Antipsychotic drugs Flashcards
What is schizophrenia?
Schizophrenia is a type of psychosis characterised by noteworthy disruption of thinking process, but unaltered sensory processing.
Unknown pathogenesis, probably genetic predisposition.
What are some symptoms of schizophrenia?
Flattened affect, no socialisation.
Lack of initiative (avolition).
Reduced speech.
Cognitive deficiency.
Negative symptoms that cannot be treated pharmacologically.
Positive symptoms might be treated with medicines.
What is phenothiazine?
Phenothiazine nucleus was synthesised in 1883 and used as anthelmintic, but did not possess antipsychotic activity.
More than 24 phenothiazine and related thioxanthene derivatives are used in medicine, for psychiatric conditions.
Phenothiazines have improved the lives of schizophrenic patients.
What are phenothiazine derivatives?
3 sub-types based on R2 residues:
Aliphatic chain
Piperidinyl group
Piperazinyl chain: more potent
Generic names: CPZ, TDZ, FPZ, PPZ, TFP
TDZ withdrawn
Why is the SAR of phenothiazines important?
Three-carbon chain connecting nitrogen is required.
(two- or four-carbon chain decreases activity)
Addition of chain length to N2 of piperazine increases receptor biding forces.
Branching on side chain decreases activity.
Branching at γ carbon is tolerated.
Substitution at both positions 1 and 4 decreases antipsychotic activity.
Position 2 is optimal for introducing substituents.
Unsubstituted phenothiazines at Pos2 have weak antipsychotic activity.
Secondary amines have decreased activity. Basic nitrogen (tert-amines) provide best activity. Tertiary amine is required for passing through brain blood barrier (BBB), but protonated ammonium species is the most important chemical species at the receptor binding site.
Groups bulkier than dimethylamino group decrease activity.
Piperidine (thioridazine) and piperazine (fluphenazine) rings are tolerated.
What is the metabolism of chlorpromazine?
Liver microsomal cytochrome P450-catalysed metabolic pathway for neuroleptic.
Demethylation to yield nor-CPZ.
Sulfoxidation to yield CPZ-SO.
Hydroxylation to yield 7-OH-CPZ.
Glucuronidation to yield 7-O-glu-CPZ.
What is the mechanism of action of phenothiazines?
Phenothiazine antipsychotics block dopaminergic receptors D2 in a stereoselective manner (post-synaptic D2 receptor blockade).
D2 receptors are involved in mesolimbic-cortical pathway (or system) that is correlated with behavioural processes (Reward pathway).
D2 Binding affinity varies depending on ligands.
Antipsychotics affinity with receptors is directly linked with antipsychotic and extrapyramidal clinical activity .
Antipsychotic activity is not accounted solely on D2-type receptor antagonism: other CNS receptor systems are involved: acetylcholine, histamine, norepinephrine and serotonin.
How does dopamine receptor binding work?
Three-point interaction of pharmacophoric groups of noradrenaline and dopamine with receptor:
Anionic site interreacts with protonated nitrogen of dopamine.
A flat hydrophobic region interacting with phenyl ring and hydrogen bonding at specific areas around phenyl rungs to accommodate hydroxy groups.
A two carbon length between anionic and ring sites.
How does phenothiazine bind to the D2 receptor?
Three-point interaction:
Protonable nitrogen interacting with anionic site on receptor.
Phenyl ring interacting with hydrophobic area.
Two carbon distance between anionic site and aromatic region attained through bending of side chain.
Maximum neuroleptic potency with aminoalkylated phenothiazines having tertiary amino group.
Groups larger than methyl decreases activity.
Quaternarisation of terminal nitrogen leads to loss of activity, due to inability of resulting polar compounds to cross BBB.
What is different about thioxanthene compared to phenothiazines?
Slightly less potent compared to phenothiazines.
The olefinic double bond gives rise Z (cis) and E (trans) isomers.
Z isomer is several-fold more active than E isomer.
What is different about Butyrophenone compared to phenothiazines?
Alternative to phenothiazine groups for manic-depressive disorder.
Benperidol is the most potent neuroleptic in European market (chlorpromazine equivalency 75-100), now used to control hypersexuality syndrome in sex offenders.
Why is the SAR of Butyrophenone important?
Haloperidol binds with equal affinity to dopamine D2 and serotonin 5-HT2 receptors in mammalian brain tissue.
Both D2 and 5-HT2 seem to mediate antipsychotic activity of butyrophenones.
What are diphenylbutyl piperidine neuroleptics?
Replacement of keto function with di-4-fluorophenylmethane unit results in diphenylbutyl piperidine neuroleptics.
eg: Pimozide - useful in controlling acute exacerbation of schizophrenia and reducing relapses.
What is the metabolism of haloperidol?
Reduced haloperidol (RHP) is the best-known metabolite of haloperidol (HAL) .
RHP is much less potent than HAL.
RHP contains an asymmetric center, it can exist in two possible enantiomeric forms, e.g., R and S.
What is benzamide?
Dopamine D2-type receptor antagonist.
Used to prevent nausea and vomiting.
S-isomer: Sulpiride - a derivative in which side chain is included in pyrrolidine ring; lower incidence of extrapyramidal effects.
What is dibenzodiazepine?
A 1,4-diazepine ring fused with two benzene rings.
Clozapine, olanzapine, loxapine and quietapine are antipsychotic drugs with low risk of extrapyramidal side effects.
Occupancy of both D2 and 5-HT2A receptors leading to psychotherapeutic effects.
Clozapine drawback: potentially fatal agranulocytosis.
Metabolised by CYP3A4 to inactive dimethyl, hydroxyl and N-oxide derivatives.
What are benzisoxazole derivatives?
Features of two chemical nuclei resulting in a combination of D2 and 5-HT2A antagonistic activity.
Antipsychotic effects with reduced extrapyramidal effects.
Risperidone is well absorbed orally and metabolised in the liver .
CYP2D6-catalysed 9-hydroxylation that yields the active metabolite hydroxyrisperidone.
Half life is approx. 22 hours.
What is the relationship between structure, potency and side-effects of common antipsychotic drugs?
Aliphatic phenothiazines - chlorpromazine:
Low potency.
Medium extrapyramidal side effects.
High sedative effects.
High hypotensive effects.
Piperazinyl phenothiazines - Fluphenazine:
High potency.
High extrapyramidal side effects.
Low sedative effects.
Very low hypotensive effects.
Thioxanthene - thiothixene:
High potency.
Medium extrapyramidal side effects.
Medium sedative effects.
Medium hypotensive effects.
Butyrophenone - haloperidol:
High potency.
Very high extrapyramidal side effects.
Low sedative effects.
Very low hypotensive effects.
Dibenzodiazepine - clozapine:
Medium potency.
Very low extrapyramidal side effects.
Low sedative effects.
Very low hypotensive effects.
What are the pharmacokinetics of antipsychotic drugs?
Absorption: Rapid, but not complete. Significant first pass metabolism. Oral doses of thioridazine and chlorpromazine have systemic bioavailability of 25-35%, whereas haloperidol 65%.
Distribution: Antipsychotics high lipo-solubility and protein bound, hence large volume of distribution.
Fat tissue distribution, duration of antipsychotic action longer than half life in plasma.
Metabolism: Compounds almost completely metabolised.
Most metabolites not important apart from:
7-hydroxychloropromazine.
Reduced haloperidol that remains active.
Mesoridazine, main metabolite of thioridazine that is more active than parent compound.
Excretion: a small amount unmodified, majority transformed in more polar derivatives.
Metabolic clearance 10 -24 hrs.
What are the extra-pyramidal side-effects?
Occur in 30-50% of patients receiving neuroleptics.
Appear early on in the treatment.
Effects include:
Dystonia (neck - lateral and backwards - whiplash, slow, sustained involuntary contractions).
Akathisia (inner restlessness / mental distress).
Parkinsonian-like symptoms (might be self-limiting): bradykinesia, cogwheel rigidity, tremor, masked face and shuffling gait.
Tardive dyskinesia, a severe effect occurring in 15-20% of patients with long term use of neuroleptics: this disorder is irreversible.
What is haloperidol-induced dyskinesia?
Characterized by involuntary and repetitive movement of the face, tongue and extremities in a choreiform motion.
Might involve similar mechanism to the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonian-inducing neurotoxin.
MPTP alters pre- and postsynaptic dopaminergic neuronal functions.
Haloperidol (HP) use is associated with tardive dyskinesia.
Microsomal-catalysed dehydration of HP affords 1,2,3,6-tetrahydopyridine HPTP.
In humans and baboons, HPTP is oxidised in vivo to pyridinium species (HPP+) with increased serum concentration.
