Antipsychotic drugs

PhenothiazinesAliphatic side chain:

-Chlorpromazine-Triflupromazine

Piperidine side chain: -Thioridazine

Piperazine side chain:-Trifluoperazine-Fluphenazine

Butyrophenones-Haloperidol-Trifluperidol-Penfluridol

Thioxanthenes-Flupenthixol

Other heterocyclics-Pimozide, Loxapine

• Atypical antipsychotics-Clozapine-Risperidone-Olanzapine-Quetiapine-Aripiprazole-Ziprasidone

Positive Symptoms(↑↑DA)Positive Symptoms(↑↑DA)HallucinationsDelusions (bizarre, persecutory)Disorganized ThoughtPerception disturbancesInappropriate emotions

Negative Symptoms(↓↓NMDA)Negative Symptoms(↓↓NMDA)Blunted emotionsAnhedoniaLack of feeling

CognitionCognitionNew LearningMemory

Mood SymptomsMood SymptomsLoss of motivationSocial withdrawalInsightDemoralizationSuicide

Schizophrenia - symptoms

FUNCTION

• Positive/active symptoms include thought disturbances, delusions, hallucinations

• Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

Prognosis of Schizophrenia

• 10% continuous hospitalization• < 30% recovery = symptom-free for 5

years• 60% continued problems in

living/episodic periods

Etiology

• A gene encodes for neuregulin-1 has been associated with schizophrenia.

• Hereditary Influences may account for 10% of schizophrenia cases

• Prenatal Biological Trauma 5-10% cases of schizophrenia

• Perinatal biological trauma

Schizophrenia PathophysiologySchizophrenia Pharmacologic Pathophysiology Profile of APDs

Past Excess dopaminergic Dopamine D2-receptor activity antagonists

Present

-Renewed interest in the Combined 5-HT2/D2 role of serotonin (5-HT) antagonists

Future

-NMDA NMDA agonists

Imbalance in cortical More selective antagonistscommunication and Mixed agonist/antagonists cortical-midbrain Neuropeptide analogs integration, involving multiple neurotransmitters

Dopaminergic Pathways and Innervation

Schizophrenia - Dopamine Hypothesis

Repeated administration of stimulants like amphetamines and cocaine, which enhance central dopaminergic neurotransmission, can cause a psychosis that resembles the positive symptoms of schizophrenia.

Low doses of amphetamine can induce a psychotic reaction in schizophrenics in remission.

Some early studies with postmortem tissue revealed increased numbers of DA receptors (in particular D2-like) in schizophrenic patients

Serotonin Hypothesis of Schizophrenia

• Hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists

• 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine.

• 5-HT2A-receptor modulate the release of dopamine in the cortex, limbic region, and striatum.

Schizophrenia - Glutamate Hypothesis• Preclinical as well as clinical studies provide evidence of

hypofunction of NMDA receptors as a primary, or at least, a contributory process in the pathophysiology of schizophrenia

• Several clinical trials with agents that act at the glycine modulatory site on the NMDA receptor have revealed consistent reductions in negative symptoms and variable effects of cognitive and positive symptoms

• These studies also provide evidence that suggests the effects of clozapine on negative symptoms and cognition may be through activation of the glycine modulatory site on the NMDA receptor.

ANTIPSYCHOTICS

• Pre-90’s– “Typical”, conventional, traditional neuroleptics,

major tranquilizors– Modeled on D2 antagonism– EPS/TD

• Post-90’s– “Atypical”, novel, 2nd generation– Modeled on 5-HT2/D2 antagonism– Less EPS, prolactin effects– Weight gain, sedation, diabetes

Adverse Effects

• Sedation initially considerable; tolerance usually develops ‑after a few weeks of therapy; dysphoria

• Postural hypotension results primarily from adrenergic ‑blockade; tolerance can develop

• Anticholinergic effects include blurred vision, dry mouth, ‑constipation, urinary retention; results from muscarinic cholinergic blockade

• Endocrine effects increased prolactin secretion can cause ‑galactorhea; results from antidopamine effect

• Hypersensitivity reactions jaundice, photosensitivity, ‑rashes, agranulocytosis can occur

• Idiosyncratic reactions malignant neuroleptic syndrome‑• Weight gain • Neurological side effects -

REACTION FEATURES TIME OF MAXIMAL RISK

PROPOSED MECHANISM

TREATMENT 

Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria

1 to 5 days Unknown Diphenhydramine, promethazine

 

Akathisia Motor restlessness; not anxiety or "agitation"

5 to 60 days Unknown Reduce dose or change drug: antiparkinsonian agents, benzodiazepines or propranololc may help

 

Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait

5 to 30 days Antagonism of dopamine

Antiparkinsonian agents helpful- trihexyphenidyl, procyclidine, benztropines

 

a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).

Neurological Side Effects of antipsychotics

REACTION FEATURES TIME OF MAXIMAL RISK

PROPOSED MECHANISM

TREATMENT 

Neuroleptic malignant syndrome

Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal

Weeks; can persist for days after stopping neuroleptic

Antagonism of dopamine may contribute

Stop neuroleptic immediately: dantrolene or bromocriptine may help: antiparkinsonian agents not effective

 

Perioral tremor ("rabbit" syndrome)

Perioral tremor (may be a late variant of parkinsonism)

After months or years of treatment

Unknown Antiparkinsonian agents often help

 

Tardive dyskinesia Oral-facial dyskinesia; widespread choreoathetosis or dystonia

After months or years of treatment (worse on withdrawal)

Excess function of dopamine hypothesized

Stop neuroleptics, then Diazepam, Change to clozapine/olanzapine,

 

Adverse Effects - EPS

Details on two main extrapyramidal disturbances (EPS):

• Parkinson-like symptoms– tremor, rigidity– direct consequence of block of nigrostriatal DA2 R

– reversible upon cessation of antipsychotics

• Tardive dyskinesia• involuntary movement of face and limbs• less likely with atypical antipsychotics (AP)• appears months or years after start of AP• ? result of proliferation of DA R in striatum

» presynaptic?

• treatment is generally unsuccessful

Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; possibly also histamine (for newer antipsychotics anyway)

Sexual dysfunction

• result from NE and SE blockade

• erectile dysfunction in 23-54% of men

• retrograde ejaculation in

• loss of libido and anorgasmia in men and women

Seizures - <1% for generalized grand mal

Neuroleptic malignant syndrome (1-2% early in trt)

• combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up)

• can be fatal in 5-20% of cases if untreated

• treatment – discontinue meds; give trts for fever and cardiac problems

Sensitivity to sun

• some phenothiazines collect in skin (chlorpromazine)

• sunlight causes pigmentation changes – grayish-purple (look bruised)

•in eye, brown cornea, brownish cloud to vision and possibly permanent impairment

Agranulocytosis - <1% (with clozapine)

• reduced white blood cell count

• lowered resistance to infection

• can be fatal

Jaundice – elevated bilirubin in liver - < ½%

Limitations Of Conventional Antipsychotics

Approximately one-third of patients with schizophrenia fail to respond

Limited efficacy againstNegative symptomsAffective symptomsCognitive deficits

High proportion of patients relapse

Side effects and compliance issues

Antipsychotic Drugs – New Generations “atypical”

About 40-60% do not respond to phenothiazines or cannot handle side effects

• Questions remain about the efficacy of phenothiazines and haloperidole for negative symptoms

• Drugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative

Antipsychotic Drugs – New Generations “atypical”

• clozapine• risperidone• olanzapine• sertindole• Quetiapine • Aripiprazole• Ziprasidone

Clozapine (1989)

• Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathway

• α-blockade

• Also blocks H1

• More strongly blocks 5-HT2 receptors in cortex which then acts to modulate some dopamine activity

• Among non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine

Clozapine

• Extrapyramidal side effects are minimal

• May help treat tarditive dyskinesia

• S/E- orthostatic hypotension effects, sedation, weight gain, increased heart rate

• Increased risk for seizures (2-3%)

• Agranulocytosis in 1%

• Agranulocytosis risks increase when co-administered with carbamazepine

Risperidone (1994)• Fewer side effects than Clozapine

• Marketed as first line approach to treatment

• Blocks selective D2, norepinephrine, and 5-HT2

• effective for positive and negative symptoms

• Extrapyramidal side effects low (but are shown at high doses)

• Shares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactin

• No agranulocytosis risks

• Increased risk of stroke in elderly

• May cause anxiety/agitation (possible OCD)

Olanzipine – 1996

• Improved negative symptom reduction

• Argued to be better than risperidone in extrapyramidal issues

• Does not cause prolactin elevation

• reduced agranulocytosis risks

Sertindole – 1995 • Improved negative symptom reduction

• Low risk for extrapyramidal side effects – major advantage

• No sedation and very mild prolactin elevation– major advantages

• Shares orthostatic hypotension, tachycardia, and weight gain

• Common side effects are rhinitis and reduced ejaculatory volume (not associated with disturbed function)

• concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998

Quetiapine - 1997

• No increased risks for extrapyramidal symptoms

• Shares sedation (sleepiness), orthostatic hypotension, weight gain

• Does cause anticholinergic side effects (like older and Clozapine) – dry mouth, constipation

• Does not elevate prolactin

Ziprasidone - 2001• Similar to advantages of others, but argued not to cause weight gain

• May induce cardiac arrhythmias

• Also has anxiolytic and antidepressant activity

Non- psychiatric Indications• As Antiemetics

-chlorpromazine, prochlorperazine, haloperidol

• Anaesthesia-droperidol (with fentanyl)

• Intractable Hiccups -chlorpromazine-haloperidol

MCQsQ1. A female suffering from psychosis, taking

fluphenazine now complains of sudden onset of high grade fever, muscle rigidity and altered sensorium. The diagnosis is:

A. Malignant hyperthermiaB. Tardive dyskinesiaC. AkathisiaD. Neuroleptic malignant syndrome

• Ans- D - Neuroleptic malignant syndrome

Q2. Antipsychotic drug induced parkinsonism is treated by:

A.LevodopaB.SelegilineC.AmantadineD.Central anticholinergic drugs

• Ans- D (Trihexyphenidyl Procyclidine

Biperiden )

Q3. Least extrapyramidal side effects are seen with:

A.ClozapineB.Haloperidol C.TrifluoperazineD.Chlorpromazine

• Ans- A- Clozapine

Q4. Risperidone is associated with the risk of:A.Cerebrovascular accidentsB.AgranulocytosisC.Diabetes Insipidus D. Gout

• Ans- A - Cerebrovascular accidents

Q5. The antipsychotic drug that can also be used as antiemetics:

A.chlorpromazineB.ClozapineC.AripiprazoleD.Loxapine

• Ans- A - chlorpromazine

Q6. The antipsychotics that can also be used as anaesthetic drug:

A.ChlorpromazineB.PenfluridolC.ClozapineD.Droperidol

• Ans- D - Droperidol

Q7. The antipsychotic drug that can also be used to treat Intractable Hiccups:

A.ClozapineB.ChlorpromazineC.HaloperidolD.Ziprasidone

• Ans- B, C - Chlorpromazine, Haloperidol

Thank you

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edition by Laurence Brunton (Editor)• Lippincott's Illustrated Reviews: Pharmacology - 6th edition by Richard A.

Harvey• Basic and Clinical pharmacology 11th edition by Bertram G Katzung• Rang & Dale's Pharmacology -7th edition

by Humphrey P. Rang• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill

Livingstone• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma• Review of Pharmacology by Gobind Sparsh