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 (Cont’d):

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 (Cont’d):

- 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 (Cont’d):

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 (Cont’d): 

 

c- Manic-depressive illness:

( bipolar affective disorder )

 

marked swings of mood between

extreme elation and excitement to

profound depression and withdrawal

 

PSYCHOSES (CONT’D): 

 

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 (Cont’d): 

❏ 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 (CONT’D): 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 (CONT’D):

   

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 (CONT’D) :

2- D2 - 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 (Cont’d):

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 (CONT’D): -

-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 (Cont’d):

 

2- Butyrophenones: -- haloperidol

 

3- Thioxanthenes: -- thiothixene

 

4- Dihydroindolones: -- molindone

 

5- Dibenzodiazepines: -- clozapine

 

  Classification Of Antipschotics (Cont’d):

6 -Dibezoxazepines: -- loxapine

 7- diphenylbutylpiperidenes:-- pimozide

 

8- Bezamides: -- remoxipride

 

9- Bezisoxazoles -- risperidone

  ANTISYCHOTIC DRUGS (CONT’D):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 (CONT’D):

 

1- Antipsychotic effect (Cont’d): - 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 (CONT’D):

 

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 (CONT’D):

  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 (CONT’D):

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 (CONT’D):

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 (CONT’D):

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 (CONT’D):

2- Antiadrenergic effects:

  - postural hypotension

  - impotence

  - failure of ejaculation

MECHANISM:

Due to blockade of alpha- adrenergic receptors

 PHARMACOLOGICAL ACTIONS OF ANTISYCHOTIC DRUGS (CONT’D):

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 (CONT’D):

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 (CONT’D):

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 (CONT’D):

e.g.

- chlorpromazine & thioridazine block alpha-drenergic and serotonin receptors more strongly than D2 receptors. Their effect on D1 receptor is weak.

 

chlorpromazine: alpha1 = 5-HT2 > D2 > D1

 

 DIFFERENCES BETWEEN ANTIPSYCHOTIC DRUGS (CONT’D):

- haloperidol has stronger effect on D2 receptors

than on D1 or D4. It has less alpha-adrenergic and serotonin receptors .

haloperidol: D2 > D1 = D4 > alpha-1 > 5-HT2

 

- clozapine has more effect on D4, alpha-        adrenergic, H1 and serotonin receptors than on

either D1 or D2 receptors

 

clozapine: D4 = alpha-1 > 5-HT2 > D2 = D1

  ANTIPSYCHOTIC DRUGS (CONT’D):

THERAPEUTIC USES:PSYCHIATRIC:

1- Schizophrenia, the PRIMARY INDICATION

 

2- Acute mania

 

3- Manic-depressive illness ( bipolar affective

disorder ) especially during the manic

phase

 PSYCHIATRIC USES OF ANTIPSYCHOTIC DRUGS (CONT’D):

4- Schizoaffective disorders, together

with antidepressants or lithium

 

5- Non-manic excited states, in combination

with benzodiazepines

 

6- Tourette`s syndrome

 

7- Progressive senile dementia of Alzheimer

type

 PSYCHIATRIC USES OF ANTIPSYCHOTIC DRUGS (CONT’D):

8- agitation or psychoses in depressed patients, together with antidepressants ( those patients tend to develop tardive dyskinesis, therefore should be dosed sparingly ) - not indicated in opioid withdrawal syndrome - not recommended for anxiety due to minor emotional disorders

 NON-PSYCHIATRIC USES OF ANTIPSYCHOTIC DRUGS:

 1- Nausea and vomiting

  - prochlorperazine and benzquinamide

are only used as antiemetics

 2- Pruritis

 3- Preoperative sedation

 - fenantyl and droperidol are given to produce analgesia and amnesia with nitrous oxide to provide what is known as NEUROLEPTANESTHESIA

 ANTIPSYCHOTIC DRUGS:

ADVERSE EFFECTS:

  C N S 1- Sedation, drowsiness, lethargy (coma)

and fatigue

  2- Extrapyramidal symptoms:

      some occurring early in treatment and

manifested as:

  a- Parkinson's syndrome: tremor and rigidity

  b- Akathesia: continual aimless motor

restlessness

   C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

2- Extrapyramidal symptoms (Cont’d):

c- Acute dystonic reactions :  tonic contractions of muscle groups

especially in the face, tongue and neck

  e.g. spastic retrocollis, torticollis

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

Treatment Of Extrapyramidal Symptoms:

❏ Parkinson's syndrome can be controlled

by antiparkinsonsm drugs from the

anticholinergic type (benzhexol,

benzotropine).

❏ Parkinson's syndrome may be self-limiting,

so an attempt to withdraw antiparkinsonism

drugs should be made every 3 - 4 months 

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

Treatment Of Extrapyramidal Symptoms

(Cont’d):

❏ Akathesia and acute dystonic reactions may be treated with antiparkinsonism drugs or sedative antihistamines with anticholinergic properties such as diphenhydramine

 

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

❏ Other extrapyramidal symptoms are 

late-occurring which include:

d- tardive dyskinesia:

(from Latin tardus, slow or late coming)

it is a disorder of involuntary movements

(choreoathetoid movements of lips,

tongue, face, jaws, and of limbs and

sometimes trunk).

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

d- tardive dyskinesia (Cont’d):

older women treated for long periods are

the most susceptible although it can

happen at any age or sex in 20-40% of

chronic patients treated with antipsychotics.

 

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

d- tardive dyskinesia (Cont’d):

Mechanism:

- suggested to be due to supersensetivity of

dopamine receptors in the caudate-putamen and there may be also a relative cholinergic deficiency.

- early recognition is important as advanced cases are difficult to reverse.

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

d- tardive dyskinesia (Cont’d):

TREATMENT:

1- decrease dopamine receptor sensitivity by

discontinuing the antipsychotic drug or at least reducing the dose

2- eliminate all drugs with central anticholinergic action such as antiparkinsonism, antidepressants

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

Treatment Of Tardive Dyskinesia (Cont’d):

3- if the above two steps fail to bring improvement, add diazepam which may help by enhancing GABA activity

 

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

e- neuroleptic malignant syndrome:

♦ rare but life threatening.

♦ symptoms are muscle rigidity and high

fever ( clinically similar to anaesthetic

malignant hyperthermia ).

♦ the stress leukocytosis and high fever

associated with this syndrome may

wrongly suggest an infection.

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

e- neuroleptic malignant syndrome (Cont’d):♦ mechanism could be due to oversensitivity

to the blockade of postsynaptic dopamine receptors .

♦ treatment of this syndrome includes dantroline, dopamine agonists such as bromocriptine, muscle relaxants such as diazepam and anticholinergic drugs e.g. procyclidine

 C.N.S. ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

3-    Antisychotics may precipitate epileptic seizures in susceptible patients, seen

more with chlorpromazine and clozapine while less with high-potency drugs

 ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

A N S

1- postural hypotension

2- dry mouth

3- urinary retention

4- constipation

5- nasal congestion

6- failure of ejaculation

7- blurred vision

 ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

ENDOCRINE

 

1- gynaecomastia: swelling of breasts in men

2- galactorrhoea: lactation in women

3- amenorrhoea: cessation of menstruation

 ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

MISCELLANEOUS EFFECTS

 1- obstructive jaundice

 2- granular deposits in cornea & lens,

thioridazine may cause retinal deposits

 3- weight gain 

4- purplish skin pigmentation after long use

 

 MISCELLANEOUS ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS (CONT’D):

5- agranulocytosis:

rare except with clozapine

(about 1-2%) usually happen after 6-18

weeks.

  Weekly CBC is mandatory

 

6- Thioridazine overdose may cause

ventricular arrhythmias

 ANTIPSYCHOTIC DRUGS (CONT’D):

PHARMACOKINETICS:

❏ Incompletely absorbed from the gut and

undergo extensive first-pass hepatic

metabolism.

Therefore, their systemic availability after

oral dose is variable:

e.g. Chlorpromazine & thioridazine 25-35% 

haloperidol 65%  

  PHARMACOKINETICS OF ANTIPSYCHOTIC DRUGS (CONT’D):

❏ Highly lipid soluble and highly protein-

bound resulting in large volumes of

distribution.

This cause their clinical duration of action

to be longer than their plasma half-lives

  PHARMACOKINETICS OF ANTIPSYCHOTIC DRUGS (CONT’D):

❏ Most of drugs have complicated

metabolism

  e.g. chlorpromazine has about 60

metabolites some of which are active

metabolites. These metabolites may

still be excreted in urine after months

of stopping the drug.

  ❏ Thioridazine & haloperidol also have

active metabolites

 ANTIPSYCHOTIC DRUGS (CONT’D):DRUG-INTERACTIONS:  ❏ Potentiation of other CNS depressants   e.g. sedatives, hypnotics, alcohol, and antihistamines  ❏ Chlorpromazine increases the miotic, sedative and analgesic effect of morphine ❏ Chlorpromazine increases the respiratory depression caused by meperidine ❏ Inhibit the action of dopaminergic agonists e.g. bromocriptine, levodopa 

 DRUG-INTERACTIONS ANTIPSYCHOTIC DRUGS (CONT’D):

 ❏ May interact with some antihypertensive

agents due to the orthostatic hypotension

effect they produce

 ❏   Phenothiazines, e.g. thioridazine, decrease

the inotropic effect of digitalis due to their

quinidine-like effect, they may also cause

arrhythmia’s

 ANTIPSYCHOTIC DRUGS (CONT’D):

CLOZAPINE : (CLOZARIL)

 - New atypical anti psychotic agent

 - Oral bioavailability 50-60%

 - 95% bound to plasma proteins

 - t ½ = 12 h

 - Completely metabolized.

 - Few extrapyramidal adverse effects

 

 CLOZAPINE (CONT’D) : - No elevation of serum prolactin 

- Postural hypotension - Strong anticholinergic effects - Excessive salivation (during sleep) - Agranulocytosis 3% of patients  (limits its clinical use) - Siezures 2 - 5% of patients

Monitoring of white cell count is done weekly - Generally reserved for severe, resistant cases

 ANTIPSYCHOTIC DRUGS (CONT’D):

MOLINDONE (MOBAN , LIDONE) :

 

• Moderate Sedation, increased activity, euphoria?

  • Anticholingergic phenothiazines

  • Less hypotension, but tachycardia

  • Rapidly absorbed, completely liner metabolized

  • Extrapyramidal prominent

  • Skin rashes, allergic?

  • Leukopenia

  • Does not cause weight gain.

 

 DOPAMINE IN THE CNS:  

- Distribution is highly non-uniform - nigrosrtiatal pathway ( 75%)   ( cell bodies in substantia nigra   axons in corpus striatum )

- mesolimbic pathway

 - tuberoinfundibular system  Dahlstrom & Fuxe fluorescence staining studies ( 1965 )