Download Antipsychotics and Mood Stabilizers: Pharmacokinetics

Antipsychotics and
Mood Stabilizers:
Pharmacokinetics
Adverse Effects
Drug Interactions
Manipal
1
Goals

Antipsychotics






Diagnostic indications
Classification
Relevant Pharmacokinetics
Serious Adverse Effects
Drug Interactions
Mood Stabilizers





Diagnostic indications
Classification
Relevant Pharmacokinetics
Serious Adverse Effects
Drug Interactions
2
Antipsychotics:
Diagnostic Indications
Psychiatric
 Schizophrenia
 Schizoaffective disorder
 Mood disorders with psychosis
 Delusional disorder
Nonpsychiatric
 Dementia/Delirium
 Psychosis secondary to a non-psychiatric medical disorder
 Developmental disability with psychosis and/or aggression
 Tourette’s disorder
 Nausea, vomiting
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Impact of Schizophrenic
Symptoms on Overall
Functioning
Positive
symptoms:
Delusions*
Hallucinations*
Disorganized speech
Catatonia
Negative
symptoms:
Social
Cognitive
symptoms: Work
Attention
Memory
Executive functions
Affective flattening
Occupational Alogia
Avolition
Anhedonia
Social inattentiveness
Interpersonal Mood
Selfcare
*Schneiderian First Rank Symptoms
symptoms:
Dysphoria
Suicidality
Helplessness
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Pharmacokinetics of
Antipsychotics

ADME profiles


All are readily absorbed
All are metabolized by the hepatic cytochrome
P450 system


T1/2 is generally 20 hours except:


prone to drug interactions
ziprasidone, quetiapine, aripiprazole
Dosing adjustment in elderly renal and/or
hepatic impairment
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Antipsychotic Agents
Class/Trade Name
Generic Name
Dosage (average range; PO, qd)
Thorazine
Chlorpromazine
100-1000 mg
Sparine
Vesprin
Promazine
Triflupromazine
25-1000 mg
20-150 mg
Mellaril
Serentil
Quide
Thioridazine
Mesoridazine
Piperacetazine
30-800 mg
20-200 mg
20-160 mg
Stelazine
Prolixin
Trilafon
Tindal
Compazine
Trifluoperazine
Fluphenzine
Perphenazine
Acetophenazine
Prochlorperazine
2-60 mg
5-40 mg
2-60 mg
40-80 mg
15-125 mg
Navane
Taractan
Thiothixene
Chlorprothixene
6-60 mg
10-600 mg
Loxitane
Loxapine
20-250 mg
Haldol
Inapsine
Haloperidol
Droperidol
3-50 mg
2.5-10 mg (IM)
Moban
Molindone
15-225 mg
Phenothiazines
Aliphatics
Piperidines
Piperazines
Thioxanthenes
Dibenzoxapines
Butyrophenones
Dihydroindolones
© Janicak
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Antipsychotic Agents (con’t)
Class/Trade Name
Generic Name
Dosage (average range; PO, qd)
Clozapine
100-900 mg
Risperidone
Paliperidone
2-10 mg
3-12 mg
Olanzapine
5-20 mg
Quetiapine
75-750 mg
Ziprasidone
40-160 mg
Aripiprazole
10-30 mg
Penfluridol
100 mg/wk
Pimozide
1-10 mg
Dibenzodiazepines
Clozaril
Benzisoxazole
Risperdal
Invega
Thienobenzodiazepines
Zyprexa
Dibenzothiazepines
Seroquel
Benzisothiazolyls
Geodon
Quinolinones
Abilify
Diphenytbutyrylpiperidines
Semap
Orap
© Janicak
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Antipsychotics:
Adverse Effect Profiles
EPS*
HPDL
CLOZ
RISP
OLZ
QTP
ZIP
ARIP
Neurological
+++
0
+
0/+
0
0/+
0/+
Weight gain/
Endocrine
+
+++
++
+++
++
0/+
0/+
++
Anticholinergic
0
+++
0/+
+/++
0/+
0/+
0
0/+
Hematological
0
+++
0
0
0
0
0
0
Cardiovascular
+
0/+
+
+
+
++
0
+
Prolactin
++
0/+
+++
0/+
0/+
0/+
0
+++
Sedation
+
+++
+
+/++
++
++
+
*At appropriate doses;
0 = none;
+ = mild;
++ = moderate;
PALI
+
+
+++ = substantial
Adapted from Masand PS et al. Handbook of Psychiatry in Primary Care. 1998.
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ADVERSE EFFECTS OF ANTIPSYCHOTICS
Acute EPS
Maximum
HIGH POTENCY
FGAs
Minimum
RISPERIDONE
OLANZAPINE
PALIPERIDONE
(DOSE-RELATED)
• Psuedoparkinsonism
CLOZAPINE
ZIPRASIDONE
QUETIAPINE
ARIPIPRAZOLE*
• Dystonia
• Akathisia
• Tardive Dyskinesia
*Based on clinical trial data
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Dementia Patients

Risks
 Mortality rate
 CVA in 4% vs 2%
 Risks may be
higher for all APs

Recommendations
 Avoid in those with
vascular dementia
 Avoid with TIA,
hypertension, Afib
 Use low doses
Monitor for
hypotension,
sedation, EPS
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Weight Gain: Overview



General population
 Increased morbidity and mortality
 Stigmatization
 Major mental disorders
This adverse effect is more common with some
recent antipsychotics
 Recognized problem since chlorpromazine
Polypharmacy may contribute
 Divalproex sodium
 Lithium
 Antidepressants
 Antipsychotics
© Janicak
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The Metabolic Syndrome




Insulin resistance
Hyperinsulinemia
Decreased beta cell function
Postprandial hyperglycemia
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SGAs and Metabolic
Abnormalities
Weight Gain
Risk for
Diabetes
Worsening
Lipid Profile
Clozapine
+++
+
+
Olanzapine
+++
+
+
Risperidone
++
D
D
Quetiapine
++
D
D
Aripiprazole*
+/-
-
-
Ziprasidone*
+/-
-
-
Drug
+ = increase effect; - = no effect; D = discrepant results.
*Newer drugs with limited long-term data.
Diabetes Care. 2004.
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Baseline Monitoring






History (personal or family) of obesity,
diabetes, dyslipidemia, hypertension, CVD
BMI
Waist circumference
Blood pressure
Fasting lipid profile
Fasting plasma glucose
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Anticholinergic Effects
Most common with:
 Clozapine
 Olanzapine
 Quetiapine
 Low-potency FGAs
© Janicak
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Hematological

Clozapine-induced agranulocytosis
Management
Stop agent
Reverse isolation; supportive measures
GSCF (filgastrim)
 Rechallenging strategies

© Janicak
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Cardiovascular

Related to both alpha1 adrenergic and
muscarinic effects




Hypotension
Tachycardia
Myocarditis
Arrhythmogenic potential possible with all
antipsychotics
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Potential Consequences of
QTc Interval Prolongation
QTc prolongation
Rarely
Torsade de pointes arrhythmia
(syncope)
Rarely
Ventricular fibrillation
(sudden death)
Royal College of Psychiatrists. 1997.
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QT interval



Time between onset
of depolarization and
repolarization
Affected by diet,
alcohol intake, time of
day, heart rate
Usually corrected for
heart rate = QTc
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Antipsychotics:
Drug Interactions

Pharmacodynamic
Anticholinergic
 Hypotension


Pharmacokinetic
P450 inhibition (quinidine)
 P450 induction (carbamazepine)

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Bipolar Disorder:
Symptom Domains
Mania
Euphoria
Grandiosity
Pressured speech
Impulsivity
Excessive libido
Recklessness
Diminished need for
sleep
Psychosis
•Delusions
•Hallucinations
•Sensory hyperactivity
Manic, depressed
or mixed
Depression
Depression
Anxiety
Irritability
Hostility
Violence or
suicide
Cognition
•Racing thoughts
•Distractability
•Poor insight
•Disorganization
•Inattentiveness
•Confusion
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Mood Disorders:
Therapeutic Options
Lithium* (A, M)
First generation
antipsychotics
Anticonvulsants
Pharmacological/Somatic
Valproate* (A)
Antidepressants; OLZ/FLU* (D)
Lamotrigine* (M)
Quetiapine* (D)
Carbamazepine (A)
Electroconvulsive therapy
Second
generation
antipsychotics
Oxcarbazepine*
Possibly:
Clozapine
Topiramate
»
»
»
»
Gabapentin
Bright light therapy
Transcranial magnetic stimulation
Vagal nerve stimulation
Sleep deprivation
Psychotherapy
Cognitive behavioral therapy Marital/family counseling
Interpersonal therapy
Group therapy
© Janicak
Olanzapine* (A, M)
Risperidone* (A)
Quetiapine* (A)
Ziprasidone* (A)
Aripiprazole* (A)
* FDA approved
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Mood Stabilizer Pharmacokinetics
Drug
Desired
Cp
Distributio
n
Metabolis
m
Eliminatio
n
Lithium
0.6-1.0
mEq/L
No PB
kidneys,
thyroid
None
Renally,
18-20
hours
CBZ
6-12
mcg/ml
Complete
Hepatic,
15-28
hours
autoinduc
er
10,11
epoxide
VPA
50-120
mcg/ml
Rapid in
CNS
Hepatic,
Inhibitor or
8-17
hours
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BIPOLAR DISORDER
LITHIUM
DISADVANTAGES



Narrow therapeutic index
Slow onset of action
Numerous adverse effects
© Janicak
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Factors Affecting Lithium Cp




Impaired Renal Function
Pregnancy
Sodium balance
Medications
Diuretics → Na depletion → Li reabsorption
 Caffeine ↓ lithium levels
 ACE Inhibitors → ↓ GFR → increase Li
concentration

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Lithium: Adverse Effects
Organ System
Clinical Presentation
Comments
Cardiovascular
ECG changes
T wave suppression, delayed or irregular rhythm, increase in PVCs
Sick sinus node syndrome (SSNS)
Myocarditis
Dermatologic
Acne
Psoriasis
Rashes
Worsens
Treatment-refractory worsening
Maculopapular and follicular
Endocrine
Hypothyroid state
About 5% goiter; about 4% clinically significant hypothyroidism
Hyperparathyroid state
Clinically nonsignificant
Fetus (teratogenic)
Tricuspid valve malformation
Atrial septal defect
Ebstein’s anomaly
Gastrointestinal
Anorexia
Nausea (10-30%)
Vomiting
Diarrhea (5-20%)
Usually early in treatment and usually transient; may be early sign
of toxicity
Slow release preparations may help
Hematological
Granulocytosis
Neurological
Cognitive; tremors
May be useful in disorders such as Felty’s syndrome, iatrogenic
neutropenia. May counter CBZ-induced leukopenia
Renal
Polyuria-polydipsia
(Nephrogenic diabetes
insipidus)
May be an indication of morphologic changes
Requires adequate hydration
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BIPOLAR DISORDER
Anticonvulsants for Mood Disorders

Valproate (VPA)

Lamotrigine (LTG)

Carbamazepine (CBZ)

Oxcarbazepine

Gabapentin (GBN)

Topiramate (TOP)

Others
© Janicak
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BIPOLAR DISORDER
VALPROATE
DISADVANTAGES

Pancreatitis
Adverse effects




Weight gain
Tremors
Hyperammonemia
PCOS (?)
Hepatotoxicity
Teratogenicity
© Janicak
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Valproic Acid
Pharmacokinetics


Usually inhibits hepatic metabolism
Occasionally induces hepatic metabolism
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CBZ Pharmacokinetics


Oxidation to CBZ-10,11-epoxide
Potent enzyme inducer


antidepressants, anticonvulsants,
antipsychotics
Autoinduction

serum level should stabilize within 4 weeks
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Carbamazepine Metabolism
Carbamazepine
oxidation
10,11 epoxide metabolite
Valproic acid
→ Toxicity
X
Further metabolism
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BIPOLAR DISORDER
LAMOTRIGINE
DISADVANTAGES


Slow titration to avoid rash
Adverse effects

Serious rashes
 SJS
 TEN
© Janicak
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Goals

Antipsychotics






Diagnostic indications
Classification
Relevant Pharmacokinetics
Serious Adverse Effects
Drug Interactions
Mood Stabilizers





Diagnostic indications
Classification
Relevant Pharmacokinetics
Serious Adverse Effects
Drug Interactions
33