Pharmacology

Section 10

Neuroleptic Drugs.

Marta Jóźwiak-BębenistaDepartment of PharmacologyMedical University of Lodz

martia1@tlen.pl

Neuroleptic DrugsNeuroleptic Drugs = = antischizophrenic antischizophrenic drugs, antipsychotic drugs, antipsychotic

drugs or major drugs or major tranquilizers tranquilizers

SchizophreniaSchizophrenia

What is the differenceWhat is the difference??

PSYCHOSISPSYCHOSIS

Psychosis is a thought disorder characterized by Psychosis is a thought disorder characterized by disturbances of reality and perception, impaired disturbances of reality and perception, impaired cognitive functioning, and inappropriate or cognitive functioning, and inappropriate or diminished affect (mood).diminished affect (mood).

Psychosis denotes many mental disorders.Psychosis denotes many mental disorders.

SCHIZOPHRENIASCHIZOPHRENIASchizophrenia is a particular kind of psychosis characterized Schizophrenia is a particular kind of psychosis characterized

mainly by a clear sensorium but a marked thinking mainly by a clear sensorium but a marked thinking disturbance.disturbance.

SchizophreniaSchizophrenia

Schizophrenia is characterized Schizophrenia is characterized by profound disruption in by profound disruption in

cognition and emotion, affecting cognition and emotion, affecting the most fundamental human the most fundamental human attributes: language, thought, attributes: language, thought,

perception, affect, and sense of perception, affect, and sense of self self

Prevalence of Prevalence of schizophreniaschizophrenia

1.1%1.1% population over the age of 18 population over the age of 18 51 mln51 mln people worldwide suffer from people worldwide suffer from

schizophreniaschizophrenia12 million12 million people in China (a rough people in China (a rough

estimate estimate based on the population) based on the population) 8.7 million8.7 million people in India (a rough people in India (a rough

estimate estimate based on the population) based on the population) 2.2 million2.2 million people in USA people in USA 285,000285,000 people in Australia people in Australia Over Over 280,000280,000 people in Canada people in Canada Over Over 250,000250,000 diagnosed cases in Britain diagnosed cases in Britain

Etiology of SchizophreniaEtiology of Schizophrenia

IdiopathicIdiopathic

Biological CorrelatesBiological Correlates1)1) Genetic FactorsGenetic Factors

2)2) Neurodevelopmental Neurodevelopmental abnormalities.abnormalities.

3)3) Environmental stressors. Environmental stressors.

The risk of getting The risk of getting schizophreniaschizophrenia

Dopamine Theory of Dopamine Theory of SchizophreniaSchizophrenia

Many lines of evidence point to Many lines of evidence point to the aberrant increased activity of the aberrant increased activity of the dopaminergic system as being the dopaminergic system as being critical in the symptomatology of critical in the symptomatology of

schizophrenia.schizophrenia.

Dopaminergic systemDopaminergic systemThere are There are 44 major pathways for the dopaminergic major pathways for the dopaminergic

system in the brain:system in the brain:

The mThe mesolimbic pathwayesolimbic pathwayfrom substantia nigra to limbic systemfrom substantia nigra to limbic system, , functions functions of memory, emotion, arousal, and pleasureof memory, emotion, arousal, and pleasure

The The mesocortical pathwaymesocortical pathwayfrom substantia nigra to neocortexfrom substantia nigra to neocortex, , cognition, cognition, social behavior, planning, problem solving, social behavior, planning, problem solving, motivation, and reinforcement in learningmotivation, and reinforcement in learning

The nThe nigrostriatal pathwayigrostriatal pathway from the substantia nigra to the striatum,from the substantia nigra to the striatum, coordination of involuntary movementcoordination of involuntary movement

The tThe tuberoinfundibular pathwayuberoinfundibular pathway from the hypothalamus to the pituitary gland,from the hypothalamus to the pituitary gland, secretion of certain hormonessecretion of certain hormones ((prolactinprolactin))

THE DOPAMINERGIC SYSTEMTHE DOPAMINERGIC SYSTEM

CatecholaminesCatecholamines

TyrosineTyrosine Tyrosine hydroxylaseTyrosine hydroxylase

L-L-DopaDopa Dopa decarboxylaseDopa decarboxylase

Dopamine (DA)Dopamine (DA) Dopamine Dopamine hydroxylase hydroxylase

Norepinephrine (NE)Norepinephrine (NE)(Noradrenaline)(Noradrenaline)

Phenylethanolamine-Phenylethanolamine-

-N-methyltransferase-N-methyltransferase

Epinephrine (EPI)Epinephrine (EPI)(Adrenaline)(Adrenaline)

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

Dopamine receptorsDopamine receptors

DD11, D, D55 dopamine receptors dopamine receptors - - cAMP by cAMP by activation of adenylyl cyclase activation of adenylyl cyclase

DD11 – putamen, nucleus acumbens – putamen, nucleus acumbens

DD55 – hypothalamus, hippocampus – hypothalamus, hippocampus DD22, D, D33, D, D44 dopamine receptors dopamine receptors - - cAMP cAMP

by inhibition of adenylyl cyclase, inhibits by inhibition of adenylyl cyclase, inhibits CaCa2+2+ channels and open K channels and open K++ channels channels

DD22 – caudate–putamen, nucleus – caudate–putamen, nucleus acumbensacumbens

DD33 – frontal cortex, medulla, midbrain – frontal cortex, medulla, midbrain

There are at least five subtypes of receptors:

The dopamine hypothesis The dopamine hypothesis (1):(1):

Most antipsychotic drugs strongly Most antipsychotic drugs strongly block postsynaptic D2 receptors in block postsynaptic D2 receptors in the CNS (meso-limbic system)the CNS (meso-limbic system)

Drugs that increase dopaminergic Drugs that increase dopaminergic activity aggravate schizophrenia and activity aggravate schizophrenia and produce psychosis produce psychosis de novode novo

Increased dopamine receptor Increased dopamine receptor density has been found density has been found post mortempost mortem in brains of schizophrenicsin brains of schizophrenics

The dopamine hypothesis The dopamine hypothesis (2):(2):

PET has shown increased dopamine PET has shown increased dopamine receptor density in schizophrenicsreceptor density in schizophrenics

Successful treatment of Successful treatment of schizophrenics changes the amount schizophrenics changes the amount of homovanilinic acid – metabolite of of homovanilinic acid – metabolite of dopamine in dopamine in cerebrospinal fluid, cerebrospinal fluid, plasma and urine. plasma and urine.

SCHIZOPHRENIASCHIZOPHRENIA

Dysfunction of DA-ergic system:

• Hyperactivity of DA system

(mesolimbic pathway)

• Hypo-activity in frontal cortex (mesocortical pathway)

• Dysfunction of 5-HT, GABA and glutamate –ergic systems

Onset of schizophreniaOnset of schizophrenia Onset - early Onset - early

adulthood, between adulthood, between the ages of 15 and 25. the ages of 15 and 25.

Men tend to develop Men tend to develop schizophrenia slightly schizophrenia slightly earlier (16 – 25 years earlier (16 – 25 years old) than women (25 – old) than women (25 – 3030 years old). years old).

The average age of The average age of onset is 18 in men and onset is 18 in men and 25 in women 25 in women

The Course of Schizophrenia

Early intervention and early use of new Early intervention and early use of new medications lead to better medical outcomes for medications lead to better medical outcomes for the individual the individual

The earlier someone with schizophrenia is The earlier someone with schizophrenia is diagnosed and stabilized on treatment, the diagnosed and stabilized on treatment, the better the long-term prognosis for their illness better the long-term prognosis for their illness

Teen suicide is a growing problem and teens Teen suicide is a growing problem and teens with schizophrenia have approximately a 50% with schizophrenia have approximately a 50% risk of attempted suicide risk of attempted suicide

Anti-psychotic medications are the generally Anti-psychotic medications are the generally recommended treatment for schizophrenia !!! recommended treatment for schizophrenia !!!

If medication for schizophrenia is discontinued, If medication for schizophrenia is discontinued, the relapse rate is about 80 percent within 2 the relapse rate is about 80 percent within 2 years. With continued drug treatment, only years. With continued drug treatment, only about 40 percent of recovered patients will about 40 percent of recovered patients will suffer relapses.suffer relapses.

Outcomes of schizophreniaOutcomes of schizophrenia After 30 years of diagnosed After 30 years of diagnosed

schizophreniaschizophrenia

25%25% Completely Recover Completely Recover 35%35% Much Improved, relatively Much Improved, relatively

independent independent 15%15% Improved, but require Improved, but require

extensive support network extensive support network 10%10% Hospitalized, unimproved Hospitalized, unimproved 15%15% Dead (Mostly Suicide) Dead (Mostly Suicide)

Symptoms of Symptoms of schizophrenia (1):schizophrenia (1):

PositivePositiveappear to reflect an excess or distortion of normal appear to reflect an excess or distortion of normal

functions:functions:* delusions* delusions (paranoid, reference, somatic, (paranoid, reference, somatic,

delusions of grandeur)delusions of grandeur)* halucinations* halucinations (visual, auditory, tactile, (visual, auditory, tactile,

olfactory, gustatory)olfactory, gustatory)* disorganized speech* disorganized speech = „word salad”= „word salad”

*disorganized or catatonic behavior*disorganized or catatonic behavior NegativeNegative

appear to reflect a diminution or loss of normal appear to reflect a diminution or loss of normal functions:functions:

* lack of emotion* lack of emotion * low energy* low energy* affective flattening * affective flattening * low motivation* low motivation*inappropriate social skills *inappropriate social skills * alogia* alogia

The terms "positive" and The terms "positive" and "negative" may be confusing. "negative" may be confusing.

They should not be interperated They should not be interperated as "good" and "bad" symptoms. as "good" and "bad" symptoms.

Symptoms of Symptoms of schizophrenia (2):schizophrenia (2):

CognitiveCognitive disorganized thinking disorganized thinking slow thinking slow thinking difficulty in understanding difficulty in understanding poor concentration poor concentration poor memory poor memory difficulty with expressing thoughts difficulty with expressing thoughts difficulty with integrating thoughts, difficulty with integrating thoughts,

feelings and behavior feelings and behavior

Symptoms of Symptoms of schizophrenia (3):schizophrenia (3):

Disorganized symptoms (?)Disorganized symptoms (?)

* thought disorder* thought disorder

* confusion* confusion

* disorientation* disorientation

* memory problems* memory problems

Disorganized symptoms may reflect an underlying dysfunction common to several psychotic disorders, rather than being unique to

schizophrenia.

SchizophreniaSchizophrenia

• Active phase

Hallucinations and delusions are

prominent symptoms

• Residual phase

U.S. diagnostic criteria for U.S. diagnostic criteria for schizophrenia (1)schizophrenia (1)

A. Characteristic symptoms: ≥2 A. Characteristic symptoms: ≥2 during a 1-month period during a 1-month period ::

delusionsdelusions

halucinationshalucinations

disorganized speech disorganized speech

disorganized behaviordisorganized behavior

negative symptomsnegative symptoms

U.S. diagnostic criteria for U.S. diagnostic criteria for schizophrenia (2)schizophrenia (2)

Only Only one one Criterion A symptom is Criterion A symptom is required if delusions are bizarre or required if delusions are bizarre or hallucinations consist of a voice hallucinations consist of a voice keeping up a running commentary keeping up a running commentary on the person’s behavior or on the person’s behavior or thoughts, or two or more voices thoughts, or two or more voices conversing with each other.conversing with each other.

U.S. diagnostic criteria for U.S. diagnostic criteria for schizophrenia (3)schizophrenia (3)

B. Social/occupational dysfunctionB. Social/occupational dysfunctionworkworkinterpersonal relationsinterpersonal relationsself-careself-care

C. DurationC. Durationcontinuous signs of the disturbance continuous signs of the disturbance

persist for persist for at least 6 monthsat least 6 months, , including 1 month of symptoms from including 1 month of symptoms from Criterion A and prodromal symptoms)Criterion A and prodromal symptoms)

U.S. diagnostic criteria for U.S. diagnostic criteria for schizophrenia (4)schizophrenia (4)

D. Schizoaffective and mood disorder D. Schizoaffective and mood disorder exclusionexclusion

no major depressive, manic or no major depressive, manic or mixed episodes have occurred with mixed episodes have occurred with the active-phase symptomsthe active-phase symptoms

E. Substance/general medical E. Substance/general medical condition exclusioncondition exclusion

F. Relationship to a pervasive F. Relationship to a pervasive developmental disorderdevelopmental disorder

Types of schizophreniaTypes of schizophrenia

Paranoid schizophreniaParanoid schizophrenia Disorganized schizophrenia Disorganized schizophrenia

(hebephrenic)(hebephrenic) Catatonic schizophreniaCatatonic schizophrenia Residual schizophreniaResidual schizophrenia Schizoaffective disorderSchizoaffective disorder Undifferentiated schizophreniaUndifferentiated schizophrenia

Neuroleptic drugsNeuroleptic drugsANTI-

PSYCHOTICDRUGS

TYPICAL NEUROLEPTICS

ATYPICAL NEUROLEPTICS

PHENOTHIAZINES

THIOXANTHENES

BUTYRO-PHENONES

BENZISOXAZOLES

DIBENZO-DIAZEPINES

PhenothiazinesPhenothiazines

ChlorpromazineChlorpromazine FluphenazineFluphenazine ProchlorperazineProchlorperazine PromethazinePromethazine ThioridazineThioridazine

Other groups of typical Other groups of typical neurolepticsneuroleptics

ThioxantheneThioxanthene

ThiothixeneThiothixene ButyrophenoneButyrophenone

HaloperidolHaloperidol

Typical neuroleptics – Typical neuroleptics – mechanism of actionmechanism of action

Mechanisms of Action of Mechanisms of Action of AntipsychoticsAntipsychotics

conventional antipsychotics

D2 receptor blockade of postsynaptic in the mesolimbic pathway

atypical antipsychotics

D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms;

enhanced dopamine release and 5-HT2A receptor

blockade in the mesocortical pathway to reduce negative symptoms;

other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia

Atypical neurolepticsAtypical neuroleptics

BenzisoxazolesBenzisoxazoles

RisperidonRisperidon

ZiprasidonZiprasidon DibenodiazepinesDibenodiazepines

ClozapineClozapine

QuetiapineQuetiapine

OlanzapineOlanzapine

Atypical neuroleptics - Atypical neuroleptics - mechanism of actionmechanism of action

What is the clinical What is the clinical difference between older difference between older

and newer drugs?and newer drugs?

New antipsychotic drugs has been New antipsychotic drugs has been shown to be more effective than older shown to be more effective than older ones for treating negative symptomsones for treating negative symptoms

Actions of neuroleptic Actions of neuroleptic drugs (1)drugs (1)

Dopamine receptorDopamine receptorall, particularly: haloperidol, fluphenazine, all, particularly: haloperidol, fluphenazine, thiothixenethiothixene

Muscarinic receptorMuscarinic receptorthioridazine, chlorpromazinethioridazine, chlorpromazine

- Adrenergic receptor- Adrenergic receptorchlorpromazinechlorpromazine

Serotonin receptorSerotonin receptorrisperidone, clozapinerisperidone, clozapine

H1 - Histamine receptorH1 - Histamine receptorpromethazine, chlorpromazinepromethazine, chlorpromazine

Actions of neuroleptic Actions of neuroleptic drugs (2)drugs (2)

Antipsychotic actions:Antipsychotic actions:reduce the halucinationsreduce the halucinationsreduce spontaneous physical reduce spontaneous physical

movementmovementOccur after 4 – 6 weeks of treatmentOccur after 4 – 6 weeks of treatment Extrapyramidal effects:Extrapyramidal effects:

Parkinsonian symptomsParkinsonian symptomsakathisiaakathisiatardive dyskinesiatardive dyskinesia

Actions of neuroleptic Actions of neuroleptic drugs (3)drugs (3)

Antiemetic effectAntiemetic effect (exept (exept thioridazine)thioridazine)

Antimuscarinic effect:Antimuscarinic effect:

blurred vision, dry mouth, blurred vision, dry mouth, sedation, confusion, inhibition of GI sedation, confusion, inhibition of GI and urinary smooth muscleand urinary smooth muscle

Other effects:Other effects:

hypotension, lightheadnesshypotension, lightheadness

Neuroleptic drugs are not curative Neuroleptic drugs are not curative and and

do not eliminate the fundamental do not eliminate the fundamental thinking disorder, but often do thinking disorder, but often do permit the psychotic patient to permit the psychotic patient to

function in a supportive environmentfunction in a supportive environment

Therapeutic usesTherapeutic uses SchizophreniaSchizophrenia Other psychosisOther psychosis Schizoaffective disordersSchizoaffective disorders DeliriumDelirium Prevention of severe nausea and vomitingPrevention of severe nausea and vomiting

(vertigo, motion sickness, cancer chemo- (vertigo, motion sickness, cancer chemo- and radiotherapy)and radiotherapy)

TranquilizersTranquilizers In combination with narcotic analgesics for In combination with narcotic analgesics for

treatment of chronic pain with severe treatment of chronic pain with severe anxietyanxiety

Intractable hiccupsIntractable hiccups

PharmacokineticsPharmacokinetics

Neuroleptics are absorbed after Neuroleptics are absorbed after oral oral administrationadministration

Pass through blood – brain barrierPass through blood – brain barrier Bind well to plasma proteins, highly Bind well to plasma proteins, highly

lipid-solublelipid-soluble Are metabolized in liver by Are metabolized in liver by P-450P-450

systemsystem

Adverse effects (1)Adverse effects (1)

Acute

• Acute dystonia

Medium- term

• Akathisia

• Parkinsonism

Chronic

• Tardive dyskinesia

• Tardive dystonia

Neurologic effects due to D2 receptor Neurologic effects due to D2 receptor blockadeblockade

Acute dystoniaAcute dystonia

Fixed muscle postures with spasm:

• clenched jaw muscles • protruding tongue• opisthotonos• torticollis • oculogyric crisis(mouth open, head back,

eyes staring upwards)

In the beginning of treatment

Common in young males

Treatment with anticholinergic drugs (procyclidine 5-10mg or benztropine i.m or i.v)

AkathisiaAkathisia

• motor restlessness

• affect lower limb

• very distressing to the patient

• Treatment – reduction of the drug dose.

ParkinsonismParkinsonism

• induced by blockade of D2 receptors in the striatum !!!

• appear after a few days to weeks

Treatment:• anticholinergic drugs (e.g

procyclidine)• reduction of dose • switching to an atypical

antipsychotic

Tardive dyskinesiaTardive dyskinesia orofacial dyskinesia -lip smacking and tongue rotating.

Tardive Tardive dystoniadystonia specific movements of the head, neck and trunk.

There is no effective treatment !!! They are irreversible.

Appear after months to years of drug treatment

ClozapineClozapine and and RisperidoneRisperidone have a low potential for have a low potential for causing extrapyramidal symptoms and lower risk of causing extrapyramidal symptoms and lower risk of tardive dyskinesiatardive dyskinesia

Adverse effectsAdverse effects (2) (2):: Anticholinergic effectsAnticholinergic effects due to muscarinic blockadedue to muscarinic blockade: : loss of accomodation, dry mouth, loss of accomodation, dry mouth, blurred vision, blurred vision,

constipation, urinary retentionconstipation, urinary retention Ortostatic hypotensionOrtostatic hypotension due to due to -adrenergic blockade-adrenergic blockade Neuroendocrine adverse effectsNeuroendocrine adverse effects due to D2 blockade due to D2 blockade

in thein the ttuberoinfundibular pathwayuberoinfundibular pathway : : Amenorrhoea-galactorAmenorrhoea-galactorrrhoeahoea InfertilityInfertility ImpotenceImpotence, , Failure to ejaculateFailure to ejaculate DrowsinessDrowsiness Weight gainWeight gain, , Urticaria, dermatitis, rashes, dermal photosensitivityUrticaria, dermatitis, rashes, dermal photosensitivity

Adverse effects of Adverse effects of clozapineclozapine

Bone marrow suppressionBone marrow suppression Cardiovascular side effectsCardiovascular side effects DiabetesDiabetes

Adverse effects of Adverse effects of chlopromazinechlopromazine Cholestatic jaundiceCholestatic jaundice

Neuroleptic Malignant Neuroleptic Malignant SyndromeSyndrome

Precise pathophysiology unknown – Precise pathophysiology unknown – deranged dopaminergic function ?deranged dopaminergic function ?

It is an idiosyncratic reaction that It is an idiosyncratic reaction that appears from a few days to weeks appears from a few days to weeks after beginning treatment, but can after beginning treatment, but can occur anytime.occur anytime.

The mortality – The mortality – 20%20% in untreated in untreated ((bromocriptinebromocriptine – D1/D2 agonist; – D1/D2 agonist; dantrolenedantrolene – sceletal muscle – sceletal muscle relaxant; supportive treatment)relaxant; supportive treatment)

Neuroleptic Malignant Neuroleptic Malignant SyndromeSyndrome (NMS) (NMS)

HyperthermiaHyperthermia Muscle rigidityMuscle rigidity Autonomic instabilityAutonomic instability Fluctuating consciousnessFluctuating consciousness Mortality due to renal failure caused Mortality due to renal failure caused

by rhabdomyolysis. by rhabdomyolysis.

InteractionsInteractions of of neurolepticsneuroleptics

Additive effects:Additive effects:

sedativessedatives

- adrenoreceptor – blocking - adrenoreceptor – blocking drugsdrugs

anticholinergic drugsanticholinergic drugs

quinidine-like action (quinidine-like action (thioridazine, thioridazine, ziprasidone)ziprasidone)

ContraindicationsContraindications

Alcohol abuseAlcohol abuse Seizure disorders (Seizure disorders (ChlorpromazineChlorpromazine)) EpilepsyEpilepsy Agranulocytosis (Agranulocytosis (ClozapineClozapine))

Neuroleptics oNeuroleptics overdoseverdose

Rarely fatalRarely fatal Drowsiness proceeds to coma, with Drowsiness proceeds to coma, with

intervening period of agitationintervening period of agitation Increased muscular excitability may Increased muscular excitability may

lead to convulsionslead to convulsions Decreased deep tendon reflexesDecreased deep tendon reflexes Ventricular tachyarrhythmiasVentricular tachyarrhythmias Gastric lavage !!!Gastric lavage !!!

Dosage of neuroleptic Dosage of neuroleptic drugsdrugs

Antipsychotics may be given in Antipsychotics may be given in divided daily doses initially while divided daily doses initially while effective dosage level is being sought.effective dosage level is being sought.

2 or more episodes of schizophrenia – 2 or more episodes of schizophrenia – therapy for 5 yearstherapy for 5 years

FluphenazineFluphenazine and and haloperidolhaloperidol i.m. i.m. slow release drugs (up to 3 weeks)slow release drugs (up to 3 weeks)