analysis
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GC/MS
LOD- 1 to 5 ng/mL
Atypical Antipsychotics
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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®)
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Structure
C17H20N4S
MW = 312.44
pKa = 5.0, 7.4
Thienobenzodiazepine Derivative
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Organic base
Olanzapine
General Information
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FDA Approval in late 1996
Tablets as free base
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2.5, 5, 7.5, and 10-mg doses
Daily doses range from 10-20 mg a day
Olanzapine Adverse Effects
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Drowsiness
Dry mouth
Hypotension
Parasthesias
CNS Depression
Tachycardia
Increased mortality in
elderly with dementiarelated psychosis
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Life-threatening
hyperglycemia
Alteration of blood lipids
Elongated Q-T intervals
Possible weight problems
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Gain and loss
Constipation
Olanzapine Pharmacokinetics
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Absorption
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Well absorbed
Extensive 1st pass metabolism - 40 %
Distribution
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Vd
T 1/2
Protein Binding
10 -20 L/kg
21 - 54 hours
93 %
Olanzapine
Pharmacokinetics
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Metabolism
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P450 CYP 1A2 & 2D6
N-desmethyl & 2 Hydroxymethylolanzapine
Glucuronidation
Elimination
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57 % dose recovered in urine
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7 % as unchanged drug
Olanzapine
Analytical Considerations
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Thio group very unstable
In-vitro
16 % in extraction
 40 % during 1 week at 4OC
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Possibly stabilize with 0.25 % ascorbic acid
Olanzapine
Analytical Methods
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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
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1653 Clinical Specimens
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Olanzapine (ng/mL)
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Range
3 - 390
Mean
36 +/- 40
Median 26
86 % of the cases
Range: 5-75
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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
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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
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16 deaths –
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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
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Developed in 1993
FDA approval in Sept. 1997
Manufactured by Zeneca Pharmaceuticals
Tablets as a fumarate salt (Seroquel®)
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25, 100 & 200 mg dose
Daily doses range from 150-750 mg
Quetiapine Chemistry
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Structure
C21H25N3O2S
MW =383.6
pKa=3.3, 6.8
Dibenzothiazepine, organic base
Structurally related to Clozapine
Quetiapine Adverse Effects
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Dizziness
Somnolence, sedation
Constipation
Dry mouth
Dyspepsia
Tachycardia
Hypotension
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Hyperglycemia
Diabetes
Headache
Quetiapine Pharmacokinetics

Absorption
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Rapidly and completely absorbed after oral
administration.
Distribution
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Vd
T 1/2
Protein Binding
10 L/kg
2.7-9.3 hours
83 %
Quetiapine Pharmacokinetics

Metabolism

CYP3A4
Sulfoxidation - Inactive
 Oxidation - Inactive
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Active Metabolite : 7-Hydroxyquetiapine
Elimination

73 % dose recovered in urine
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Less 1% as unchanged drug
Quetiapine Dosage Regimen
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Peak Plasma conc within 1.5 hours
Steady state within 2 days of dosing
Dosing
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Day 1:
Day 2-3:
Target:
25 mg bid
25-50 mg bid or tid
300-400 mg a day
Quetiapine
Therapeutic Concentrations
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
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)
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Wise and Jenkins, JFS, 2005 (3 cases)
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Heart blood 0.72-18.37 mg/L
Langman, Kaliciak, Carlyle, JAT, 2004 (3 cases)

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
> 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
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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
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
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.