atypical antipsychotics

Dr. Karrar Husain Moderator :Dr. Piyush P. Singh

Pharmacology of 2nd generation antipsychotics

HISTORY Before 1952 –lobotomy, convulsive therapy, physical restrain,

seclusion ,sedation.

Chlorpromazine – first antipsychotic drug

Discovered by chance

After 2 yrs- side effects

This is followed by development of subsequent antipsychotic agent.

Drawbacks- dystonia, akathisia, tardive dyskinesia and negligible effects on negative symptoms.

Clozapine 1958 bern Switzerland

Low chance of EPS and also ameliorate negative symptoms

Released in european market in 1972

Becoz of hematological toxicity 50 patient had died worldwide ….it was withdrawn

However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics,

the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia.

In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or schizoaffective patients.

Classification of Antipsychotic drugsMain categories are:

Typical antipsychotics Phenothiazines (chlorpromazine,

perphenazine, fluphenazine, thioridazine ) Thioxanthenes (flupenthixol, clopenthixol) Butyrophenones (haloperidol, droperidol)Atypical antipsychotics (e.g. clozapine,

risperidone, sulpiride, olanzapine)

What makes an antipsychotic atypical clinical perspective, it is “low EPS” and “good for negative symptoms.

From a pharmacological perspective,the atypical antipsychotics as a class may be defined in at least four ways: as “serotonin dopamine antagonists” as

“D2 antagonists with rapid dissociation” ,as

“D2 partial agonists (DPA)”

or as “serotonin partial agonists (SPA)”at 5HT1A receptors.

Classification of atypical antipsychotics Benzisoheterazoles

Resperidone

Ziprasidone

Dibenzazepines

Clozapine

Quetiapine fumarate

Thiobenzodiazepenes

Olanzapine

MECHANISM OF ACTION Dopamaine pathways

1. Mesolimbic,

2. Mesocortical,

3. Nigrostriatal, and

4. tuberoinfundibular dopamine pathways

Mesolimbic dopamine pathway Projects from the ventral tegmental area of the brainstem to nucleus

accumbens in the ventral striatum.

Hyperactivity of the mesolimbic dopamine pathway hypothetically accounts for positive psychotic symptoms.

The mesolimbic dopamine pathway is also thought to be the site of the brain’s reward system or pleasure center.

Mesocortical dopamine pathways Project ventral tegmental area to areas of the prefrontal cortex

cognitive and some negative symptoms deficit of dopamine activity in mesocortical projections to dorsolateral prefrontal cortex.

affective and other negative deficit of dopamine activity in mesocortical projections to ventromedial prefrontal cortex.

Nigrostriatal dopamine pathway Deficiencies in dopamine in this pathway cause movement disorders,

including Parkinson’s disease.

Dopamine deficiency in the basal ganglia can also produce akathisia and dystonia .

These movement disorders can be replicated by drugs that block dopamine-2 receptors in this pathway

Chronic blockade of dopamine-2 receptors in this pathway may result in a hyperkinetic movement disorder known as neuroleptic-induced tardive dyskinesia

Tuberoinfundibular dopamine pathway Project from the hypothalamus to the anterior pituitary.

Normally, these neurons are active and inhibit prolactin release.

Blockage of dopamine in this pathway would result in hyperprolactinemia.

Serotonin Serotonin is also known as 5-hydroxytryptamine.

Synthesis of 5HT begins with the amino acid tryptophan

Serotonin receptors presynaptic (5HT1A and 5HT1B/D)

postsynaptic (5HT1A, 5HT1B/D as well as 5HT2A, 5HT2C, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7).

Presynaptic 5HT receptors are autoreceptors

5HT1A receptors act as an accelerator for dopamine release, whereas 5HT2A receptors act as a brake on dopamine release

5HT2A antagonism makes an antipsychotic atypical 5HT2A antagonism reduces EPS

5HT2A antagonism stimulate dopamine relaese in striatum

Increased dopamine competes with drug at D2 receptors and reduces binding of drug there enough to eliminate EPS.

5HT2A antagonism reduces negative symptoms

5HT2A antagonism increase DA release in prefrontal cortex.

The increased availability of dopamine to these areas may lead to improvement in the negative, cognitive, and affective symptoms.

5HT2A antagonism may improve positive symptoms

Activation of 5HT2A receptors in the prefrontal cortex may contribute to positive symptoms of hallucinations by enhancing the excitation of glutamate neuron

5HT2A antagonists block glutamate release thus reducing hallucinations and other positive symptoms.

5HT2A antagonist actions reduce hyperprolactinemia

Dopamine inhibits prolactin whereas serotonin promotes prolactin release by stimulating 5HT2A receptors.

Thus 5HT2A antagonism reduce prolactin release and chance of hyperprolactinemia

Rapid dissociation from D2 receptors makes an antipsychotic atypical atypical antipsychotics also have the ability to rapidly dissociate from

D2 receptors.

Theoretically, such an agent is able to stay at D2 receptors long enough to exert an antipsychotic action

but then leaves prior to producing an extrapyramidal side effect, elevation of prolactin, or worsening of negative symptoms.

clozapine and quetiapine have faster dissociation from the D2 receptor than risperidone with olanzapine in the middle.

This roughly correlates with the abilities of these drugs to cause motor side effects..

Sulpiride and amisulpride also dissociate rapidly from D2 receptor …this explain the atypical clinical properties of these drugs even in absence of serotonin antagonism

D2 partial agonism (DPA) makes an antipsychotic atypical DPAs theoretically bind to the D2 receptor in a manner that is neither

too antagonizing, like a conventional antipsychotic

nor too stimulating, like a stimulant or dopamine itself.

DPAs reduce D2 hyperactivity in mesolimbic dopamine neurons to a degree that is sufficient to exert an antipsychotic action on positive symptoms, even though they do not completely shut down the D2 receptor.

At the same time, DPAs reduce dopamine activity in the nigrostriatal system to a degree that is insufficient to cause EPS

5HT1A partial agonist (SPA) actions make an antipsychotic atypical 5HT1A increase dopamine release and reduce glutamate release.

Enhanced dopamine release in the striatum improve extrapyramidal actions;

in the pituitary would reduce the risk of hyperprolactinemia;

in the prefrontal cortex would improve negative, cognitive, and affective symptoms of schizophrenia

Reduced glutamate release in prefrontal cortex could reduce positive symptoms.

Pharmacology of individual antipsychotics(common)

CLOZAPINE Pharmacokinetics

only available as an oral preparation

peak plasma levels 2 hours after oral administration

half-life is approximately 12 hours(dosing should be twice daily)

steady-state plasma concentrations reach in less than 1 week

Demethylation and oxidation of the terminal nitrogen of the piperazine side chain form the two main metabolites(N-demethyl and N-oxide metabolites )

Receptor binding

D2 receptor activity < traditional antipsychotic agents

5-HT2 receptor activity is among the highest for antipsychotic agents.

Blood concentration

Women and older adults have higher plasma levels.

smokers slightly lower plasma levels

Patients are more likely to respond when their clozapine plasma concentrations are greater than 350 ng/mL.

Therapeutic indication

Treatment-Resistant Patients

Severe Tardive Dyskinesia : clozapine can suppress abnormal movements in tardive dyskinesia

Patients with a Low Extra pyramidal Side Effect Threshold

Treatment-Resistant Mania

Severe Psychotic Depression

Suicidal Patients with Schizophrenia or Schizoaffective Disorder

Treatment Resistance in Other Disorders:Autism of childhood, or obsessive-compulsive disorder (OCD.

Neurological Illnesses : secondary psychotic symptoms of Idiopathic Parkinson's disease (doses of 25 to 75 mg).

Precautions and Adverse Reactions

Agranulocytosis: contraindications a WBC count below 3,500 cells per mm3,

a previous bone marrow disorder,

a history of agranulocytosis during clozapine treatment,

or the concomitant use of another bone marrow suppressant drug such as carbamazepine

The risk is greatest during the first 3 months of treatment,

The risk increases with age and is higher in women

Monitoring : weekly for the first 6 months, then every 2 weeek and continued for at least 1 month after it is discontinued.

If the patient has a WBC count below 2,000 cells per mm3 or a granulocyte count below 1,000 cells per mm3, clozapine must be discontinued

Others : leukocytosis (0.6 percent), eosinophilia (1 percent), and leukopenia, neutropenia, decreased WBC count (3 percent), and, rarely, thrombocytopenia

Sialorrhea

CVS: most frequent are tachycardia and postural hypotension

Orthostatic hypotension is more likely to occur during initial titration of clozapine in association with rapid dose escalation but may occur after the first dose.

Hypertension.

Myocarditis

Peripheral Anti cholinergic Effects

Weight Gain

Diabetes Mellitus

Extra pyramidal Side Effects : lower incidence of extra pyramidal side effects than do other antipsychotics.

Lowering of Seizure Threshold

Drug Interactions

CYP isoenzyme 1A2

fluvoxamine and Risperidone Erythromycin and ketoconazole will elevate clozapine concentrations,

Cimetidine, SSRIs, tricyclic drugs, and divalproic acid decrease clearance.

Phenytoin and carbamazepine may decrease concentrations of clozapine

Benzodiazepines a few case reports of delirium, increased somnolence, and acute respiratory suppression have appeared.

RISPERIDONE PHARMACOKINETICS

Food does not affect the rate or extent of absorption in the gut.

Risperdal Consta long-acting (IM) preparation of risperdone

Aqueous suspension minimizes pain and inflammation at the injection

twice-per-week

It has a lower incidence of side effects such as extrapyramidal symptoms, insomnia, orthostatic hypotension, sexual dysfunction (<2 percent), and weight gain.

BLOOD CONCENTRATIONS AND CLINICAL ACTIVITY

No relationship exists between clinical efficacy and plasma concentrations of risperidone.

Dose response curve is an inverted U with two optimal dosages.

Most patients will require the lower of the two dosages (4 mg per day), experiencing some loss of efficacy with higher doses, whereas others will do best with 6 to 8 mg per day.

RECEPTOR BINDING

Potent central antagonism of both serotonin (particularly 5-HT2A) and D2 receptors

Treatment Indications

Acute Psychosis

Maintenance Treatment in Schizophrenia and Schizoaffective Disorder

Tardive Dyskinesia : tardive dyskinesia is significantly less severe in risperidone (vs haloperidol).

Case reports also suggest that tardive dyskinesia may improve with risperidone

Patients with a Low Extrapyramidal Side Effect Threshold

Other : acute mania, Children with severe disruptive behavioral disorders and conduct disorders, Behavioral and psychological symptoms of dementia.


Extra pyramidal side effects: usually occur at higher dose.

rise in plasma prolactin concentration

Other common side effects : sedation, dizziness, constipation, tachycardia, and weight gain.

Interactions : not significant.

OLANZAPINE pharmacokinetics

Food does not affect absorption of olanzapine

Peak plasma levels of olanzapine are reached in 5 hours.

The half-life is 31 hours (range 21 to 54 hours), ie once-daily dosing

Age, gender, and ethnicity effects on olanzapine concentration are small.

Olanzapine has a very weak affinity for hepatic P450 cytochromes , Ie it has little effect on the metabolism of other drugs and that other drugs minimally affect its concentration in blood.

Receptor binding

Olanzapine specifically blocks 5-HT2A and D2 receptors and additionally blocks muscarinic (M1), H1, 5-HT2C, 5-HT3, 5-HT6, α1, D1, and D4 receptors.

5-HT: dopamine blockade is approximately 8:1

Also has 5-HT1A agonist properties antianxiety and antidepressant effects.


Side effects do not appear to be dose dependent.

Women tend to have higher olanzapine levels than men.


Acute Psychosis

Tardive Dyskinesia: risk during 1 year of treatment is less than one-tenth that associated with haloperidol

Patients with Low Extra pyramidal Side Effect Threshold

acute mania and bipolar mania

Other diagnosis: schizoaffective disorder, psychosis in dementia, Tourette's syndrome, and as an adjunct to SSRIs for PTSD, weight gain in patients with anorexia nervosa


Main side effects are transient sedation, orthostatic hypotension, excessive weight gain, and its metabolic and cardiovascular consequences

Extra pyramidal side effects: significantly lower than with haloperidol.

Hyperlipidemia and Weight Gain: significant, Compared with clozapine its lower.

Diabetes Mellitus: significantly increased risk of developing diabetes.

Dosage: effective at dosages between 7.5 and 30.0 mg per day.

Treatment-resistant patients or chronic patients with poor response may need higher dosages (30 to 40 mg).

Drug Interactions

The small effects on hepatic metabolism suggest that interactions with other drugs are not significant.

Ethanol increases olanzapine absorption (>25 percent) increased somnolence and orthostatic hypotension

Smokers may require higher dosages.

QUETIAPINE Pharmacokinetics

Food doesn’t affect absorption

half-life of 6.9 hours

But No difference was found between twice- and thrice-daily dosing.

RECEPTOR BINDING

Quetiapine has a high affinity for 5-HT2, H1, 5-HT6, α1, and α2 receptors

It has a transiently high D2 occupancy, which decreases to low levels by the end of the dosing interval (faster dissociation), suggesting that transient D2 occupancy may be sufficient to induce antipsychotic response while minimizing side effects.


Quetiapine response is independent of dosage.

In elderly people the dosage may need to be reduced, with 300 mg generally the optimum dosage.

Patients with impaired renal or hepatic clearance need to receive 30 to 50 percent lower dosages.

There is no evidence of gender or ethnic differences in terms of clinical activity or plasma concentration.


acutely exacerbated schizophrenic and schizoaffective patients

functional and organic psychoses in the elderly

levodopa-induced psychosis in Parkinson's disease patients

acute and long-term treatment of bipolar mania and bipolar relapse prevention.


most frequent are somnolence, postural hypotension, and dizziness ,tolerance quickly develops to these side effects

Rarely diabetic coma, and ketoacidosis

Extrapyramidal side effects were generally not observed(low chance)

wt gain

Inclusion body in eye

cataract

Dosage

dosage range of 500 to 750 mg daily

must be titrated to avoid postural hypotension and syncope. 25 mg per day be given initially, with increments of 25 to 50 mg twice to three times daily.

Drug Interactions

Only phenytoin caused a fivefold increase in quetiapine clearance through CYP 3A4 induction

others have minimal effect

ZIPRASIDONE Benzisothiazolyl piperazine

Pharmacokinetics

Bioavailability doubles when ziprasidone is administered with food

plasma half-life ranges from 5 to 10 hours

Age, gender, or mild to moderate renal or hepatic impairment has no significant effect.

RECEPTOR BINDING

very potent antagonist at the 5-HT2A receptor, with a very high 5-HT2A to D2 ratio of 11.

Ziprasidone is an agonist at the 5-HT1A receptor and a potent antagonist at 5-HT2C and 5-HT1D receptors


positive, negative, and depressive symptoms in patients with schizophrenia and schizoaffective disorder

Tourette's syndrome

The IM formulation for acutely agitated and psychotic patients


Extra pyramidal side effects : infrequent and mild

Akathisia has been notably absent

The major side effects include somnolence, dizziness, nausea, and light-headedness

incidence of clinically significant weight gain (>7 percent) was low.

Dosage

20 – 80 mg twice a day with food

IM dosage is 10 to 20 mg administered every 2 hours for the 10-mg dose and every 4 hours for the 20-mg dose, up to a maximum dosage of 40 mg per day.

Drug Interactions

low potential for clinically significant drug interactions

ARIPIPRAZOLE Aripiprazole is a highly lipid-soluble quinolinone derivative. Its

chemical structure does not resemble any of the available antipsychotics

Pharmacokinetics

Aripiprazole's absorption is not affected by administration with food.

half-life of aripiprazole is approximately 75 hours

Aripiprazole is extensively metabolized in the liver by dehydrogenation, hydroxylation, and N-alkylation. Metabolism is primarily by CYP 3A4 and CYP 2D6 enzymes

RECEPTOR BINDING

D2 partial agonism

partial agonist at 5-HT1A receptors - decrease anxiety

binds with high affinity to D3, 5-HT2A, 5-HT2C, and H1 receptors


Acute Psychosis:Its effectiveness similar to that of haloperidol and risperidone

May be effective in acute mania

Acute Agitation: Short-acting intramuscular aripiprazole has been approved for acute agitation..

Maintenance Treatment in Schizophrenia and Schizoaffective Disorder

Bipolar disorder


low rate of extrapyramidal side effects

least sedating of available antipsychotics

only minimal weight gain

DOSAGE

10-30 mg

Drug Interactions

metabolized by CYP 3A4 and CYP 2D6.

carbamazepine induces CYP 3A4 and may reduce aripiprazole concentrations.

CYP 3A4 inhibitor, such as ketoconazole, may increase the concentrations.

CYP 2D6 inhibitors such as quinidine, may raise aripiprazole concentration.

Amisulpride amisulpride is unusual in that it lacks the combined antagonism of

5HT2/D2 receptors.

At low doses, amisulpride enhances dopaminergic neurotransmission by preferentially blocking pre-synaptic D2/D3 dopamine receptors.

At higher doses, amisulpride antagonises post-synaptic D2/D3 dopamine receptors, reducing dopaminergic transmission.

It is selective for dopamine receptors in the limbic system rather than the striatum, which should reduce its tendency to produce EPS.

Pharmacokinetics

Amisulpride is absorbed rapidly

Amisulpride undergoes minimal metabolism

Excretion is primarily via urine (mainly as unchanged drug).

The elimination half life is approximately 12 hours.( twice daily dosing)

Adverse effects

dose-related EPS and hyperprolactinemia.

insomnia, anxiety, agitation and weight gain.

sedation and hypotension are not prominent

Dosage and administration

The recommended dose varies according to which symptoms predominate.

Acute positive symptoms: 400-800mg/day

May be increased to 1200mg/day in individual cases

Predominantly negative symptoms: 50- 300mg/day given once daily.

Interactions : via the CYP450 system are unlikely as amisulpride is not significantly metabolised by the liver.

Caution is advised when used with other renally cleared drugs eg. lithium, which may interfere with clearance of amisulpride.

Use with Class IA and III antiarrhythmic agents eg. flecainide and amiodarone respectively, is contraindicated

Antipsychotic in special patient group Hepatic impairment:

Recommended drugs:

low dose haloperidol

Sulpride and amisulpride

Renal impairment

Recommended drugs: haloperidol and olanzapine

Sulpride, amisulpride and highly anticholinergic drugs are avoided

Breast feeding

Recommended drugs : sulpride and olanzapine

Resperidone, quetiapine and aripiprazole can also be used

Pregnancy

1st generation can be used, most experience is with chlorpromazine,trifluperazine and haloperidol

Olanzapine and clozapine can be used but metabolic side effects should be monitored

Epilepsy

Good choices: trifluperazine, haloperidol and sulpride

Resperidone, olanzapine, quetiapine, amisulpride and aripiprazole should be used with care.

Clozapine, chlorpromazine, loxapine, and depot antipsychotic should be avoided.

CATIE and CUtLASS The US Clinical Antipsychotic Trials of Intervention Effectiveness

(CATIE) was a double-blind trial to compare the effectiveness of perphenazine with several second-generation antipsychotics.

CATIE included a subsequent trial for those participants who discontinued the first phase because of a lack of efficacy.

They were invited to be re-randomised to a comparison of open-label clozapine v. other second-generation antipsychotics.

The UK Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) comprised a pair of smaller, open randomised trials comparing classes of drug

first-generation v. second-generation drug other than clozapine (CUtLASS 1),

and other second-generation drug v. clozapine.

The trials were designed wholly separately of each other and conducted in different healthcare systems.

Both trials were government funded and both were designed to reflect routine clinical practice as much as possible, with broad inclusion criteria intended to enroll representative patients.

The participants were very similar clinically and demographically in the two trials.

In both trials, the second-generation antipsychotics were not found to be more effective (with the exception of olanzapine in CATIE).

Moreover, they did not produce measurably fewer extrapyramidal side-effects overall.

In both trials, clozapine was the most effective for treatment-resistant patients.

Thank you

atypical antipsychotics

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