Antipsychotics

There is no cure for Schizophrenia just symptomatic control is done

Schizophrenia

• A mental disorder where person can’t grasp reality and shows behavioral and cognitive dysfunction

• Positive symptoms: abnormality of normal function leading to presence of inappropriate behaviors – Delusions (false belief)and hallucination (false perception), speech disturbances

• Negative symptoms: loss of normal function leading to absence of appropriate behaviors – lack of motivation, social withdrawal, lack of interest in fun activity, doesn’t respond to questions

SCHIZOPHRENIA IS FOR LIFE

CausesWe don’t know the exact cause but it is believed that excess of dopamine activity is the reason for the diseaseThe evidence for this is-• 1st Drugs for psychosis was Chlorpromazine and it is

a D2 antagonists• Antiphycotic drugs produce Parkinson-like symptoms • Drugs that promote dopamine activity, L-Dopa and

amphetamine, produce or increase Schizophrenia • There is increase in number of brain dopamine

receptor.

Counter evidence of the dopamine hypothesis• Older drugs are not effective in all patients• Newer atypical drugs low affinity for dopamine

receptors• Drugs that block NMDA produce more

Schizophrenia than even drugs that promote dopamineThis suggests other NT than dopamine is also

involved

Major Dopamine pathwaysPathway Significance Associated disease

The Nigro-straital pathway

Movement Low dopamine causesEPS (Extra Pyramidal symptoms)

The Mesocortical pathway

Motivation, pleasure, socialization

High Dopamine causesnegative symptoms of schizophrenia

The Mesolimbic pathway

Speech, grasp of reality

High dopamine causespositive symptoms of schizophrenia

The Tuberoinfundibular pathway

Prolactin Hormone release

Prolactin Hormone deficiency

Ideally we would want dopamine blockade only in Mesocortical and Mesolimbic pathway but that has not been realized till now

Dopamine and EPS

• We studied in Parkinson that Dopamine is a Neurotransmitter (NT) involved in movement (in balance with acetylcholine)

• When dopamine levels decreases, due to action of antipsychotic drugs in all Dopamine pathways, movement related disorders called Extra Pyramidal symptoms (EPS) arise which includes – akinesia (inability to initiate movement) and– akathisia (inability to remain motionless) and – acute dystonia (twisting of muscles)

Other Neurotransmitters also have their own pathways and unique function associated with it

• DOPAMINE RECEPTORSReceptor 2o Messenger SystemD1 cAMP D5 cAMPD2* cAMP, D3 cAMP,D4 cAMP*Most antiphycotic drugs antagonize or inverse agonize block D2 but newer atypical drugs have other mechanism too based on acetylcholine, histamine, serotonin, adrenaline

Ideally receptor are silent or non-functional without being bound by their natural agonist.

But some receptor are active even when they are not bound by any agonist. In this case inverse agonists work to produce opposite response.

Inverse agonism is a property seen in only those receptors (not enzymes) that are active even without any binding to their agonist/ligand/substrate.

Ref: Continuing Education in Anaesthesia, Critical Care & Pain | Volume 4 Number 6, page 181-184 2004

Understanding Inverse Agonism

• Inverse Agonist produce negative response

Classification1st Gen/Typical: High affinity for Dopamine receptor and

consequently have Extra Pyramidal symptoms (EPS)• Butyrophenones: Haloperidol*, Droperidol• Phenothiazines

– Aliphatic : Chlorpromazine*, Trifluopromazine – Piperidine : Thioridazine, Piperacetazine– Piperizine : Fluphenazine, Perfenazine

• Thioxanthines: Flupenthixol, Thiothixene

2nd Gen/Atypical: They primarily affect other NT but for exact reason have a wide Side effect profile including obesity

• Olanzapine, Quetiapine, • Aripiprazole, Risperidone

Potency

Discovery of Butyrophenones

SAR of Butyrophenones

1) Modification of benzoyl group• Anything other than fluorine in the para

position lowers activity• A is 4 times more potent than B due to F

C

O

CH2 N

3

F

C

O

CH2 N

3

A

B

2) Replacing the carbonyl group with isoteric group or any other functional group lowers activity

X can’t be N or S or C X can’t be OH, NH2, SH

An important exception - DiphenylbutylpiperidinesReplacement of the carbonyl of haloperidol with para fluro phenyl group creates a new class of compounds called diphenylbutylpiperidines that has following advantage– Long acting–NO sedative, autonomic, extrapyrimidal side

effects–Useful in autism (Autism is a mental disorder

in children characterized by impaired social interaction and verbal and non-verbal communication, and by repetitive behavior)

DiphenylbutylpiperidinesThe keto group has been replaced with para Fluro group

3) Modification of the -CH2- linker group The linker has to be a propylene. Any alteration

to the -CH2- linker region such as shortening, lengthening, branching, or incorporation into a ring system, results in a marked decrease or even complete loss of neuroleptic activity.

C

O

CH2 N

nF

only n= 3 is activeR2

R1

NC

O

F

R1

R2no cyclic form allowed

4) Modification of the amino groupa) A tertiary amino group should be presentb) A tertiary amine in some cyclic form

(piperidine, tetrahydropyridine or piperazine ring) increases potency

c) Further modification of the ring at para position can de done for better potency and reducing toxicity

Potency

Ref:Paul A. J. Janssen, Willem F. M. Van BeverStructure-Activity Relationships of the Butyrophenones and DiphenylbutylpiperidinesHandbook of Psychopharmacology,1978, pp 1-35

•R is always amine•Amine is always teritary•It can be para substituted for better potency or lower toxicity

Haloperidol• It is a Butyrophenone derivative used in the treatment of

schizophrenia and delirium• It has High incidences of Extra Pyrimidal Side efects(EPS

– tremor and motor dysfunction) but Low hypotension and low autonomic side effects

and sedative effects lower than Chlorpromazine• Decanoate Esterifation at the OH group forms a long

acting derivative• MOA- It is an inverse agonist in Dopamine D2 receptor

in the Mesocortical and Mesolimbic pathwayRef: British Journal of Pharmacology (1997) 121,731± 736

Haloperidol synthesisCH2CH2CH2Cl C

O

Cl F

CH2CH2CH2Cl C

O

F

4-Chlorobutyryl Chloride

Fluorobenzene

4-Chloro-4-fluorobutyrophenone

-HCl

Cl NH

HO

4-(p-Chlorophenyl)-4-piperidionol

Cl N

HO

CH2CH2CH2 C

O

F

-HCl

Haloperidol

SAR of Phenothiazines

SAR of Phenothiazines

1) Unsubstituted Phenothiazines has no activity but has enough lipophilicity for good brain penetration. Substitution at C2 and N10 is required for activtiy

2) C2 must have an electrowithdrawing group. The activity for these various group is as

X = - SO2NR2 > -CF3 > -CO-CH3 > -Cl

Electron Donating Electron Withdrawing

3) A terminal amino substituent must be present at N10. It can be piperazine, piperidine or aliphatic and their intensity could be ranked as follows: piperazine group >piperidine group > aliphatic chain

•Esterification of the OH containing piperazine derivatives extensively increases the duration of action

4) There must be an linear (ie unbranched) alkyl linker between the core ring and the terminal amino ring those length is optimum at three methylene units ie CH2-CH2-CH2Reduction of these carbon number changes receptor affinity

Chlorpromazine

• It is a phenothiazine derivative used in treatment of schizophrenia. It was the first antiphycotic drug

• It’s also used as antiemetic and against hippcup• Has high incidence of Extra Pyramidal side effects• It’s metabolite has strong antiadrenergic, weak

anticholinergic and slight antihistaminergic and antiserotonergic properties (not parent molecule)

• MOA: It antagonizes Dopamine D2 in the the Mesocortical and Mesolimbic pathway

Chlorpromazine synthesis

S

N Cl

H

Cl CH2 CH2 CH2 N

CH3

CH3

3-Chloropropyl-dimethylamine2-Chlorophenothiazine

Refulx in presence oftoulene andsodamide

S

N Cl

CH2 CH2 CH2 N

CH3

CH3

Chloropromazine

R1

R2

R1R2

Trans has R groups onopposite side of double bond

Cis has R groups onsame side of double bond

Decide cis and trans in these compounds?

Flupenthixol

• It is a Thioxanthine derivative used for treatment of schizophrenia• It can exist in cis and trans form and only cis is active because it mimics the conformation of Dopamine• It’s duration of action is long (2-3 weeks) and hence useful in patients who have a poor compliance with medicationMOA- It is nonselective and antagonizes both Dopamine D1

and D2 in the the Mesocortical and Mesolimbic pathway

Olanzapine

• It is an atypical drug used for treatment ofof schizophrenia and also used in bipolar disorder• Olanzapine is a potent antagonist of the muscarinic M3

receptor and this has been linked to it’s diabetic side effect

• It can cause heart failure, sudden death, or pneumonia when used in older adults suffering from dementia

• MOA: It has low antagonist activity in Dopamine D2 receptor and primary action is believed to have occurred through inverse agonism at Serotonin 5HT2A and antagonism at adrenergic receptors

Schizophrenia vs Dementia

Schizophrenia Dementia

Both Positive and Negative symptoms MUST occur

multiple cognitive problems occur

Schizophrenia is independent disease

It is a physiological result of an illness or substance eg Dementia in Parkinson and Alzheimer

Quetiapine

• It is a short-acting atypical antipsychotic used for the treatment of schizophrenia and bipolar disorder

• It is a dopamine, serotonin, and adrenergic antagonist, and a potent antihistamine with negligible anticholinergic properties.

• MOA: It has low antagonist activity in Dopamine D2 receptor and primary action is believed to have occurred through antagonism at both Serotonin 5HT2A and adrenergic receptors

Aromaticity

Which one of these tricyclic rings is flat?

Aripiprazole

• It is a atypical antipsychotics used in the treatment of schizophrenia, bipolar disorder, irritability associated with autism and as an adjunct in depression

• Extra Pyramidal Side effects is low • It agonizes 5HT2C also which control satiety. Thus

this drug does not cause weight gain which is seen with other antiphycotic drug

• MOA: It is a partial agonist at both Dopamine D2 and Serotonergic 5HT2A receptors

Drug Dopamine (D2) Serotonin (5HT2A) Adrenergic

Haloperidol Inverse agonist

No action by 1st Gen

No action by 1st Gen

Chlorpromazine Antagonist No action by 1st Gen

No action by 1st Gen

Flupenthixol Both D1 & D2 antagonist

No action by 1st Gen

No actionby 1st Gen

Olanzapine Weak Antagonist

Inverse agonist Antagonism

Quetiapine Weak Antagonist

Antagonist Antagonist

Aripiprazole Partial agonist Partial agonist -

Summary: The MOA of antipsychotic Drugs are not the same

THANK YOU

Revision

Special topic

Antipsychotic Drugs can make you fat. So fat that it can kill you!!!

Neuropsychiatric Disease and Treatment 2008:4(1)

• People suffering from schizophrenia, on average, die about 25 years earlier than individuals from the general population.

• Some of this reduced life expectancy is due to Coronary heart disease (CHD) which is turn is due to high cholesterol due to obesity

Ref: Focal Point: Youth, Young Adults, & Mental Health. Healthy Body - Healthy Mind, Summer 2012, 26(1)

Antipsychotic drugs increases appetite

You become fat

Arteriole wall are squeezed by fat deposition

Coronary Heart DiseaseQuestion is how does antipsychotic drugs make you

fat?

• Research led to finding that activation of TGFβ1/SMAD3 signaling pathway led to obesity based side effects

• Blockade of SMAD3 was speculated to counter obesity

• Mouse who has their SMAD3 knocked out (alteration in their DNA so that no SMAD3 is produced by body naturally) did not become diet induced fat*

• Also, the antiphycotic action and obesity action were completely independent from each other.

* Ref: Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling Cell Metab. 2011 July 6; 14(1): 67–79.

Antiphycotic drugs

Activate SMAD3

Activate PPAR

Activate Adipogenesis (increase in fat cells)

This is how antipsychotic drugs and obesity are connected

Ref: Getting ‘Smad’ about obesity and diabetes. Nutrition and Diabetes (2012)2, e29

It means• It is possible to create antiphycotics drugs that

DO NOT cause obesity (ie enhance selectivity to avoid SMAD3 receptor blockage)

• SMAD3 can be a new independent target to reduce obesity

Lesson to learn: Pharmacology is a cool subject• The side effects of antipsychotics drugs was investigated and a good target for completely

different diseases was established

2.5 marks questions

1. How do atypical antipsychotic drugs differ from typical ones?

2. What is the meaning of positive and negative symptoms of Schizophrenia?

3. How antipsychotic drugs cause Parkinson?4. What is unique about Aripiprazole in context

of obesity?