ANTIPSYCOTICS

Dr. ASHFAQ

Brain

Mind

Psychosis ……… Thinking Depression …… Mood

Brain • CNS Stimulant (Analeptics)• CNS Depressant

Mind• Antidepressants• Psychosis …. Antipsychotics…

(Neuroleptics)

Psychosis

a variety of mental disorders e.g.,

Schizophrenia:

characterized by a “ clear sensorium ”

but a “ marked-disturbed thinking ”

- Hallucination

- Delusions ( False beliefs)

Not curatives Decrease intensity of symptoms

i.e. • Hallucination,

Auditory, Visual, Tactile, Olfactory • Delusions (False Beliefs)

Patient can function/move in supportive enviornament

Pathophysiology

Genetic & Environmental Factors

Single gene predisposes

Environmental factors required for Schizophrenia to develop.(appear with age)

Identical twins one has schizophrenia…. Probability 50% … points towards Environmental factors

Neurodegeneration ? [Prgressive Development

Neuroanatomical & Neurochemical Basis of Shizopherania

Malfunction in different Neuronal Circuits• Changes in Mesolimbic pathways +ive• Changes in Mesocortical pathways - ive

Dopamine Hypothesis Serotonin Hypothesis Glutamate Hypothesis

• (NMDA Hypofunction Hypothesis [Coyle 2006])

On the basis of indirect pharmacological evidence

Symptoms of Schizophrenia

Positive Symptoms Delusions

Hallucinations

Thought Disorders

Abnormal disorganized behaviour

Catatonia (purposeless motor activity)

Negative Symptoms Withdrawal from social

contact

Flattening of emotional responses

Anhedonia (inability to express pleasure)

Reluctance to perform every day tasks

Amphetamine release dopamine in brain behavioural syndrome …. Mimic Schizophrenia “CARLSON 2000”

I. Dopamine-Hypothesis: Evidence of Dopaminergic activity underlying this disorder. a). D - agonists leads to Schizophrenic symptoms. b). Increased Dopamine-Density in brains of Schizophrenic patients ( post mortalm reports ).

c). Typical Antipsychotic are D2 blockers…… d). Positron Emission Tomography (haloperidol binding)

“excessive”

Against Dopamine Hypothesis

Dopminergic activity is suggesteted as cause of Cognitive Impairment & Negative symptoms of Scizopherania

Dopaminergic Innervation in Medial Temporal Cortex, Dorsolateral prefrontal cortex, Hippocampus In decreased levels of DOPAC

(dihydroxyphenylacetic acid)

Several atypical drugs has much less effect on D2 receptors & yet are effective

Serotonin Hypothesis 5HT2A receptor blockade is key factor In M.O.A.

of ATYPICAL drugs (Inverse agonists)

5HT2A receptors modulate the releases of Dopamine (Cortex, Limbic Region)

5HT2A stimulation leads to depolarization of Glutamate Neurons

5HT2A Also stabilize NMDA receptors 5HT2C currently being studied as antipsychotic

Glutamate/NMDA Hypofuntion Hypothesis

NMDA receptor antagonists (ketamine,

Phencyclidine,dizocilpine) can produce +ive & -ive symptoms

• Amphetamine produce only +ive symptoms

It has been postulated “ schizophrenia may result from disruption of

Glutamatergic neurotransmission [Moghaddam, 2003]… Evident as reduction in function of NMDA receptors [ Coyle, 2006]”

Dopamine Receptors Two Families: D1-like receptors group(Gs coupled …. Stimulate adenylcyclase

( no correlated antipsychotic activity ).

D2-like receptor group (correlated with antipsychotic activity )

(Gi/G0 coupled … inhibitadeny cyclase …activate K+ channels, inhibit Ca++, may also activate Phosphlipase C)

i. D-2 receptor ( found pre- & postsynaptically in the caudate-putamen, nucleus accumbens and

olfactory tubercle ):decreases cAMP and inhibits Ca++

channels but opens K+ channels. ii. D-3 receptors ( located in the frontal cortex,

medulla and midbrain ): decreases cAMP.

iii. D-4 receptors also decreases cAMP.

Dopaminergic PathwaysFive important pathways / systems in the brain.

1. Mesolimbic-mesocortical Pathways: more closely related to behavior; ( it projects from cell bodies near to substantia nigra to the limbic system and neocortex ) …+ive & -ive Symptoms

2. Nigrostriatal Pathways: involved in coordination of voluntary movement; ( it projects from substantia nigra to the caudate and putamen.)

[ Extrapyramydal Effects …. Dystonias, Tardive dyskinasias]

3. Tuberoinfundibular System: inhibits prolactin secretion; ( connects arcuate nuclei and periventricular neurons to the thalamus and posterior pituitary.)

4. Medullary-periventricular Pathways: involved in eating behavior; ( consists of neurons in the nucleus of the vagus whose projections are not well defined.)

5. Incertohypothalamic Pathways: It regulates the anticipatory motivational phase of copulatory behavior in rats; ( connections from the medial zone incerta to the hypotalamus and amygdala.)

II. Role of Other Neurotransmitters:

excessive Serotonin / GABA etc. Activity.

a). Decreased 5-HT2 activity

by Risperidone, Olanzapine.

b). Decreased GABA, Glutamatergic &

Cholinergic activity, or some α1-blockers.

5-HT Receptorsi. 5-HT1A receptorsii. 5-HT2A receptors: LSD – Lysergic acid Diethylamide - is an agonist here

produces transient hallucinations and other mental aberrations including insomnia. Similarly Psilocin ( found in mushrooms ), DMT- Dimethyltryptamine - are also hallucinogens. Ectasy produces euphoria followed by depression etc.

Classification

Typical…. (First generation, Classical, Conventional)

• Chlorpromazine• Haloperidol• Fluphenazine• Flupentixol• Clopentixol

Atypical…. (2nd generation)

• Clozapine• Risperidone Recpetor Profile

• Sertindole Incidence of ex.P.effects

• Quetipine Efficacy in Resistant cases

• Amisulpride Efficacy against -ive sympt.

• Aripiprazole• Zotepine• Ziprasodine

According to Receptor Selectivity ( In descending order )

a) On Dopamine Receptors Thiothixene, Chlorpromazine, Fluphenazine, Haloperidol, Aripiprazole, Clozapine, Risperidone, Olanzapine, Quetiapine, Ziprasidone.

b) On 5-HT2A

Receptors Clozapine, Risperidone, Olanzapine, Quetiapine, Ziprasidone, Aripiprazole, Haloperidol, Chlorpromazine, Fluphenazine, Thiothixene.

Highly selective for D2 Receptors(Newer Drugs)

Sulpride Amisulpride Remoxipride

On Basis of Clinical uses

• Behavioural Changes

Chlorpromazine Haloperidol Olanzepine Risperidone

• Schizophrenia Flupentixol Amisulpride Clozapine

Classification ( Chemically – Based )

I. Phenothiazines a). Open-Chain: 1. Chlorpromazine 2. Promazine 3. Promethazine b). Piperazine-Chain: 1. Trifluoperazine 2. Perphenazine 3. Fluphenazine c). Piperidine-Chain: 1. Thioridazine

II. Thioxanthines

1. Thiothixen

2. Chlorprothixene

III. Butyrophenones

1. Haloperidol

2. Droperidol

IV. New / Atypical Drugs (Hetrocyclics) a). Di-benzodiazepine: Clozapine b). Dihydro-indolone: Ziprasidone Molindone c). Di-benzo-oxazepine: Loxapine d). Dibenzo-thiazepine: Quatiapine e). Dihydro-carbostyril: Aripiprazole f). Benzisoxazole: Risperidone g). Thienobenzodiazepine: Olanzapine h). Fluorophenylindole: SertindoleV. Anti-manic Lithium

DOPAMINE

DECREASED INTRACELLULAR

RESPONSEDOPAMINE RECEPTOR BLOCKED

Neuroleptics

Li+

Neuroleptics

SomeAntipsychotics

Sites of Action of Neuroleptics & Lithium

DA

Li+

D1R

Stimulants

DA

D2

R

D 2R

D 3R

ATP

cAMP

DA

Presynaptic PostsynapticDopamine Neurons Receptive Membrane

Relative Affinitiesof

Clozapine,Chlorpromazine,

Haloperidol.at D2 & D1- receptors

More antipsychotic activity

Rapid but incomplete absorption;

Significant first pass metabolism ( oral bioavailability of chlorpromazine & thioridazine is 25% to 35% while of haloperidol

is about 65%.)

Highly lipid soluble & protein-bounded ( 92-99%); Vd > 7 L/kg.

Prolonged D2 & other receptors occupancy, so longer duration of action than their half lives.

Pharmacokinetics

Pharmacokinetics ( cont.)

metabolites are not so active but mesoridazine, a metabolite of thioridazine is more potent than parent drug.

Excretion Almost all are completely metabolized into more water soluble substances. Metabolites of chlorpromazine may be excreted in the urine after weeks of the last dose of chronically given drugs.

Concerning hypothesis for pathophysiological basis of schizophrenia, which statement is accurate? a: All clinically effective antipschotic drugs

have high affinity for D2 receptors b: Dopamine receptor blocking drugs are used

to alleviate psychotic symptoms in parkinsonism

c: Drug induced psychosis can occur without activation of brain dopamine receptors

d: Serotonin receptors are present at lower than normal levels in the brains of untreated schizophrenics

E: The clinical potency of clozapine correlate well with its dopamine receptor blocking activityC

Regarding Classification of antipsychotic drugs which is highly selective for D2 receptors

a: Sulprideb: Clozapinec: Olanzapined: Quetiapinee: Risperidone

a

Pharmacological Effects

Risperidone Clozapine,etc.

Serotonin Receptors

All TypicalAnti-psychotics esp.Haloperidol

DopamineReceptors

a ). CNS

1.

i). Behavioral Effects dopaminergic site at

limbic system & reticulating activating system:

- Depressing- anesthesia like state;

- Open Chain are more sedating & less Antipsychotic;

but chlorpromazine after longer use is antipsychotic

( pt. is less disturbed & having fewer hallucinations &

delusions );

- In acute cases– a quietening effect in agitated &

disturbed patients.

Tolerance develops only to sedative effects ii). Extra pyramidal Effects(acute dystonias & Tardive dyskinesias)

Dystonia …involunry movements, retlessness, Muscle spasm, Protuding

tounge, fixed upward gaze, Torticolis (Involuntry spasm of neck muscles) Dopaminergic Sites: at Nigrostriatal Sites:

rarely in acute cases;

Parkinsonism like: due to increased cholinergic activity in CNS ( to counter act the decreased dopaminergic activity ) so Antipsychotic with high anticholinergic activity like Thioridazin will have lowest incidence of parkinsonism like symptoms but has high esdative & hypotensive effects.

Tardive Dyskinesia: ( after months ….. Tardive)Disabeling. Irreversible,

involuntry movements of face & tongue, also trunk & limbs perhaps due to imbalance of Ach. & Dopamine activity ( esp. decreased cholinergic activity leads to up regulation of dopaminergic receptors – super sensitivity which may occur after prolong therapye.g., by thioridazine like drugs which intensify this syndrome ) Treatment is to discontinue all drugs with anticholinergic activity or reduce the dose. If it fails give Diazepam in larger doses.

2. Medulla at CTZ( therapeutic doses ) & Vomiting Center( larger doses ): Anti- Emetic effect

b). Autonomic Nervous System i). α- Receptors: α – Blockade with initial small dose (orthostatic hypotension & impaired ejaculation) but with chronic dose stimulation occurs.

ii). Muscarinic & Nicotinic Receptors: weak action & blocked

iii). Histaminergic Receptors: Antihistaminic Effect

Uses

a). Psychiatric Uses 1. Schizophrenia

some patients do not respond at all.

2. Schizoaffective Disorders

antipsychotic with antidepressants, lithium or

valproic acid.

3. Manic episode in Bipolar Disorders

Olanzapine alone may be useful here

which is withdrawn when mania subsides.

4. Nonmanic Excitated State Benzodiazepines are combined.

5. Tourette’s Syndrome 6. Alzheimer Senile Dementia 7. Anxiety with Emotional Disorders with sedative drugs.

b). Non-psychiatric Uses1. Anti-emetic due to dopamine receptors blockade at CTZ & Stomach e.g.,

Prochlorperazine, Benzquinamide.

2. Anti-histaminic for pruritus.

3. Preoperative Sedative Promethazine.

4. As neuroleptanalgesia Droperidol with

Fentanyl.

Adverse Effects

a). Behavioral Effects Pseudo-depression; Toxic-confusional states:

b). Neurological Effects Extra pyramidal Effects: Parkinsonism, Akathisia — uncontrolled restlessness, Acute Dystonic Reactions — spastic retrocolis or torticollis. Tardive Dyskinesia

Seizures with chlorpromazine, clozapine.

c). Hypothalamus

i). Temperature Regulating Center by depressing it .…Hypothermia ; but in high environmental temperature hyperthermic episode may occur due to failure to lose body temperature.

ii). Prolactin Release …. Hyperprolactinemia results: in women amenorrhea - galactorrhea & infertility, and in men loss of libido, impotence & infertility

d). Pituitary i). Increased Melanocyte Hormone Activity

– Hyper pigmentation esp. with those drugs which

have high antipsychotic activity.

ii). Increased Gonadotropin Activity –

Delayed Ovulation & Menstruation ; with high doses amenorrhea.

iii) . False positive pregnancy test

iv). Hyperglycemia in non-diabetic patients.

v). Weight gain occurs esp. with

clozapine and olanzapine.

e). CVS Orthostatic hypotension and High resting pulse rates due to large doses of low potency drugs. Decreased mean arterial pressure, peripheral resistance

and stroke volume but increased heart rate. ECG Cardiac toxicity esp. with thioridazine

Ventricular arrhythmias, Conduction block & sudden death;

Prolongation of QT interval and abnormal ST- segment & T waves esp. with Sertindol & Ziprasidone ;

but all are reversible.

f). Allergic Reactions at skin ( eruption rarely ), liver ( homeostatic jaundice ), Blood ( agranulocytosis ) esp. with clozapine which is potentially fatal but reversible.g). Miscellaneous Ocular Complications Drug Deposits in cornea & lens; retinal

deposits with thioridazine associated with browning

of vision. Use in Pregnancy Dysmorphogenesis: teratogenesis

Neuroleptic Malignant Syndrome ( life threatening disorder in patients

who are extremely sensitive to extra pyramidal effects of antipsychotic;

there is

Excessive & rapid blockade of postsynaptic dopamine receptors.

Symptoms are: Muscle rigidity, Impaired sweating, Hyperpyrexia, Leucocytosis. Autonomic instability with altered B.P & pulse rate. Creatine kinase isozyme are elevated reflecting muscle

damage.

D/D Malignant Hyperthermia [ anesthetic Complication] Serotonin Syndrome …. [ Tremour, Clonus, Hypereflexia ]

An adverse effect that is common to most phenothiazines is

a: A marked increase in blood pressure

b: Rigidity and tremour at rest especially with prolong use

c: Suppression of lactation

d: A diminished response to CNSdepressants

e: Nausea

b

The least likely side effect seen in patient taking chlorpromazine for two months would be

a: Extrapyramidal symptoms b: Hypotension c: Lethargy d: weight gain e: Nausea & Vomiting

e