Chapter 2.3. Antipsychotics

Antipsychotics are dugs that ameliorate mental aberrations that are characterictic of the psychoses.

Antipsychotics are also referred to as neuroleptic drugs, or simply neuroleptics. The word neuroleptic is derieved from Greek. 'Neuro' refers to the nerves and 'lept' means 'to take hold of'. Thus the word means 'taking hold of one's nerves' which implies their role in mood stabilization.

The most frequent use of the antipsychotics are in schizophrenia (精神分裂症 ), mania (狂躁症 ) and delusional disorder, although antipsychotics might be used to counter psychosis associated with a wide range of other diagnoses.

Mechanism of action

All antipsychotic drugs tend to block the D2 receptors in the dopamine pathways in the brain, so the normal effect of dopamine release in the relevant synapses is reduced.

It is the blockade of D2 and D3 receptors in the brain which is thought to produce the intended antipsychotic effect.

Schizophrenia is considerd due to the overproduction of dopamine

Types of antipsychotics

There are currently two main types of antipsychotics in use:

Typical antipsychotics-----Chlorpromazine (Thorazine®)

Atypical antipsychotics-----Clozapine (Clozaril®)

A new class of antipsychotic drugs has recently been discovered, known as dopamine partial agonists. Clinical development has progressed rapidly on partial dopamine agonists, and one drug in this class (aripiprazole) has already been approved by the US FDA.

Typical antipsychotics-----Chlorpromazine

Structure and Nomenclature

Chemical Synthesis

N

S

N

ClHCl

Chemical Properties Reducibility

The benzothiozine mother ring is easy to be oxidized

The injection will be deteriorated under the inter- action of light, pH value is dropped down

Phytotoxification probably happens after administra- tion for some patients

N

S

RN

S

R

O

N

S

R

OHO

Photochemical Reaction

Anaphylactic reaction

Metabolism

SAR

N

S

RCl

HCl

Chloride is necessaryfor keeping activity

Could be replaced byother electron-withdrawgroup like –CF3, -COCH3,-SO2N(CH3)2, activity increases 3-5 times

When sulfur is replaced by –C- or -C-C-, -C=C-, the antipsychotic activity is maintained.

Could be replace by C

Side chain may be changed, eg. Piperidinyl replaced –N(CH3)2 will change the LogP value

Chapter 2.4. Antidepressants

Symptom of depressants

Be down in spirits Strong tendency of suicide

Simultaneous phenomena of autonomic nerve orbody

An antidepressant is a medication designed to treat or alleviate the symptoms of clinical depression.

There are three major classes of antidepressants:

1. Monoamine oxidase inhibitors (MAOIs) and were discovered in the early 1950s. The original member of this group was iproniazid, which was originally developed to treat tuberculosis.

2. Tricyclic antidepressants. The first was imipramine. They were effective and safer than the MAOI. but still quite dangerous in overdose. They are still used today but have been largely replaced by another group.

3. Selective serotonin reuptake inhibitors (SSRIs). The first SSRI was fluoxetine. Drugs from all three groups have been found to improve the mood of depressed patients. The SSRI antidepressants were early examples of rational drug design.

Tricyclic antidepressants.

Imipramine Hydrochloride (盐酸丙咪嗪 )(sold as Antideprin®, Janimine®, Tofranil®) 　

3-(10,11-Dihydro-5H-dibenez[b, f]azepine-5-yl)propyldimethylamine hydrochloride

N,N-二甲基 -10, 11-二氢 -5H-二苯并 [b, f]氮杂卓 -5-丙胺盐酸盐

NCH2CH2CH2 N

CH3

CH3

HCl.

Imipramine was, in the late 1950s, the first tricyclic antidepressant to be developed. Initially, it was tried against psychotic disorders (e.g. schizophrenia), but proved insufficient. During the clinical studies its antidepressant qualities, unsurpassed until today, became evident. Subsequently it was extensively used as standard antidepressant and later served as a prototypical drug for the development of the later released tricyclics. It is not as commonly used today but sometimes used to treat major depression as a second-line treatment.

Mechanism of ActionImipramine, a tertiary amine, inhibits the reuptake of serotonin. it blocks the reuptake of neurotransmitters serotonin and noradrenaline almost equally.

MetabolismImipramine is converted to desipramine in the body.

DosageAmbulatory patients : starting with 25 to 75mg daily, increasing up to a maximum of 200mg daily, after remission dose is often reduced to 50-100mg daily.

NCH2CH2CH2 N

CH3

CH3

NCH2CH2CH2 NH

CH3

demethylation

Metabolism

Imipiramine is metabolized in the liver to give despramine, which is also been used.

Stability

Is stable in solid or solution

Decomposed when heated

Selective Serotonin Reuptake Inhibitors (SSRIs)

Floxetine (Brand names: 百忧解 --China, Prozac--US)

F3C

O NHCH3*

Eli Lilly's Prozac was approved by the FDA on December 29, 1987 and introduced in the US at the beginning of 1988. The drug became very popular, with millions around the world having taken the medication. In the fall of 2001, Eli Lilly lost a patent dispute with Barr Laboratories and now fluoxetine hydrochloride is manufactured by many companies.

Fluoxetine hydrochloride is approved in the United States to treat depression, and other neurological indication.

Mechanism of actionPer the prescribing label, the mechanism of action of fluoxetine is unknown. Recent research indicates that fluoxetine may increase the production of new neurons (brain cells) in adult brain (adult neurogenesis).

MetabolismFluoxetine is eliminated very slowly by the human body. The half-life of fluoxetine after a single dose is two days. The liver metabolizes fluoxetine to a desmethyl metabolite.

Interaction and Mechanism

Selctive 5-HT reuptake inhibitor (SSRI) -increase the concentration of 5-HT synaptic junction clearance, therefore meliorate the mood of patientsfor treatment of depressant with high selectivityif compared with tricyclic antidepressants -equivalent effect -less side effect of anti-M receptor and heart toxicity