1
Q
Older Agents (typicals, conventionals)
A
- Exhibit substantial risk of adverse extrapyramidal neurological effects (EPS) (bradykinesia, mild rigidity, tremor, subjective restlessness (akathisia))
- Increased release of prolactin
- Reduced initiative and interest in the environment as well as manifestations of emotion
- Fall into chemically distinct classes
2
Q
Newer Agents (atypicals)
A
- Less EPS
- Hypotension
- Seizures
- Weight gain
- Increased risk of DM type II
- Hyperlipidemia
- Cannot be grouped chemically
3
Q
Pharmacologic Therapy
A
- decrease severity of disease during acute initial phase
- stabilize patient against relapses during remission
- maintain patient after symptoms have remitted
4
Q
Patients requiring comprehensive and continuous care
A
Onset in adolescence or early adulthood
5
Q
Pathogenesis
A
- Unknown
- Dopamine hypothesis proposed, but incomplete
- Genetic component apparent (risk increases 10-fold in first-degree biologic relatives)
6
Q
The Dopamine Hypothesis and Dopamine Receptors
A
- Most antipsychotics block postsynaptic D2 receptors in CNS, particularly in the mesolimbic-frontal system
- No correlation with D1 receptors, but high correlation with D2 receptors
- Drugs that increase dopaminergic activity aggrevate schizophrenia or produce psychosis in some patients
- Untreated schizo pts –> inc dopamine receptor density
- Treated schizo pts –> change in amount of DA metabolite in urine, CSF and plasma
7
Q
Caveats to Dopamine Hypothesis
A
- all evidence is circumstatial
- antipsychotic drugs are only partly effective in most pts
- 2nd generation drugs are not very potent antagonists at D2 receptors, yet ARE effective clinically!
8
Q
Pharmacologic Effects
A
- Dopamine receptor blockade is major effect that correlates with therapeutic benefit for OLDER agents
- Other effects variable and correlate with effect on other receptors
9
Q
- Atypical
- Exception to criteria of dopamine antagonist
- Partial agonist at D2 and 5-HT1a receptors and antagonist activity at 5-Ht2a receptors
- Competitively inhibits DA response until its Emax is reached (Emax is 25% that of DA)
A
Aripiprazole
10
Q
- Exception to D2 blocker (does not block D2)
- higher affinity for D4 and 5-HT2A
- Atypical
A
Clozapine
11
Q
- Typical
2. Blocks D2 receptor very strongly
A
Haloperidol
12
Q
Therapeutic benefit for schizophrenia (typicals)
A
- alleviate positive but not negative symptoms
- typical agents are antagonists at DA receptors
- provoke EPS and increase prolactin
- antagonist at D2 receptors in pituitary
- higher D2 blockade relative to 5-HT2 blockade
13
Q
Therapeutic benefit for schizophrenia (atypicals)
A
- reduce positive symptoms and appear to reduce neg
- perhaps because atypicals have higher 5-HT2 relative to D2 blockade activity
- decreased or absent EPS and prolactin secretion
- produce increased DA blockade of neurons derived from mesolimbic region as compared to neurons derived from nigrostriatal region
14
Q
Clozapine vs. Haloperidol
A
- Clozapine has a decreased risk of EPS since not as good of a D2 agonist as Haloperidol
- However, Haloperidol has a lower risk of adverse effects resulting from blockage of other receptors
15
Q
Pharmacokintetics
A
- Readily (though incompletely) absorbed PO
- Erratic and unpredictable absorption
- High first-pass transformation
- 25-35% bioavail. (65% for Haloperidol)
- Parenteral forms have much higher bioavailability
- Lipid soluble (accum. in brain, lungs, tissue of rich blood supply)… enter fetal circul. and breast milk
- 92-99% bound to plasma proteins
- Sequestered in lipid compartments, so longer duration than half-life suggests
16
Q
Metabolism
A
- Oxidative processes (P450s)
- Glucuronidation, sulfation, other conjugate processes
- Metabolites not important for therapeutic action with exception of Mesoridazine, a metabolite of thioridazine, which is more active than parent compound
17
Q
Excretion
A
Little if any of the drugs are excreted unchanged due to extensive metabolism to more polar substances
18
Q
Aripiprazole Drug Interactions
A
- 3A4, 2D6 convert to active metabolite with long t1/2
2. Dose adjustment required with strong 3A4 or 2D6 inhibitors and 3A4 inducers
19
Q
Clozapine Drug Interactions
A
Many interactions, primarily with 1A2 inhibitors and inducers
20
Q
Olanzapine Drug Interactions
A
Low potential, serum concentrations altered by strong 1A2 inhibitors and inducers
21
Q
Quetiapine Drug Interactions
A
Dose adjustments required with 3A
22
Q
Risperidone Drug Interactions
A
Dose adjustments required with 3A4 or 2D6 inhibitors and 3A4 inducers
23
Q
Paliperidone Drug Interactions
A
Low potential
24
Q
Ziprasidone Drug Interactions
A
Serum concentrations modestly affected by 3A4 inhibitors and inducers
25
Elimination Half-Lives (Typicals)
1. Chlorpromazine - 24 hrs
2. Fluphenazine - 18 hrs
3. Haloperidol - 24 hrs
26
Elimination Half-Lives (Atypicals)
1. Clozapine - 12 hrs
2. Risperidone - 20-24 hrs (estimated)
3. Olanzapine - 30 hrs (20-54 range)
4. Quetiapine - 6 hrs!
5. Ziprasidone - 7.5 hrs!
6. Aripiprazole - 75 hrs!
27
Dosing of Antipsychotics
1. Biological effects usually persist for at least 24 hrs, permitting once-daily dosing once patient has adjusted to initial side effects
2. Exceptions include Quetiapine and Ziprasidone
28
Depot Preparations
Absorbed and eliminated more slowly than oral preparations
29
Principal determinants for choosing initial therapy
1. Avoidance of adverse effects based upon patient and drug characteristics
2. Exploitation of certain medication properties ("is it more sedating than others?")
30
Exception to choosing initial therapy
1. Clozapine
2. Superior efficacy in treatment-refractory schizophrenia
3. Use limited by risk of agranuolocytosis
31
Toxicity (Behavioral)
"Pseudodepression" may be due to drug-induced akinesia (responds to antiparkinsonism drugs)
32
Toxicity (Reversible Neurologic Effects)
1. Dose-dependent EPS effects including Parkinson-like syndrome with bradykinesia, rigidity and tremor (max risk 5-30 days)
2. Toxicity reversed by decreasing dose and antagonized by concomitant use of antimuscarinic agent
3. Occurs most frequently with Haloperidol and more potent Piperazine side-chain phenothiazines (Fluphenazine, Trifluoperazine)
4. Occurs infrequently with Clozapine, much less common with newer drugs
33
Toxicity: Dose-dependent EPS effects
1. Occurs most frequently with Haloperidol and more potent Piperazine side-chain phenothiazines (Fluphenazine, Trifluoperazine)
2. Occurs infrequently with Clozapine, much less common with newer drugs
34
Toxicity: Akathisia and Dystonias
1. Akathisia - max risk 5-60 days
2. Dystonias - max risk 1-5 days
3. Respond to treatment with Diphenhydramine (Benadryl) or muscarinic blocking agents (e.g. Benztropine)
35
Tardive Dyskinesias
1. The most important unwanted effect of antipsychotic drugs
2. Choreoathetoid movements of the muscles of the lips and buccal cavity and may be irreversible
3. Develop after several years though have appeared as early as 6 months after drug initiation
Treatment:
1. Discontinue or reduce dose of current antipsychotic
2. Eliminate all drugs with central anticholinergic action
3. Add diazepam (high dose if necessary) to enhance GABAergic activity
36
Toxicity: Autonomic Effects
1. Due to blockade of peripheral muscarinic and alpha receptors
2. Thioridazine has strongest autonomic effects
3. Haloperidol has weakest autonomic effects
4. Clozapine and most atypicals have intermediate autonomic effects
37
Muscarinic Blockade
1. Atropine-like effects
2. Pronounced with Thioridazine and Phenothiazines
3. Also occurs with Clozapine and most of the atypicals except Ziprasidone and Aripiprazole
4. Antimuscarinic CNS effects may include toxic confusional state similar to that produced by Atropine and TCAs
5. Urinary retention would indicate need to switch to agent with less antimuscarinic action
38
Toxicity: Alpha Adrenergic Receptor Blockade
1. Postural hypotension is common manifestation, particularly with Phenothiazines and can be caused by all of the atypical drugs
2. Failure to ejaculate is common in men treated with Phenothiazines
39
Toxicity: Endocrine and Metabolic Effects
1. Predictable manifestations of dopamine D2 receptor blockade in pituitary
- hyperprolactinemia
- gynecomastia
- amenorrhea-galactorrhea syndrome
- infertility
2. Significant weight gain and hyperglycemia reported for several atypical agents (especially Clozapine and Olanzapine, not so with Aripiprazole)
3. Hyperlipidemia may occur
4. Some patients may develop Diabetes Mellitus
40
Weight Gain from Antipsychotic Drug Use
1. Mechanism not fully understood
2. Antagonism of 5-HT2C receptor may contribute
3. May involve effects on leptin levels
4. FDA requires warnings about hyperglycemia and diabetes to be included on all atypicals (though Aripiprazole and Ziprasidone unlikely to cause either)
41
Toxicity: Neuroleptic Malignant Syndrome
1. Muscle rigidity, impairment of sweating, hyperpyrexia, autonomic instability, which may be life-threatening
2. Patients who are particularly sensitive to EPS effects of antipsychotics may develop
3. Drug treatment involved prompt use of Dantrolene and perhaps Dopamine Agonists (Bromocriptine)
4. Max risk within weeks of beginning treatment; can persist for days after stopping neuroleptic
5. Most severe adverse effect of typical agents (fatal in 10% of cases)
6. Thought to arise in part from actions on DA systems in hypothalamus
42
Toxicity: Sedation
1. More marked with Phenothiazines (particularly chlorpromazine) than with others
2. Fluphenazine and Haloperidol are least sedating of older drugs
3. Aripiprazole is least sedating of newer drugs
43
Toxicity: Cardiac Toxicity
1. Prolongation of QT interval, especially Thioridazine, also Chlorpromazine, Haloperidol
2. Atypicals associated with increased risk, particularly Ziprazidone, also Clozapine, Quetiapine, Risperidone, Paliperidone
44
Ocular Complications
1. Thioridazine causes retinal deposits
| 2. Chlorpromazine associated with deposits in cornea and lens
45
Drug Specific Toxicities
1. Clozapine has small but important (1-2%) incidence of agranulocytosis
2. Reversible
3. Weekly blood counts mandatory for first 6 months of therapy, every three weeks thereafter
4. High doses has caused seizures (2-5% of patients)
46
Toxicity: Overdosage
1. Usually not fatal (except thioridazine)
2. Hypotension responds to fluid replacement
3. Most neuroleptics lower convulsive threshold and may cause seizures (managed with Diazepam or Phenytoin)
47
Clinical Use and Choice of Agent Short-Term Treatment: Delirium and Dementia
1. Antipsychotics NOT FDA approved, but commonly used
2. Avoid those with anti-muscarinic properties
- Haloperidol or Risperidone often drugs of choice
3. Reduce dosage in dementia
4. ODT preparations useful
5. IM if necessary
48
Clinical Use and Choice of Agent Short-Term Treatment: Mania
1. All atypicals except Clozapine and Ilopereidone
2. Titrate rapidly to max dose over 24-72 hours
3. Typical drugs also effective, but risk for EPS
4. Clinical response within 7 days, sometimes by day 2
5. May continue Rx for months, sometimes with mood stabilizer
6. Oral Aripiprazole and Olanzapine (though Olanzapine use declingin due to metabolic effects)
49
Clinical Use and Choice of Agent Short-Term Treatment: Schizophrenia
1. Newer atypicals are not more effective than typical agents for acute symptoms
2. Newer atypicals DO offer better neurological side-effect profile
3. Sedation may be desirable, but often use non-sedating antipsychotic plus low dose Benzodiazepine
4. Improved neurological risk profile plus aggressive marketing: atypicals largely replaced typicals in U.S.
5. Ziprasidone, Aripiprazole most weight and metabolically neutral
6. Newest drugs have limited experience
50
Major Depression
1. When response to antidepressant inadequate, augment with antipsychotic
2. Quetiapine, Aripiprazole FDA approved
3. Olanzapine in combination with Fluoxetine (SSRI) FDA approved
51
Clinical Use and Choice of Agent Long-Term Treatment: Delirium and Dementia
1. Safety concerns, limited long-term efficacy data dampen enthusiasm
2. Justification for use often mandated in long-term care settings
52
Clinical Use and Choice of Agent Long-Term Treatment: L-DOPA psychosis
1. PD patients with advanced disease, exquisitely sensitive to D2 blockade
2. Clozapine has extensive clinical evidence
3. Quetiapine, Aripiprazole use increasing
53
Clinical Use and Choice of Agent Long-Term Treatment: Schizophrenia
1. Choice on avoidance of adverse effects or prior history of response
2. Treatment acceptability is key to management
3. Typicals vs. atypicals ongoing debate, but meta-analysis find little difference in relapse risk
4. Atypicals significant advantage due to reduced neurological toxicity
5. Atypicals raise significant concern over metabolic effects
54
- typical antipsychotic
- aliphatic phenothiazines
- D2 blocker
- alpha1 blocker
- antihistamine that has unusual tranquilizing effects effective for treating psychosis
- EPS effects
Chlorpromazine
55
- typical antipsychotic
- D2 blocker
- strong muscarinic (M) blocker
- alpha 1 blocker
- EPS effects
Thioridazine
56
- typical antipsychotic
- very strong D2 blocker
- small alpha1 block
- no M block
- no histamine block
Haloperidol
57
- atypical antipsychotic
- less EPS effect
- no D2 block
- strong D4 block!!!
- alpha1 block
- 5-HT2 block
- M block
- H1 block
Clozapine
58
- atypical antipsychotic
- less EPS effect
- not used clinically
- D2 block
- mild alpha1 block
- no 5-HT2 block
- mild M block
- H1 block
Molindone
59
- atypical antipsychotic
- less EPS effect
- mild D2 block
- mild alpha1 block
- stronger 5-HT2 block
- mild M block
- H1 block
Olanzapine
60
- atypical antipsychotic
- less EPS effect
- mild D2 block
- mild alpha1 block
- stronger 5-HT2 block
- mild M block
- H1 block
Quetiapine
61
- atypical antipsychotic
- less EPS effect
- strong D2 block
- mild alpha1 block
- strong 5-HT2 block
- mild M block
- mild H1 block
Risperidone
62
- atypical antipsychotic
- less EPS effect
- strong D2 block
- strong alpha1 block
- strong 5-HT2 block
- no M block!!!
- mild H1 block
Ziprasidone
63
- atypical antipsychotic
- less EPS effect
- mild D2 block
- mild alpha1 block
- strong 5-HT2 block
- no M block!!!
- mild H1 block
Aripiprazole
Antipsychotics
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