Anti Psychotic Drugs

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ANTIPSYCHOTIC DRUGS

PSYCHOSES:1- affective psychoses: The term " affect " refers to the mood. Affective psychoses are those in which the mood is out of proportion to the patient circumstances. The affective state appears to be determined by the balance of activity between central neurons containing monoamines ( noradrenaline, dopamine and serotonin ) and those containing Ach.

1- affective psychoses (Contd): There are mainly 3 types of affective psychoses: a- Mania: - Excitement and excessive locomotor activity (excessive talking and activity) - the manic patient may be so involved with his activity that he will violently oppose interference and he may suffer from lack of food and sleep.

a- Mania (Contd): - it is mainly due to overactivity in noradrenaline-containing neurons and possibly a dysfunction of cholinergic neurons - drugs that are effective in treatment of mania result in a decrease in the availability of noradrenaline as a neurotransmitter in the brain

1- affective psychoses (Contd): b- Depression: - transitions of mood from normal to depression and withdrawal - it is mainly due to impairment of noradrenaline and serotonin neurons and overactivity of Ach neurons

1- affective psychoses (Contd): c- Manic-depressive illness: ( bipolar affective disorder ) marked swings of mood between extreme elation and excitement to profound depression and withdrawal

PSYCHOSES (CONTD):2- Schizophrenia : It is a mental disorder characterized by a marked thinking disturbance and has symptoms such as hallucinations and delusions.

THEORIES OF SCHIZOPHRENIA: 5-HT theory: A suggestion that serotonin deficiency might be the underlying cause of schizophrenia was based on the observation that LSD, an ergot derivative synthesized in 1943, which antagonizes some peripheral actions of 5-HT, produces hallucinations.

5-HT theory (Contd): This theory is no longer accepted as no biochemical evidence suggesting reduced 5-HT production in schizophrenia and LSD hallucinations are not very similar to schizophrenia There is now a renewed interest with the action of the atypical antipsychotics, such as clozapine, on 5-HT2 receptors.

THEORIES OF SCHIZOPHRENIA (CONTD): Dopamine theory: Schizophrenia is believed to be caused by increased dopaminergic activity in the limbic system of the brain. this may be due to: 1- increased sensitivity or number of dopamine receptors 2- increased synthesis or release of dopamine 3- reduced enzymatic destruction of dopamine

EVIDENCE FOR THE DOPAMINERGIC INVOLVEMENT IN SCHIZOPHRENIA:

1- most antisychotic drugs block postsynaptic dopamine (D2) receptors in the CNS 2- drugs that increase dopaminergic activity in the brain produce schizophrenic symptoms or aggravate schizophrenia: e.g. levodopa (dopamine precursor) amphetamine (cause release of endogenous dopamine) apomorphine (direct dopamine receptor agonist)

EVIDENCE FOR THE DOPAMINERGIC INVOLVEMENT IN SCHIZOPHRENIA (CONTD):

3- studies of postmortem brain specimens and brain PET scans show that schizophrenic patients have increased dopamine receptor densities than normal people. 4- treatment of schizophrenia is accompanied by changes (first increase, and after 1-3 weeks a decrease) in the CSF, plasma and urine levels of homovanillic acid ( HVA, a major metabolite of dopamine)

Evidence Against dopamine theory: 1- Antipsychotic drugs are only partially effective for most, and ineffective for some patients 2- Several atypical antipsychotic drugs (e.g. clozapine) are effective in schizophrenia inspite of weak effect on D2 receptors (strong effect on D4 & 5-HT2) 3- Even with traditional phenothiazines, clinical efficacy is more correlated with alpha 1-blocking activity than with dopamine blocking activity

Anti Psychotic drugs act on the following receptors : 1- dopaminergic 2- alpha 1 - adrenergic 3- muscarinic 4- H1 histaminic 5- Serotonergic (5-HT2)

Dopaminergic pathways in the brain : 1- mesolimbic - mesocortical pathway (behavior) 2- nigrostriatal pathway (co-ordination of voluntary movements) 3- tuberunfundibular pathway (endocrine effects) 4- medullary - periventricular pathway (metabolic effects) 5- incerto hypthalamic pathway ( function not yet defined)

DOPAMINE RECEPTORS : 1- D1 - like receptors : D1 - receptor : - Coded by a gene on chromosome 5 - increase C-AMP by activation of adenylyl cyclase - in putamen, nuclens accumbens, olfactory tubercle D5 - receptor : - coded on chromasome 4 - increase C-AMP - in hippocampus, hypothalamus

DOPAMINE RECEPTORS (CONTD) : 2D2 - like receptors D2 - receptor : - Coded on chromosome 11 - decrease C-AMP - blocks calcium channels - opens potassium " - found pre _ and postsynaptically in candate - putamen, nucleus accumbens, olfactory tubercle

2- D2 - like receptors (Contd): D3 - receptor : - Coded on chromosome 11 - decrease C-AMP - found in frontal cortex, medulla, midbrain D4 - receptor : - latest to be identified - decrease C-AMP - atypical antipsychotic drugs (e.g. clozapine) blocks this receptor.

ANTISYCHOTIC DRUGS: HISTORY: RESERPINE (REUWOLFIA SERPENTINA) - First antipsychotic drug - Role in mental disturbances (India, 1931) - Nathan Kline established its uses. - F. Yonkman introduced the word "tranquilizer" --- describes its effects in animals.

ANTISYCHOTIC DRUGS: HISTORY (CONTD): - Phenothiazine -- anthelminitc properties - Chlopromazine (1950 - Paul Charpentier) - Henri Laborit (Role of histamine in surgical shock) -Delay & Deniker - Paris (1952) a study in 38 psychotic patients showed - less aggressive - fewer delusions and hallucinations

Antipsychotic drugs are also called neuroleptics, major tranquilizers Classification: according to chemical structure into: 1- Phenothiazines: subclassified according to the substitution at position 10 into 3 groups: A- aliphatic -chlorpromazine B- piperidine -thioridazine C- piperazine -trifluoperazine

Classification Of Antipschotics (Contd): 2- Butyrophenones: 3- Thioxanthenes: 4- Dihydroindolones: ---haloperidol thiothixene molindone clozapine

5- Dibenzodiazepines: --

Classification Of Antipschotics (Contd): 6- Dibezoxazepines: -loxapine

7- diphenylbutylpiperidenes:-- pimozide 8- Bezamides: 9- Bezisoxazoles --remoxipride risperidone

ANTISYCHOTIC DRUGS (CONTD): PHRMACOLOGICAL ACTIONS: C.N.S: 1- Antipsychotic effect: - produce emotional quieting and psychomotor slowing - decrease paranoid ideation, delusions and agitation

CNS ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

1- Antipsychotic effect (Contd): - in normal subjects, they produce sleepiness, restlessness, dysphoria and impairment of intellectual functions as judged by psychomotor and psychometric tests MECHANISM: Due to blockade of dopamine receptors in the mesolimbic system

CNS ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

2- Extrapyramidal symptoms: cause abnormal involuntary movements such as tremors, dystonia, Parkinsonism and tardive dyskinesia. MECHANISM: Due to blockade of dopamine receptors in the nigrostriatum and supersensitivity of dopamine receptors

CNS ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

3- Endocrine effects: cause galactorrhea, amenorrhea, gynecomastia and impotence MECHANISM: - On the hypothalamic control over pituitary function - antipsychotics reduce the inhibition of prolactin production by dopamine ----- increase in release of prolactin ---- hyperprolactinemia - other effects may be due to increase in conversion of androgens to estrogens

CNS ACTIONS OF ANTISYCHOTIC DRUGS (CONTD): 4- Metabolic effects: cause changes in eating behavior and weight gain MECHANISM: Due to blockade of dopamine receptors in the medullary-periventricular pathway

CNS ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

5- Antiemetic effect: effective against drug and disease-induced vomiting but ineffective against motion sickness MECHANISM: Due to blockade of dopamine receptors in the chemoreceptor trigger zone of the medulla and peripherally on receptors in the stomach 6- EEG changes: cause slowing and increase in synchronization of EEG patterns

PHARMACOLOGICAL ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

A N S: 1- Anticholinergic effects: - loss of accommodation - dry mouth - urinary retention - constipation MECHANISM: Due to blockade of muscarinic receptors

ANS ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

2- Antiadrenergic effects: - postural hypotension - impotence - failure of ejaculation MECHANISM: Due to blockade of alpha- adrenergic receptors

PHARMACOLOGICAL ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

OTHER ACTIONS: 1- Temperature regulation: May cause lowering of body temperature MECHANISM: may be due to heat loss as result of vasodilatation ( caused by the alpha-adrenergic block ) and may have central mechanism

OTHER ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

2- ECG changes: cause prolongation of QT interval and abnormal configuration of the ST-segment and the T wave. The T wave become rounded, flattened or notched. These effects are seen especially with thioridazine

OTHER ACTIONS OF ANTISYCHOTIC DRUGS (CONTD):

3- Antihistaminic effect: cause H1-receptor blocking effect which may account for the sedative effect 4- some drugs have quinidine-like effects especially the phenothiazines

DIFFERENCES BETWEEN ANTIPSYCHOTIC DRUGS: the clinical potency of antipsychotics correlate with their binding affinity to D2 receptors all effective antipsychotics block D2 receptors. But, the degree of blockade in relation to their effects on other receptors in the brain vary between drugs:

DIFFERENCES BETWEEN ANTIPSYCHOTIC DRUGS (CONTD): e.g. - chlorpromazine & thioridazine block alphadrenergic and serotonin receptors more strongly than D2 receptors. Their effect on D1 receptor is wea