antipsychotics are drugs used to treat psychoses, which is a disorder
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Antipsychotics. Antipsychotics are drugs used to treat psychoses, which is a disorder associate with loosely organized thoughts, bizarre and illogical behaviors, hallucinations (usually auditory) and delusions. Schizophrenia is associated with these characteristics (positive symptoms). - PowerPoint PPT PresentationTRANSCRIPT
Antipsychotics are drugs used to treat psychoses, which is a disorder associate with loosely organized thoughts, bizarre and illogical behaviors, hallucinations (usually auditory) and delusions. Schizophrenia is associated with these characteristics (positive symptoms).
Psychoses can be organic and related to drugs such as central anticholinergic agents, NMDA antagonist (PCP, phenyclidine) and dementia. Idiopathic psychoses possibly caused by stress.
Drugs are used in psychotic patients to produce a calming effect thus some are classified as major tranquilizers. The ones the lessen response to emotional stimuli without altering consciousness are called neuroleptics.
Typical antipsychotic blocks the dopamine at mesolimbic D2 and D3 receptors.
Atypical antipsychotic blocks the dopamine at mesolimbic D2 and D3 receptors in addition 5-HT2A
Antipsychotics
Amphetamine and lysergic acid diethylamide (LSD) used in animal models to produce schizophrenia.
Central anticholinergic produce schizophrenia by blocking M1 or M3.
Phenyclidine (PCP) induce psychosis a CNS stimulation (Dissociative Agents)
Drugs that cause schizophrenia
Treatment for psychosis
Phenothiazine
SAR Substitution at the 2-position with electron withdrawing groups increase activity alone with unshared electron pair.
Substitution at the 3-position can increase activity in comparison with unsubstituted but lesser of effect than substitution at 2-position.
Three-carbon atom chain is essential for activity. Shortening or lengthening will decrease activity (pseudo ring formation).Branching -position by methyl activity varies. Dextro isomers are more activity of chiral isomers. Alkyl groups larger than methyl cause a decrease activity.
N
S
12
34567
8 9 10
N
Cl
Dimethyl amino require for optimal activity. The monomethyl amino has less activity. Activity can be enhanced by fusion the dimethyl groups to form a piperidinepiperazines groups
The substitutes are believed to for a pseudo ring with the protonated amino group (X-ray crystal structure). Align the p-hydroxyl of Dopamine with sulfur and aliphatic amine portions. Substitution at 1-position is believe interfere with the pseudo ring formation thus a decrease in activity.
SAR continued
Important Notes for Antipsychotics
Side effects associated with antipsychotics
Extrapyramidal Side Effects (EPS): dystonia, motor restlessness Parkinson-like (rigidity and tremor), tardive dyskinesia (irreversible); alone with tachycardia, hypotension, hyperprolactinemia, gynecomastia.
Atypical antipsychotics have less risk of producing EPS
Atypical antipsychotics are effective in treating negative symptoms(social withdraw, apathy, speech deficit)Both cause increase risk of weight gain and diabetes but more so withatypical psychotics
Metabolism:Major metabolism is hydroxylation aromatic ring para to 10-nitrogen (not ring bearing EW) follow by conjugation with glucuronic acid.
Dialkylamino
Sparine (Promazine) It was introduce after 2-chloro substituted Thorazine. It is less activity than Thorazine.
Thorazine (Chlorpromazine) It was the first phenothiazine used as antipsychotic.Uses include nausea and vomiting and hiccough alone psychoses. It has significant sedative and hypotensive properties. Contraindication with antidepressant and anesthetics as with other antipsychotics.
N
S
12
34567
8 9 10
N
N
S
12
34567
8 9 10
N
Cl
Vesprin (Triflupromazine hydrochloride)Greater activity per mg in comparison with Thorazine. Lower sedative and hypotensive side effects than Thorazine
N
S
12
34567
8 9 10
N
CF3
Piperidine subgroup
Mellaril (Thioridazine hydrochloride) High anticholinergic activity.Sedation and hypotension are its side effects.Pigmentary retinopathy
Serentil (Mesoridazine Besylate)Metabolite of MellarilDoes not cause pigmentary retinopathy.
N
S
SCH3
N
N
S
123
4567
8 9 10S
N
CH3
O
C6H5SO3H
Piperazine
Compazine (Prochlorperazine maleate) More activity per mg in comparison with Thorazine. Mainly use as antiemetic.
Trilafon (Perphenazine)Use as antipsychotic and antiemetic. Ester (decanoate)IM Depot
N
S
12
34567
8 9 10
NN
Cl
2C4H4O4
N
S
NN
Cl
OH
Stelazine (Trifluperazine) Tindal (Acetophenazine)Ester (IM Depot)
Torecan (Triethylperazine)
N
S
NN
CH3
CF3 N
S
NN
COCH3
OH
N
S
NN
CH3
SCH2CH3
Prolixin (Fluphenazine HCl) Most potent on the mg basisEster (IM Depot)
Thioxanthene
Navane (Thiothixene)Replacement of the nitrogen with a double bonded carbon.Z isomers is the most active.Modified Ethyl alcohol ester (Decanoate) (Flupenthixol)
N
S
123
4567
8 9 10
NN
CF3
OH
C
S
12
34567
8 9 10S
HN
N
N
O
O
Fluorobutyrophenones
SARAR1 is a aromatic system (p-fluoro increase activity)X is carbonyl (highest activity) CHOH and CH aryl (good activity)When n=3 (highest activity) longer or shorter chain decrease activityPiperidine ring (highest activity) AR2 is required attached at 4-position.Y group as hydroxyl can improve activity.Neurotoxic metabolite (pyridine quaternary salt form)Student tried to make meperidine
meperidine
AR1 X(CH2)n NAR2
Y
N
CH3
C2H5OOC
Toxicity of Haldol
N
HO
R
Cl
R = (CH2)3 CO
F
NR
Cl
NR
Cl
+ NR
Cl
+HP HPTP
HPP +
NCH3
MAO-B
NCH3
+ NCH3
+
MPTP MPDP + MPP +
Haldol (Haloperidol)Use as antipsychotic in the treatment schizophrenia, psychoses caused by brain damage and Tourette’s syndrome.
Inapsine (Droperidol) Antipsychotic with antiemetic properitiesUsed in combination Fentanyl preanesthetic (Innovar)
F
O
N
HO
Cl
F
O
N
N
NH
O
Risperdal (Risperidone)Atypical antipsychotic Hydroxyl active metabolite (*)Antipsychotic/antidepressant (Trazodone)Structure likeCombination with Haldol for Parkinson5HT2A and D2 antagonist
Invega (Paliperidone)Approved Dec. 2006Atypical antipsychotic
N
ON
F
N
N
O
*
N
ON
F
N
N
O
OH
Daxopin (Loxapine succinate)DibenzoxazepineSide effects similar to phenothiazines.
Clozaril (Clozapine) DibenzodiazepineNot potent antipsychotic on mg basisAgranulocytosis (clinical monitoringWeekly for 6 months)
**Atypical psychotics**
67
8 9N
C
O
N
N
Cl
CH2COOH
CH2COOH NC
HN
N
N
Cl
Zyprexa (Olanzapine)Atypical antipsychoticThienobenzodiazepineD2 and strongly 5HT2
receptor antagonist
Loxitane (Loxapine)Typical antipsychoticUndergoes N-dealkylationto an active metaboliteUse often as anti-depressant
NC
HN
N
N
S CH3
NC
O
N
N
Cl
Seroquel (Quetiapine)DibenzothiazepineBinds to H1 and a1 and a2; 5-HT2A Receptors and low affinity D2 receptors
Asendin (Amoxapine)
Use often as anti-depressant
67
8 9N
C
O
N
NH
Cl
NC
S
N
NO
OH
Reglan (Metoclopramide)D2 receptor antagonistAntiemetic (chemoreceptortrigger in brain stem)Prokinetic (GI emptying)
Roxiam(S-Remoxipride)BenzamideLess EPS than Haldol
Benzamide
NH
O
N
CH3O OCH3
Br
NH
O
CH3O
Cl
NH2
N(C2H5)2