antipsychotics, neuroleptics
TRANSCRIPT
04/11/2023 1
Hiwa K. Saaed, [email protected]
Antipsychotics“neuroleptics or major
tranquilizers”
FIRST-GENERATION ANTIPSYCHOTIC(low potency)Chlorpromazine Prochlorperazine Thioridazine FIRST-GENERATION ANTIPSYCHOTIC(high potency)FluphenazineHaloperidol Pimozide Thiothixene SECOND GENERATION ANTIPSYCHOTICAripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Quetiapine Paliperidone Risperidone Ziprasidone
Learning objectivesPharmacy 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
04/11/2023 2
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. Cognition2. Behavior 3. Emotions
04/11/2023 3
04/11/2023 4
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
Schizophrenia
04/11/2023 5
Symptoms of Schizophreniahttp://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
-ve symptoms: the absence of appropriate behaviors
Lack of motivation
social withdrawal
blunted affect
poverty of speech
anhedonia
(lack of interest in pleasurable activities)
04/11/2023 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
04/11/2023 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.
04/11/2023 8
04/11/2023 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.
04/11/2023 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.
04/11/2023 11
AntipsychoticsDecrease dopaminergic and/or serotonergic
neurotransmission.
Effective in controlling +ve symptoms
Typical ‘Classic’ drugs (D2)• Chlorpromazine• Fluphenazine• Haloperidol • Thioridazine• trifluperazine
Effective in controlling -ve symptoms, More costly, less EPS
Atypical ‘Newer’ 5-HT2• Clozapine• Quetiapine • Risperidione• Ziprasidone• aripiprazole
04/11/2023 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
04/11/2023 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.
04/11/2023 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.
04/11/2023 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.
1604/11/2023
04/11/2023 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 D2- receptors of the chemoreceptor trigger zone (CTZ) of the medulla.
04/11/2023 18
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
pharmacological actions
04/11/2023 19
Antipsychotics autonomic effect
04/11/2023 20
Therapeutic uses1. 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).
04/11/2023 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
04/11/2023 22
1. Extrapyramidal side effects:http://www.youtube.com/watch?v=QYYx1mZDpPwhttp://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.
04/11/2023 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
04/11/2023 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.
04/11/2023 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.
04/11/2023 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.
04/11/2023 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.
04/11/2023 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.
04/11/2023 29
04/11/2023 30
04/11/2023 31
04/11/2023 32