Antipsychotics
“neuroleptics or major
tranquilizers”
Hiwa K. Saaed, PhD
hiwapharm@yahoo.com
Hiwa.saaed@univsul.net

11/29/...
Learning objectives
Pharmacy students should:
– be familiar with the symptoms
& health consequences of
schizophrenia
– be ...
Schizophrenia
The Greek translation is
schizein “split” and phren
“mind” which refers to a split
from reality.
A group of ...
Schizophrenia
is a particular type of psychosis-that is, a mental disorder
caused by some inherent dysfunction of the brai...
Symptoms of Schizophrenia
http://www.youtube.com/watch?v=gGnl8dqEoPQ

+ve symptoms: the presence
of inappropriate behavior...
Dopamine Hypothesis of Schizophrenia

This hypothesis is suggests that excessive dopaminergic activity
plays a role in the...
Dopaminergic systems:
• Mesolimbic-mesocortical pathway: the one most
closely related to behavior (mental and emotional)
•...
11/29/2013

8
Antipsychotics
(neuroleptics, antischizophrenic)
• Used primarily to treat
schizophrenia,
• also effective in other psycho...
Antipsychotic drugs
Neuroleptic drugs are not curative and do not
eliminate the fundamental thinking disorder, but
they of...
Antipsychotics
Decrease dopaminergic and/or serotonergic neurotransmission.

Typical ‘Classic’ drugs (D2)
• Chlorpromazine...
Chemical classification of antipsychotic agents:
A. Phenothiazine derivatives (tricyclic+S+side chain)
Divided depending o...
Chemical classification of antipsychotic agents:
B. Thioxanthene derivatives: (thiothixene, flupenthixole) less potent
tha...
Dopamine receptor-blocking activity in the brain:

D1 and D5 receptors: activate adenylyl cyclase.
D2, D3, and D4 receptor...
Serotonin receptor-blocking activity in the brain:
• Clozapine has high affinity for D1, D2, D4, 5-HT2A, muscarinic,
and α...
11/29/2013

16
pharmacological actions
1. Antipsychotic actions:
Neuroleptic stage-ALL the drugs also have
• a calming effect
• reduce sp...
pharmacological actions
3. Antimuscarinic effects:
SOME; particularly thioridazine, chlorpromazine, clozapine, and
olanzap...
Antipsychotics autonomic effect

11/29/2013

19
Therapeutic uses
1. Schizophrenia Rx
2. Mania (bipolar disorder):
initial Rx of Mania. Atypical antipsychotic drugs are
of...
Other uses:
4. As tranqulizers to manage agitated and disruptive
behavior.
5. Treatment of chronic pain with severe anxiet...
1. Extrapyramidal side effects:
http://www.youtube.com/watch?v=QYYx1mZDpPw
http://www.youtube.com/watch?v=WAg2iLEWVh0

1. ...
1.

Tardive Dyskinesia, TD
(D2 supersensitivity phenomenon):

• Patients display rhythmical involuntary movements,
includi...
Avoiding EP Adverse effects
• Using Those drugs that exhibit strong
anticholinergic activity, such as thioridazine,
show f...
Avoiding EP adverse effects
•
•

Risperidone should be included among the
first-line antipsychotic drugs,
whereas clozapin...
2.

Neuroleptic malignant syndrome:

this potentially fatal reaction to neuroleptic drugs
is characterized by muscle rigid...
3.

Other effects:

•

Anticholinergic; dry mouth, urinary retention,
constipation, and loss of accommodation.
Thioridazin...
Cautions and contraindications:

1. acute agitation accompanying withdrawal
from alcohol or other drugs may be
aggravated ...
11/29/2013

29
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Antipsychotics, Neuroleptics

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Antipsychotics, Neuroleptics

  1. 1. Antipsychotics “neuroleptics or major tranquilizers” Hiwa K. Saaed, PhD hiwapharm@yahoo.com Hiwa.saaed@univsul.net 11/29/2013 FIRST-GENERATION ANTIPSYCHOTIC (low potency) Chlorpromazine Prochlorperazine Thioridazine FIRST-GENERATION ANTIPSYCHOTIC (high potency) Fluphenazine Haloperidol Pimozide Thiothixene SECOND GENERATION ANTIPSYCHOTIC Aripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Quetiapine Paliperidone Risperidone Ziprasidone 1
  2. 2. Learning objectives Pharmacy students should: – be familiar with the symptoms & health consequences of schizophrenia – be able to describe the mechanism(s) of action and adverse effects of antipsychotics 11/29/2013 2
  3. 3. Schizophrenia The Greek translation is schizein “split” and phren “mind” which refers to a split from reality. A group of severe disorders characterized by atypical: 1. Cognition 2. Behavior 3. Emotions 11/29/2013 3
  4. 4. Schizophrenia is a particular type of psychosis-that is, a mental disorder caused by some inherent dysfunction of the brain, possibly an overactivity of the mesolimbic dopaminergic neurons. It is characterized by: 1. Positive symptoms; are those that can be regarded as an abnormality or exaggeration of normal function. 2. Negative symptoms; are those that indicate a loss or decrease in function 11/29/2013 4
  5. 5. Symptoms of Schizophrenia http://www.youtube.com/watch?v=gGnl8dqEoPQ +ve symptoms: the presence of inappropriate behaviors  Delusions (false belief)  Hallucinations (false perception) often in the form of voices  thinking or speech disturbances  bizarre behavior 11/29/2013 -ve symptoms: the absence of appropriate behaviors  Lack of motivation  social withdrawal  blunted affect  poverty of speech  anhedonia (lack of interest in pleasurable activities) 5
  6. 6. Dopamine Hypothesis of Schizophrenia This hypothesis is suggests that excessive dopaminergic activity plays a role in the disorder: 1. many antipsychotic drugs strongly block D2 receptors in the CNS, especially in the mesolimbic-frontal system. 2. Dopamine precursor or agonist, either aggravate schizophrenia or produce psychosis de novo in some patients; such as  levodopa (a precursor),  amphetamines (releasers of dopamine),  apomorphine (a direct dopamine receptor agonist), 3. Increase in brain dopamine receptor density 11/29/2013 6
  7. 7. Dopaminergic systems: • Mesolimbic-mesocortical pathway: the one most closely related to behavior (mental and emotional) • Nigrostriatal pathway: it is involved in the coordination of posture and voluntary movement • Tuberoinfundibular pathway: inhibit prolactin secretion • Medullary-periventricular: eating behavior • Incertohypothalamic: It has a role in sexual behaviour. 11/29/2013 7
  8. 8. 11/29/2013 8
  9. 9. Antipsychotics (neuroleptics, antischizophrenic) • Used primarily to treat schizophrenia, • also effective in other psychotic disorders, such as manic states with psychotic symptoms such as grandiosity or paranoia and hallucinations, and delirium. 11/29/2013 9
  10. 10. Antipsychotic drugs Neuroleptic drugs are not curative and do not eliminate the fundamental thinking disorder, but they often: 1. Decrease the intensity of hallucinations and delusions. 2. Permit the psychotic patient to function in a supportive environment. 11/29/2013 10
  11. 11. Antipsychotics Decrease dopaminergic and/or serotonergic neurotransmission. Typical ‘Classic’ drugs (D2) • Chlorpromazine • Fluphenazine • Haloperidol • Thioridazine • trifluperazine Effective in controlling +ve symptoms 11/29/2013 Atypical ‘Newer’ 5-HT2 • Clozapine • Quetiapine • Risperidione • Ziprasidone • aripiprazole Effective in controlling -ve symptoms, More costly, less EPS 11
  12. 12. Chemical classification of antipsychotic agents: A. Phenothiazine derivatives (tricyclic+S+side chain) Divided depending on side chain: • Aliphatic group: chlorpromazine oldest • Piperazine group: trifluperazine, fluphenazine, terphenazine, prochlorperazine, thiethylperazine • Piperidin group: thioridazine, mesoridazine 11/29/2013 12
  13. 13. Chemical classification of antipsychotic agents: B. Thioxanthene derivatives: (thiothixene, flupenthixole) less potent than phenothiazine group. C. Butyrophenone derivatives: (haloperidol) highly potent like piperazine phenothiazine D. Miscellaneous structures: pimozide, molindone ,loxapine,clozapine, quetiapine,Risperidone sertindole, olanzapine, and zeprasidone. 11/29/2013 13
  14. 14. Dopamine receptor-blocking activity in the brain: D1 and D5 receptors: activate adenylyl cyclase. D2, D3, and D4 receptors: inhibit adenylyl cyclase , or mediate membrane K+ channel opening leading to neuronal hyperpolarization. the clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain. On the other hand, the atypical drug clozapine has a high affinity for the D4 receptor and 5-HT2, very low affinity to D2 which may explain its minimal ability to cause extrapyramidal side effects. 11/29/2013 14
  15. 15. Serotonin receptor-blocking activity in the brain: • Clozapine has high affinity for D1, D2, D4, 5-HT2A, muscarinic, and α-adrenergic receptors. • Olanzapine, Risperidone and quetiapine, blocks 5-HT2 receptors to a greater extent than it does D2 receptors. • Ziprasidone an antagonist at the D2, 5-HT2A and 5-HT1D an agonist at 5-HT1A • Aripiprazole • is a partial agonist at D2 and 5-HT1A receptors • but strong antagonist at 5-HT2A receptors. 11/29/2013 15
  16. 16. 11/29/2013 16
  17. 17. pharmacological actions 1. Antipsychotic actions: Neuroleptic stage-ALL the drugs also have • a calming effect • reduce spontaneous physical movements, • produce emotional indifference to environment. The antipsychotic effects usually take several weeks to occur, suggesting that the therapeutic effects related to secondary changes in the corticostriatal pathways. 2. Antiemetic effects Except thioridazine, MOST of the neuroleptic drugs D2receptors of the chemoreceptor trigger zone (CTZ) of the medulla. 11/29/2013 17
  18. 18. pharmacological actions 3. Antimuscarinic effects: SOME; particularly thioridazine, chlorpromazine, clozapine, and olanzapine 4. Blockade of α-adrenergic receptors: causes orthostatic hypotension and light-headedness. Other effects 5. Alter temperature-regulating mechanisms and can produce poikilothermia (body temperature varies with the environment). 6. Increases in prolactin release (block D2 receptor) 7. Sedation (H1 blockade) all except haloperidol 11/29/2013 18
  19. 19. Antipsychotics autonomic effect 11/29/2013 19
  20. 20. Therapeutic uses 1. Schizophrenia Rx 2. Mania (bipolar disorder): initial Rx of Mania. Atypical antipsychotic drugs are often used with Lithium. maintenance Rx of bipolar disorder Olanzapine and aripiprazole are approved. 3. Prevention of severe nausea and vomiting: Most commonly prochlorperazine are useful in the treatment of drug-induced nausea, but NO nausea arising from motion sickness (scopolamine is the drug of choice). 11/29/2013 20
  21. 21. Other uses: 4. As tranqulizers to manage agitated and disruptive behavior. 5. Treatment of chronic pain with severe anxiety in combination with opiates. 6. Hiccups: chlorpromazine 7. Antipruritus and sedation: promethazine 8. Pimozide is primarily indicated for treatment of the motor and phonic tics of tourette disorder 11/29/2013 21
  22. 22. 1. Extrapyramidal side effects: http://www.youtube.com/watch?v=QYYx1mZDpPw http://www.youtube.com/watch?v=WAg2iLEWVh0 1. It is appearance is time dependent, -Early phase (reversible) • Acute dystonias* occurring within few days, (*Rx by Trihexphenidyl, orphenadrine, procyclidine, or diazepam), • followed by **akathisias (the inability to remain seated due to motor restlessness). • #Parkinson symptoms occur a bit later on. (**&# Rx by propranolol, or antimuscarinic), -Late phase (irreversible) • Tardive Dyskinesia: inappropriate postures of the neck, trunk, and limbs, which is irreversible, occurs with chronic treatment after months or years of treatment. 11/29/2013 22
  23. 23. 1. Tardive Dyskinesia, TD (D2 supersensitivity phenomenon): • Patients display rhythmical involuntary movements, including lateral jaw movements, and “fly-catching” motions of tongue. • TD is postulated to result from an increased number of dopamine receptors • This makes the neuron supersensitive to the actions of dopamine, and it allows the dopaminergic input to this structure to overpower the cholinergic input, causing excess movement in the patient. • NB: antimuscarinic increase the severity of TD • Increase the dose of neuroleptic! Attenuate temporarily 11/29/2013 23
  24. 24. Avoiding EP Adverse effects • Using Those drugs that exhibit strong anticholinergic activity, such as thioridazine, show few EP disturbances. • This contrasts with haloperidol and fluphenazine, which have low anticholinergic activity and produce EP effects. • Clozapine and risperidone: these drugs have a low potential for causing EP symptoms and lower risk of Tardive Dyskinesia. 11/29/2013 24
  25. 25. Avoiding EP adverse effects • • Risperidone should be included among the first-line antipsychotic drugs, whereas clozapine should be reserved for severely schizophrenic patients who are refractory to traditional therapy. Clozapine can produce bone marrow suppression and CV side effects. The risk of severe agranulocytosis necessitates frequent monitoring of WBC count. 11/29/2013 25
  26. 26. 2. Neuroleptic malignant syndrome: this potentially fatal reaction to neuroleptic drugs is characterized by muscle rigidity, fever, stupor, unstable BP, and myoglobinemia. Treatment necessitates 1. discontinuation of the neuroleptic 2. supportive therapy, administration of: • Dantrolene • diazepam • or bromocriptine may be helpful. 11/29/2013 26
  27. 27. 3. Other effects: • Anticholinergic; dry mouth, urinary retention, constipation, and loss of accommodation. Thioridazine, clozapine, haloperidol (high to less) • Antiadrenergic; Lowering BP and orthostatic hypotension (α-blocker), ex, phaenothiazine • • Endocrine alteration: The neuroleptics depress the hypothalamus, causing amenorrhea, galactorrhea, infertility, and impotence. Significant weight gain & hyperglycemia due to a diabetogenic with atypical clozapine & olanzapine. 11/29/2013 27
  28. 28. Cautions and contraindications: 1. acute agitation accompanying withdrawal from alcohol or other drugs may be aggravated by the neuroleptics (Tx; benzodiazepine). 2. Chlorpromazine and clozapine are contraindicated in patients with seizure disorders, because these drugs can lower seizure threshold. The neuroleptics can also aggravate epilepsy. 11/29/2013 28
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