Anti-psychotic drugs

Antipsychotics

Drugs used to treat serious mental illness

Behavioral problems or psychotic disorders

Antipsychotics

Thioxanthenes: flupenthixol,thiothixene
Butyrophenones: haloperidol, trifluperidol Dihydroindolones: molindone

Dibenzoxazepine: loxapine
Phenothiazines: three structural groups

OLDER DRUGS

Three major groups :

1) Phenothiazines 2) Thioxanthines 3) Butyrophenones

Antipsychotics Phenothiazine Structural Groups

Aliphatic: chlorpromazine , triflupromazine

Piperidine: mesoridazine , thioridazine Piperazine: fluphenazine, perphenazine prochlorperazine , trifluoperazine

Largest group of psychotropic agents

Antipsychotics Atypical Antipsychotics

clozapine
risperidone olanzapine

Quetiapine
Aripiprazole Ziprasidone amisulpirde

Antipsychotics: Mechanism of Action

Block dopamine receptors in the brain (limbic system, basal ganglia)areas associated with emotion, cognitive function, motor function Dopamine levels in the CNS are decreased
Result: tranquilizing effect in psychotic patients

Antipsychotics: Mechanism of Action

The newer, atypical antipsychotics also block specific serotonin receptors (serotonin-2 [5HT2] receptors).
This is responsible for their improved efficacy and safety profiles.

Antipsychotics/Neuroleptics

It appears that the specific interaction of antipsychotic drugs with D2 receptors is important to their therapeutic action.

The affinities of most older classical agents for the D2 receptors correlate with their clinical potencies as antipsychotics.

Antipsychotics/Neuroleptics

Both D1 and D2 receptors are found in high concentrations in the striatum and the nucleus accumbens. Clozapine has a higher affinity for the D4 receptors than for D2. Recently it has been found that most antipsychotic drugs may also bind D3 receptors (therefore, they are non-selective).

Antipsychotics/Neuroleptics

Antipsychotics produce catalepsy (reduce motor activity).

BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.

Antipsychotics reverse hyperkinetic behaviors (increased locomotion and stereotyped behavior).

BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.

Antipsychotics prevent the dopamine inhibition of prolactin release from pituitary.

BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.

hyperprolactinemia

Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment. Blockade of D2 receptors

Short term/Compensatory effects:

Firing rate and activity of nigrostriatal and mesolimbic DA neurons. DA synthesis, DA metabolism, DA release

Antipsychotics/Neuroleptics
Presynaptic Effects Blockade of D2 receptors Compensatory Effects

Firing rate and activity of nigrostriatal and mesolimbic DA neurons. DA synthesis, DA metabolism, DA release.

Postsynaptic Effects Depolarization Blockade

Inactivation of nigrostriatal and mesolimbic DA neurons.

Receptor Supersensitivity

Antipsychotics: Drug Effects

Block dopamine receptors in CNS

Block alpha receptors (causing hypertension, other cardiovascular effects) Block histamine receptors (causing anticholinergic effects) Block serotonin Also function as antiemetics

Antianxiety effects

Pharmacokinetics
Absorption and Distribution

Most antipsychotics are readily but incompletely absorbed.

Significant first-pass metabolism. Bioavailability is 25-65%. Most are highly lipid soluble. Most are highly protein bound (92-98%). High volumes of distribution (>7 L/Kg).

Slow elimination.

**Duration of action longer than expected, metabolites are present and relapse occurs, weeks after discontinuation of drug.**

Pharmacokinetics Metabolism

Most antipsychotics are almost completely metabolized. Most have active metabolites, although not important in therapeutic effect, with one exception. The metabolite of thioridazine, mesoridazine, is more potent than the parent compound and accounts for most of the therapeutic effect.

Pharmacokinetics Excretion

Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged.

Elimination half-lives are 10-24 hrs.

Antipsychotic/Neuroleptics
Butyrophenone

Phenothiazine
Thioxanthene

[Drug dose]

Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2= D2>D1 >M>2
Haloperidol: D2>D1= D4>1>5-HT2 >H1>M = 2 Clozapine: D4 = 1>5-HT2 = M>D2 = D1 = 2;H1 Quetiapine: 5-HT2 = D2 = 1 = 2; H1 Risperidone: 5-HT2 >>1 >H1 >D2 >2>>D1

Sertindole: 5-HT2>D2=1

Indications for Antipsychotic Drugs

Schizophrenia Schizoaffective disorders Acute control of mania Tourettes syndrome Huntingtons chorea and ballism Intractable hiccups

Antipsychotics: Therapeutic Uses

Treatment of serious mental illnesses:

Bipolar affective disorder Depressive and drug-induced psychoses Schizophrenia Autism

Movement disorders (such as Tourettes syndrome) Some medical conditions

Nausea, intractable hiccups

Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs:
1) 2)
a) b) c) d) e)

Failure to control negative effect Significant toxicity

Parkinson-like symptoms TardiveDyskinesia (10-30%) Autonomic effects Endocrine effects Cardiac effects

3)

Poor Concentration

Antipsychotics: Side Effects

Body System Effects

CNS Cardiovascular

Sedation, delirium, drowsiness Orthostatic hypotension, syncope, dizziness, ECG changes Photosensitivity, skin rash, hyperpigmentation, pruritis

Dermatologic

Spectrum of Adverse Effects Caused by Antipsychotic Drugs

Low Potency
Fewer extrapyramidal reactions (especially thioridazine)
More sedation, more postural hypotension Greater effect on the seizure threshold, electrocardiogram (especially thioridazine) More likely skin pigmentation and photosensitivity

High Potency

More frequent extrapyramidal reactions

Less sedation, less postural hypotension Less effect on the seizure threshold, less cardiovascular toxicity Fewer anticholinergic effects

Occasional cases of cholestatic jaundice

Rare cases of agranulocytosis

Occasional cases of neuroleptic malignant syndrome

Antipsychotics: Side Effects

Body System Effects

GI GU Hematologic Metabolic/endocrine

Dry mouth,constipation Urinary hesitancy or retention, impaired erection Leukopenia and agranulocytosis Galactorrhea, irregular menses increased appetite, polydipsia

Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome

Occurs in pts. hypersensitive to the Ex.Py. effects of antipsychotics. Due to excessively rapid blockade of postsynaptic dopamine receptors. The syndrome begins with marked muscle rigidity. If sweating is impaired, a fever may ensue. The stress leukocytosis and high fever associated with this syndrome may be mistaken for an infection.

Autonomic instability with altered blood pressure and heart rate is another midbrain manifestation.
Creatine kinase isozymes are usually elevated, reflecting muscle damage.

Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome

Treatment
Vigorous treatment with antiparkinsonian drugs is recommended as soon as possible. Muscle relaxants such as diazepam, dantrolene or bromocriptine may be helpful.

Antipsychotic/Neuroleptics
Drug Interactions

Additive effects with sedatives.

Additive effects with anticholinergics. Additive effects with antihistaminergics.

Additive effects with -AR blocking drugs.

Additive effects with drugs with quinidine-like action (thioridazine).

Anti manic drugs (mood stabilizing agents):

Lithium:
Mechanism of action:

Can substitute for sodium in generating action potentials may affect ionic fluxes May decrease norepineprine and dopamine turnover Inhibits inositol monophosphatase -Inhibits the conversion of IP2 to IP1 leads to depletion of PIP2 reduced IP3 and DAG -effects of transmitter on the cell diminished

Pharmacokinetics:
well absorbed orally Initially distributed extracellularly, not metabolised Excreted mostly in urine. found in saliva and sweat. Plasma concentration:0.6-1.25 mEq/L

Indications:

bipolar affective disorder Acute manic episode Adjunct to antidepressants in severe recurrent depression Schizoaffective disorders Cancer chemotherapy induced leucopenia SIADH

Adverse effect:
a)neurologic: tremor , Choreoathetosis, ataxia
b)thyroid function: benign, diffuse,nontender thyroid enlargement c)renal: polyuria,polydipsia-loss of ability of kidney to concentrate urine nephrogenic diabetes insipidus long term use chronic interstitial nephritis d)Edema, increase in polymorphonuclear leukocytes

e)cardiac: depresses SA node, ECG changes Twave flattening

f)pregnancy: neonatal goiter, CNS depression, floppy baby syndrome, Ebsteins anomaly

g)misc:nausea,diarrhea,sedation,acneiform eruptions.
Acute intoxication: vomiting, profuse diarrhea, coarse tremor, convulsions, Cardiac arrhythmia, hypotension

Treatment: supportive
Osmotic diuretics and sodium bicarbonate Hemodialysis

Interactions:
1.Diuretics decreased renal clearance 2.insulin/sulphonylureas Sodium valproate: efficacy equivalent to that of lithium Carbamazepine: reasonable alternative to lithium