Anti-Psychotics

Mgr. Malek AzarCHARLES UNIVERSITY IN PRAGUE

FACULTY OF PHARMACY

Psychosis

• A mental disorder characterized by loss of contact with reality caused by excess of dopamine in the limbic system in the brain.

• Types of psychosis: Schizophrenia, Bipolar disorder, others. Psychosis Symptoms

Positive NegativeHallucination Cognitive, Emotional Impairment

Delusions IsolationAgitation Apathy

Anti-Psychotics

• They are medications used in psychosis by inhibiting dopamine (D).

• They are divided into two main parts:1st Generation 2nd Generation

• They may be used in: Aggressive patients, vomiting, bipolar disorder, refractory pain, depression and anxiety.

Pharmacokinetics

• Mainly orally• Good absorption• High lipophilicity• Extensively metabolized in the liver by CYP450• Once daily (long half life)

Side Effects

Mainly they inhibit dopamine receptors so they cause Extra-pyramidal side effects: • Dystonia: sustained muscle contraction• Akathisia: restlessness, constant movement• Parkinsonism• Dyskinesia: involuntary muscle movement

Other Side EffectsMany of them inhibit many receptors

• Alpha: hypotension, sexual dysfunction• Muscarinic: dry mouth, blurred vision, constipation,

urinary retention,…• Histaminic: sedation, weight gain • QT prolongation.

1st GENERATION ANTI-PSYCHOTICS

• These are divided into two parts:Basal Incisive

Incisive Anti-Psychotics

• High affinity to D2 receptors• Low affinity to other types of receptors. • They affect positive symptoms of schizophrenia mainly.• They bring extrapyramidal symptoms (EPS).

Incisive Anti-Psychotics

Pheno-thiazines / Thio-xanthenes Butyro-phenones

Perphenazine Haloperidol

Fluphenazine Melperone

Flupenthixol

Basal Anti-Psychotics

• Lower affinity to D2 receptors• Higher affinity to other receptor types. • They affect positive and negative symptoms of

schizophrenia. • They have sedative, anticholinergic, antihistaminic and

cardiovascular side effect, but extrapyramidal symptoms are less frequent.

Basal Anti-Psychotics

Pheno-thiazines Thio-xanthenes

Chlor-promazine Chlor-prothixene

Levome-promazine Zuclo-penthixol

2nd GENERATION ANTI-PSYCHOTICS(ATYPICAL ANTI-PSYCHOTICS)• In general, they are serotonin-dopamine antagonists

(antagonists of D2 and serotonin receptors 5HT-2A)• They affect in general many other types of receptors.• They are much more efficient in treatment of negative

symptoms of schizophrenia in comparison with conventional antipsychotics.

• Have lower side effects (lower EPS)

2nd GENERATION ANTI-PSYCHOTICS

• They are metabolized by CYP450 in liver.• They potentiate the sedation effects of analgesics, alcohol

and antihistamines.

Atypical anti-psychotics

Multi Acting Receptor Targeted

Antagonists

Dopamine-Serotonin

AntagonistsD2-D3

AntagonistsDopamine

Partial Agonist

Multi Acting Receptor Targeted Antagonists(MARTA)

• They block many types of receptors: D2, M, A, H1, 5HT2• They have low risk of causing Extrapyramidal SE and

hyperprolactenemia• They have other side effects (due to their multi

antagonism): sedation, weight gain and hypotension.• Risk of induction of Diabetes Mellitus 2.• Clozapine – Olanzapine – Quetiapine – Zotepine.

Dopamine-Serotonin Antagonists

• They block D2-D3 and 5HT2 receptors and some others (H-A).

• They cause less sedation and hypotension but more risk of hyperprolactinemia and extrapyramidal SE.

• Similar effects to MARTA compounds.• Risperidone – Paliperidone – Sertindole – Ziprasidone

Dopamine D2-D3 Antagonists

• They block selectively D2-D3 receptors• In low dose, they block the presynaptic receptors

affect negative symp.• In high dose, they block the postsynaptic ones affect

positive symp. • High risk of Extrapyramidal and hyperprolactinemia SE. • Sulpiride – Amisulpiride

Dopamine Partial Agonist

• It has D2 , 5HT1A partial agonism and 5HT2A antagonism.• It has a very low incidence of side effects.• Aripiprazole

Therapeutic Strategy

• Atypical anti-psychotics are the drugs of choice.• Onset of beneficial effects may take 2-3 weeks and till the

optimal effects, it requires 4-6 weeks of therapy.• Discontinuation may lead to relapse.