Antipsychotic drugs @@@@@

Schizophrenia occurs among about 1% of the population, and initially affects people during adolescence. It is characterized by chronic disturbances in perception and in the integration of reality, which produce delusions and hallucinations, disorganized behavior and speech.

1. The illness has basic symptoms called 4A by Bleuler.

Association

Loosening of association of
ideas and thinking

Affect

Mood disorders
Blunted affect

Ambivalence

Inability to make decisions 

Autism

Retreat into an inner world and incomprehensible to the outsider


2.  First rank symptoms by Schneider  
They are auditory hallucinations, thought insertion, thought broadcast, somatic passivity, delusional percept, thought withdrawal and made feelings/acts/ impulses.

3.  Symptoms are roughly divided into positive symptoms and negative symptoms.

Positive symptoms

psychomotor excitement, insomnia, anxiety, hallucination, delusion, metal disorder etc. 

Negative symptoms

Volition loss, spontaneity lack, misanthropy, autism, social withdrawal, mood disorder etc. 

Although the typical drugs are well effective against positive symptoms, it is less  effective against negative symptoms. 


4. Following changes are reported in schizophrenic brains.


The developmental disorders of the nervous system

1) Hypofrontality: observation of low blood flow in the frontal lobe by PET and SPECT and it correlates with negative symptoms.
2) Extensive nerve circuit disorder of the neocortex- limbic system.
3) Developmental disorder of cognitive network. 

Abnormalities of dopaminergic systems     (excessive dopaminergic activity)

Increase of D4 receptor, reduction of D1 receptor.
Point mutations of D2 receptor. 
DA level in synapse gap is high.
Occupation rate of D2 receptor by DA is high which correlates with positive symptoms.

Abnormalities of a glutamatergic system

Functional disorder of  NMDA receptor. 

Abnormalities of serotonergic system

5-HT2 inhibitors, clozapine and risperidone, are effective. 5-HT2A mRNA in the forebrain cortex is decreased in schizophrenic patients.
LSD, psilocibin etc. cause hallucination. 

Activation of retrovirus

RNA of the retrovirus (HERVs) origin is detected in 29% patientfs cerebrospinal fluid. 

Gene analysis

Although there is no clear heredity in schizophrenia, it is thought that it is a multi-factor disease. The gene locus of schizophrenia is still unknown. 


5. Discovery of drugs for schizophrenia
Two epoch-making drugs were discovered as a curative medicine of  schizophrenia in 1953. 
They are chlorpromazine and reserpine. (Reserpine.html)

6. Classification of antipsychotic drugs

Atypical Drugs

High potency group

Low potency group

Middle and variant group

D2 blocking action is strong. Extrapyramidal symptoms is often seen.. Few side effects on circulatory system. 

Sedative action is strong. Extrapyramidal symptome is weak. More side effects on autonomic nerves and circulatory system. 

Sedative action and extrapyramidal symptoms is slight. Effective against negative syndromes

Phenothiazines

fluphenazine
perphenazine  

chlorpromazine
thioridazine  

propericiazine  

Butyrophenones

haloperidol
spiperone  

floropipamide  

moperone  

Iminodibenzyls

|
-

|
-

carpipramine
clocapramine  

Benzamides

|
-

|
-

sulpiride
sultopride  

Atypical drugs

Efficacy is middle. Effective against both positive and negative symptoms. Blocking action to both D2 and 5-HT2 receptors. Used for non-resistance patients or first time episode patients. 

Heterocyclics

SDA (serotonin-dopamine antagonist)

risperidone  

perospirone@  

quetiapine@  

olanzapine@


 Although the older D2 receptor blockers (typical) are effective against positive symptoms, it is less effective against negative symptoms, and side effects, such as extrpyramidal syndromes, are often seen. However, atypical drugs have 5-HT2 receptor blocking action which is stronger than D2 receptor blocking action, and are characterized by better improvements of negative symptoms and much less occurrence of extrapyramidal symptoms. It is thought that 5-HT2 receptor inhibition suppresses the extrapyramidal side effects by promoting the increase in the firing of  the nigral DA neurons and the DA release in the striatum.

@
 @@

@@Chlorpromazine@@@@active residue„€„Ÿ„£here          


7, Pharmacological actions of Chlorpromazine (CPZ)

Pharmacological actions

Comments

Sedative action

It becomes easy to deal with an atrocious animal which is due to . the suppression of DA neuron in the limbic system. Symptoms of delusion and hallucination disappear in a patient. Reactivity to various stimuli and spontaneous movement decrease. 

Suppression of conditioned avoidance behavior

Although this action shows good correlation with antipsychotic effects, it reflects the extrapyramidal actions.

Antiemetic action

Blocks D2 receptor on CTZ of the 4th cerebral ventricle. 

Relaxation  of skeletal muscle

Mediated by the cerebral basal ganglia. 

Hypothermal action

It works to the regulation-of-body-temperature center in the hypothalamus. 

hypnotic action

It is based on sedative action. 

Anti-pruritic action

It is based on an anti-histamine action. 

Increase of prolactin  release


It is based on control of DA action. 

suppression of the autonomic nervous system

Inhibition of receptors for various neurotransmitter (DA, Norepi, 5-HT, Histamine) actions 

@

8. Mode of action of chlorpromazine

Dopaminergic synapse and ‚c‚Q receptor
In D2 receptor, two kinds of D2S and D2L (29AA is inserted in the 3rd intracellular loop) exist, and D2S receptors exist mainly in a pre-synaptic membrane, and work as autoreceptors. D2L receptors are mainly in post-synapse membranes. Since a D2L receptor stimulation activates Gi of G protein and then suppresses adenylate cyclase activity, it decreases the production of cAMP and causes the decrease of protein kinase A activity, which results in the decrease of phosphorylation of calcium and potassium  channels. The changes of phosphorylation of channels suppress Ca++ influx and promote K+ flux, which causes slow IPSP (hyperpolarization)  and suppresses action potential.
Chlorpromazine (CPZ) has Kd of 1-20nM and suppresses dopaminergic transmission by inhibiting D2 receptor. 






9. Correlation between the affinity for D2 receptor and clinical dosage

1:spiroperidol
2:trifluperidol
3:fluphenazine
4:droperidol
5:haloperidol
6:thiothixene
7:trifluperazine
8:prochlorperazine
9:clozapine
10:thioridazine
11:chlorpromazine
12:sulpiride
13:promazine

D2 receptor blocking action correlates well with clinical dosage. (P.Seeman,Biochem.Pharm,26,1741,1977)



10, the side effects of Chlorpromazine

Side effects

Symptoms and Comments

Acute dystonia

Symptoms appear after 1-5 days. The movement disorder of the head neck immediately after medication starts, difficulty of swallow. Anticholinergic drugs are effective. 

akathisia

Symptoms appear after 5-6 days. A seat is not intently (uncontrollable restlessness). 

extrapyramidal symptoms

Symptoms appear 5- 50 days. It is based on D2 blocking action.

Malignant syndrome

Symptoms appear after several days - several weeks. High fever and stiffness of skeletal muscles, confusion, tachycardia. Dantrolene is a curative medicine (inhibition of Ca release from SR). 

Tardive dyskinesia
 

Symptoms appear after several months and occur  at 20-25%. Since the symptoms improves temporarily by the increase of dose, it is postulated that  DA function is increased by the supersensitivity of DA receptors due to the long-term inhibition of D2 receptors. It is mostly irreversible even after stopping the drug.
The involuntary movement of the mouth circumference (rabbit syndrome) 

Orthostatic hypotension

Based on  alpha-1 inhibition. 

Skin hypersensitivity

Sunlight hypersensitivity

Hepatotoxicity

Bile retention

Anti-cholinergic action

Thirsty, constipation, urination retention

Suppression of Hematopoietic function

Hypoplastic anemia, hemolytic anemia

Reproductive system

Inhibition of FSH or LH secretion. An ovulation obstacle, infertility, and non-ability are caused. 

Lowering of seizure threshold

Cautious of the patient of epilepsy. 

Weight gain

Based on appetite rise. It is seen in low potency drugs. 





11. Actions and side effects of antipsychotic drugs on DA neurons

@

@

The drugs works on (1) mesocortical DA system and  (2) mesolimbic DA system, and shows antipsychotic and sedative actions. Extrapyramidal effects are caused by the inhibition of D2 receptor of (4) the nigrostriatal system. Secretory inhibition such as prolactin is caused by DA block in the hypothalamus and hypophysis system(3). In addition, there is an inhibitory action of central histamine and serotonin receptors. Moreover, the side effects by inhibition of peripheral muscarinic  and alpha1 receptors are also produced. 



12. Chemical structure, pharmacological effects and the side effects

Atypical drugs

High potency group

Low potency group

Middle and a variant group

D2 blocking action is strong. Extrapyramidal symptoms is often seen.. Few side effects on circulatory system. 

Sedative action is strong. Extrapyramidal symptome
is weak. More side effects
on autonomic nerves and
circulatory system. 

Sedative action and extrapyramidal
symptoms is slight.
Effective against
negative syndromes

Phenothiazines

fluphenazine
perphenazine  

chlorpromazine
thioridazine  

propericiazine  

Butyrophenones

haloperidol
spiperone  

floropipamide  

moperone  

Iminodibenzyls

|
-

|
-

carpipramine
clocapramine  

Benzamides

|
-

|
-

sulpiride
sultopride  


Atypical drugs

Drug Name


Receptor block

Side effects, etc.

Less extrapyramidal effects and mental side effects. As common side effects, increase in body weight, prolong of QTc and sexual disorder. 

Dibenzodiazepines


clozapine


D4>5-HT2>D2

Effectve against negative symptoms.
Agranulocytosis(0.8%) . 

Heterocyclics system SDA (serotonin-dopamine antagonist)

risperidone


5-HT2>D2

Orthostatic hypotension by alpha1block 

perospirone

Developed in Japan. Effect is quick.
Antipsychotic effect is strong. 

quetiapine

Almost no anticholine action. Effect is slow. 
Orthostatic hypotension by alpha1 block.
Increase of blood sugar.  

olanzapine

Increase of blood sugar.

@@

@@

@@@@haloperidol
 

It has a high antipsychotic potency and develps strong extrapydamida effects, although its anticholinergic action is weak. Fluphenazine and thiothixene are other high potency drugs. 


@

@@ risperidone
 

It is an atypical drug and characterized by the improvement action of negative symptoms and weak extrapyramidal effects, because it blocks 5-HT2 receptor stronger than D2 receptor. Recently, perospirone and olanzapine are approved as an atypical drug. 


13. Topics
When the brain MRI picture was examined in early-onset schizophrenic patients of 13 years old, his parietal lobe (related to visuospatial and associated thinking) reduced by 5% per year and the loss gradually expanded to frontal and temporal lobes, and the psychotic symptoms also proportional to the effected lesions. On the other hand, although loss of parietal lobe is seen in adult-onset schizopherenia, it is considered to be environmental. (PNAS, 98, 11650, 2001)




(2002/11/7)