Antipsychotic Drugs

Question 1

What are antipsychotic drugs?

Answer 1

Antipsychotic drugs (neuroleptics) are the drugs which eliminate the symptoms of psychotic disorders (psychoses).

Question 2

What is psychosis?

Answer 2

Psychiatric disorder,
with a significant impairment of
thinking and sensations.

Question 3

Symptoms of psychoses?

Answer 3

1) positive:
- delusions (false ideas, beliefs)
- hallucinations

2) negative: (loss of normal functions):
- emotional blunting (lack of emotions);
- cognitive disorders (impairment of learning, thinking);
- social withdrawal (lack of communication with other people).

Question 4

What is Schizophrenia?

Answer 4

●Schizophrenia is the most important psychotic disease.
●The most accepted of schizophrenia pathogenesis is the dopamine hypothesis:
●the symptoms are caused by the excessive influence of the dopaminergic neurons on the mesolimbic area of the brain.
●There are also data about the role
of the increased influence of serotonin (serotonin hypothesis) and decreased influence of glutamate through NMDA-receptors (glutamate hypothesis) in the pathogenesis of schizophrenia.

Question 5

Classificaton of antipsychotic drugs?

Answer 5

●Typical antipsychotic drugs
●atypical antipsychotic drugs

Question 6

What are Typical antipsychotic drugs?

Answer 6

●phenothiazine derivatives:
▪︎aliphatic: chlorpromazine;

▪︎piperazine:
trifluoperazine,
fluphenazine decanoate (moditendepo),
prochlorperazine;

▪︎piperidine:
thioridazine;

●Other chemical groups:
Haloperidol
(Trifluperidol)
Droperidol
Chlorprothixene

Question 7

List out atypical antipsychotic drugs.

Answer 7

▪︎clozapine
▪︎olanzapine
▪︎risperidone
▪︎quetiapine
▪︎ziprasidone
▪︎aripiprazol

Question 8

The mechanism of the action of Typical antipsychotic drugs.

Answer 8

●blocking of dopamine D₂ receptors.

Question 9

The main mechanism of the action of atypical antipsychotic drugs.

Answer 9

●Suggested to be the block of serotonin 5-HT₂ receptors.

Question 10

Other mechanisms of antipsychotic drugs.

Answer 10

Antipsychotic drugs can also block,

•muscarinic cholinoceptors,
•alpha adrenergic receptors,
•histamine H1 receptors.

Question 11

What drug show affinity to all 3 types of the receptors?

Answer 11

●chlorpromazine

(these effects do not contribute to the beneficial effect in schizophrenia but can lead to some side effects.)

Question 12

What are the distinctive features of the mechanisms of action of atypical antipsychotic drugs?

Answer 12

●more significant antagonist properties for serotonin 5-HT₂ receptors.

●lower affinity to D₂ receptors or rapid dissociation from the bond to these receptors (for quetiapine).

● higher affinity to D4 than to D₂ receptors (clozapine).

● some drugs (aripiprazole) are partial agonists of dopamine D₂ and D3 receptors.

Question 13

Adverse effects of the antipsychotic drugs.

Answer 13

the interaction with several types of receptors can explain many adverse effects of antipsychotic drugs.

Question 14

Sedative effect
(drowsiness, impaired memory, decreased activity, etc)
(Mechanism?)

Answer 14

Blockade of
▪︎cholinoceptors
▪︎adrenoceptors
▪︎histamine H1 receptors

Question 15

Early extrapyramidal disorders.
(Parkinsonism, akathisia, acute dystonia, malignant neuroleptic syndrome)
(Mechanism?)

Answer 15

●Blockade of D2 receptors in the neostriatum.

Question 16

Late extrapyramidal disorders (tardive dyskinesia)
(Mechanism?)

Answer 16

Up-regulation (Increased number) of D2 receptors.

Question 17

Increase of appetite, weight
Increased synthesis of prolactin,
Decreased synthesis of gonadotropins?
(Mechanism)

Answer 17

Blockade of,
▪︎dopamine D2 receptors
▪︎serotonin 5-HT2 receptors
(For increase of weight) in the
hypothalamus.

Question 18

Dry mouth, loss of accommodation, increase of the ocular pressure, constipation, urinary retention.
(Mechanism)

Answer 18

Blockade of M-cholinoceptors

Question 19

Orthostatic hypotension
(Mechanism?)

Answer 19

Blockade of alfa adrenoceptors.

Question 20

What are the Extrapyramidal disorders caused by antipsychotic drugs?
Symptoms & Treatment?

Answer 20

The symptoms of drug-induced parkinsonism include:
▪︎muscle rigidity (muscle tension, resistance to passive movements), ▪︎bradykinesia (slow movements),
▪︎tremor.

The treatment of drug-induced parkinsonism is the administration
of centrally acting antimuscarinic drugs. ▪︎trihexyphenidyl,
▪︎benztropine, etc.

●It is not obligatory to stop the treatment by antipsychotic drugs, but the dose can be reduced
or the atypical antipsychotic drug can be administered instead of typical.

Question 21

Akathisia?

Answer 21

●Akathisia is a kind of the extrapyramidal disorders, it is expressed by a feeling of
restlessness,
tension, which compels the patient to make some movements (to rock, to walk about, etc.).

The mechanism is not clear enough, it can involve other structures than neostriatum.

The drugs, which can reduce symptoms of akathisia, include:
▪︎beta adrenoblocker propranolol, ▪︎benzodiazepine derivative - -clonazepam.

Question 22

Acute dystonia?

Answer 22

●Appears very early (a few days after the beginning of the treatment by antipsychotic drugs).

●It is expressed by
spastic,
long-term contractions of some groups of muscles,
causing such symptoms as
muscle spasms of the face,
tongue,
neck or back,
involuntary eye movements,
facial grimacing,
abnormal postures.

●The management of acute dystonic reactions includes central antimuscarinic drugs (see above), antihistamine drug diphenhydramine (the drugs
are administered intravenously or intramuscularly).

●In resistant cases,
the local injection of botulinum toxin can be administered.

Question 23

Neuroleptic malignant syndrome?

Answer 23

●Neuroleptic malignant syndrome is the most severe kind of antipsychotic-induced extrapyramidal disorders.

●It starts with a marked, rapidly progressing muscle rigidity.

●Then a high fever (sometimes up to 41-42 °C)
develops, followed by impairment of consciousness,
coma,
and death.

●The increased creatine kinase is an important laboratory marker of this
disorder.

●The management of the neuroleptic malignant syndrome:
▪︎The use of anti-parkinsonian drugs from the group of dopamine D₂ receptor agonists (bromocriptine),
▪︎muscle relaxant dantrolene,
▪︎cooling by physical measures (ice) is also recommended.
▪︎The strict control of respiratory and cardiovascular systems is necessary.

Question 24

Tardive dyskinesia?

Answer 24

●Tardive dyskinesia appears after a long-term treatment by the antipsychotic drugs (in most cases after several years).

●The nature of tardive dyskinesia is completely different from the other antipsychotic-induced extrapyramidal disorders:
it is linked with the compensatory increase in number of dopamine D₂ receptors as a response on their block by antipsychotic drugs.

●The typical symptoms are uncontrolled movements

(of the face,tongue, lips, jaws, extremities).

●Tardive dyskinesia is difficult for correction,
sometimes can be irreversible.
●The possible approach to the correction of tardive dyskinesia:
▪︎drugs, decreasing a level of dopamine in the CNS (tetrabenazine);
▪︎the benzodiazepine derivative clonazepam;
▪︎switching to atypical antipsychotic drugs or decreasing the dose of the
antipsychotic drug is also proposed but not proven enough.

Question 25

Comparison of the antipsychotic drugs…

Answer 25

Pg86
Table 14

Question 26

Distinctive features of atypical antipsychotic drugs.
(In comparison with typical)

Answer 26

●low possibility of extrapyramidal disorders.
●higher possibility of increased appetite and weight.
●more effective against negative symptoms.
▪︎Clozapine has a high risk of agranulocytosis (appr. 3%) and is administered only when other antipsychotic drugs are ineffective.
▪︎There are reports about a higher risk of strokes in older patients using atypical antipsychotic drugs.

Distinctive features of aripiprazole.
•lower possibility of weight gain
•improves the results of treatment of the depressions if added to antidepressants;
•the effect in the nicotine dependence was reported.
•specific adverse effects due to the partial agonist properties for the dopamine receptors
(Hypersexuality, gambling, pathological
Shopping)

Question 27

Application of antipsychotic drugs.

Answer 27

●Schizophrenia and other psychotic disorders.

●neuroleptanalgesia -
▪︎a method of analgesia, which is obtained by simultaneous administration of the
opioid analgesic fentanyl
&
antipsychotic drug droperidol
with prominent sedative properties.
This combination causes
a state of tranquility and
calmness.
This method can be used for
relieving severe pain in myocardial infarction,
or for the management of some operations;

●prevention or relief of vomiting (prochlorperazine, perphenazine) -
antipsychotic drugs inhibit the vomiting reflex due to the
block of D₂ receptors of the vomiting center.