Transcript Mechanism of Action

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
S
HCl
Cl
N
N
Chemical Properties
Reducibility
The benzothiozine mother ring is easy to be oxidized
S
S
N
R
N
R
O
HO
S
O
N
R
 The injection will be deteriorated under the interaction of light, pH value is dropped down
Phytotoxification probably happens after administration for some patients
Photochemical Reaction
Anaphylactic reaction
Metabolism
SAR
Chloride is necessary
for keeping activity
S
When sulfur is replaced by
–C- or -C-C-, -C=C-, the
antipsychotic activity is
maintained.
HCl
Cl
Could be replaced by
other electron-withdraw
group like –CF3, -COCH3,
-SO2N(CH3)2, activity
increases 3-5 times
N
R
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 or
body
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®)
N
CH2 . HCl
CH2
CH3
CH2 N
CH3
3-(10,11-Dihydro-5H-dibenez[b,
f]azepine-5yl)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
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 Action
Imipramine, a tertiary amine, inhibits the reuptake of serotonin.
it blocks the reuptake of neurotransmitters serotonin and noradrenaline almost
equally.
Metabolism
Imipramine is converted to desipramine in the body.
Dosage
Ambulatory 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.
Metabolism
Imipiramine is metabolized in the liver to give
despramine, which is also been used.
demethylation
N
CH2
CH2
CH3
CH2 N
CH3
N
CH2
CH2
CH2 NH
CH3
Stability
Is stable in solid or solution
 Decomposed when heated
Selective Serotonin Reuptake Inhibitors (SSRIs)
Floxetine (Brand names: 百忧解--China, Prozac--US)
F3 C
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 action
Per 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).
Metabolism
Fluoxetine 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 patients
for treatment of depressant with high selectivity
if compared with tricyclic antidepressants
-equivalent effect
-less side effect of anti-M receptor and heart toxicity