Antipsychotic Drugs

Classification of Antipsychotic Drugs

1. Typical Antipsychotics (Old generation)

Tricyclic Antipsychotics

Phenothiazines

a. Aliphatic (least used)

Chlorpromazine

b. Piperidine

Thioridazine –no antiemetic effect

Mesoridazine

c. Piperazine (most used)

            Prochlorperazine -antiemetic

Trifluoperazine

Fluphenazine decanoate

Thioxanthines

Thiothixine

Chlorprothixene

Flupenthixol

2. Hetrocyclic Antipsychotics

Butyrophenones

Haloperidol

Droperidol

Atypical Anti psychotics

Clozapine –decreased risk of suicide

Olanzapine

Quetiapine

Risperidone

Ziprasidone –least weight gain

Aripiprazole –partial dopamine agonist

Molindone

Pimozide

Loxapine

Asenapine

Peridone

Sertindole

Zotepine

Mechanism of Action

Biochemical defect

Highly dependent on biochemical defect present in patients.

Schizophrenia

E.g. in schizophrenia there is functional over activity of dopamine especially in mesolimbic and mesocortical pathway.  Drugs which are potent dopamine receptor antagonists will be effective in treating the symptoms of schizophrenia. However, there are a few short comings. All symptoms are not effectively treated by these drugs. Some antipsychotics are not potent D2 receptor antagonists, yet they are good antipsychotics.

Role of non-dopamine receptors

Monoamines, serotonin and norepinephrine play role in normal psychotic functions, so some antipsychotics are potent alpha 1, serotonin 2 receptor antagonists. E.g.

Piperazine, Butyrophenones, Chlorpromazine, Resperidone, Clozapine

1. Among phenothiazines, piperazine group has most potent dopamine receptor blocking action.
2. Piperidines are least potent D2 receptor blockers.
3. Aliphatic group is intermediate in blocking D2 receptors.
4. Butyrophenones are more potent D2 receptor blockers than phenothiazines.
5. Chlorpromazine has D2 blocking activity as well as effects on alpha 1 receptors, muscarinic receptors, serotonin and H1 receptors. Alpha 1 blockage is most potent, responsible for antipsychotic effect.
6. Reseperidone is used in resistant cases of Schizophrenia, it blocks D2 and serotonin 2 receptors.
7. Clozapine blocks D4, alpha 1 and serotonin 2 receptors.

Receptor Blockade by Antipsychotic Drugs

• Chlorpromazine
• a1=5HT2A>D2>D1
• Haloperidol
• D2>a1>D4>5HT2A>D1>H1
• Clozapine (agranulocytosis)
• D4=a1>5HT2A>D2=D1
• Olanzapine
• 5HT2A>H1>D4>D2>a1>D1
• Aripiprazole
• D2=5HT2A>D4>a1=H1>>D1
• Quetiapine
• H1>a1>M1,3>D2>5HT2A

Phenothiazines

Phenothiazine nucleus has tricyclic structure. They are further subdivided into 3 sub families

Aliphatic-sedative effects, less potent, in agitated pts.

If substitution is by straight chain then these are aliphatics like Chlorpromazine.

1. This has most sedating effect
2. used in agitated Schizophrenic patients.
3. D2 blockage is intermediate so less potent antipsychotics

Piperadine– sedative effect, least potent, marked anticholinergic effect, in agitated pts.

If substitution is with piperadine group, we get piperadine derivatives.

1. Strong sedative effects, weight gain
2. D2 blockage is least but have marked anticholinergic effects.

Piperazine– least sedation, highly potent, less anticholinergic effects, in depressed pts.

If substitution is by piprazine group we get piperazine derivatives.

1. Least sedation
2. Used in depressed or socially withdrawn patients
3. D2 blockage is most potent
4. Have less anticholinergic effects

Pharmacological Actions

1. Behavior

• Produce apathy.
• Loss of interest
• Decreased social interactions
• Hallucinations are suppressed and delusions reduced
• Decrease psychomotor functions
• Decrease agitation, hostility of person
• Marked improvement in behavior of psychotic person but no prominent effects in normal persons
• Produce minimal drowsiness, pseudo depression
• Due to akinesia produce lethargy
• Spontaneous motor activity is reduced and exploratory behavior is also reduced
• b.      Suppress conditioned reflexes.

2. Motor activity

• Spontaneous motor activity is reduced and exploratory behavior is also reduced
• Suppress conditioned reflexes.

3. Spinal reflexes

Have little effect on spinal reflexes.

4. Sleep

Pattern is normalized with these antipsychotics.

5. Anti emetic actions

As D2 receptors are blocked in CTZ, thus have potent anti-emetic effects. (phenothiazine, butyrophenones)

6. Extrapyrimidal effects

(Piperazine derivatives, Butyrophenones, Resperidone, Clozapine, Olanzapine)

Extrapyramidal effects are produced by blockage of D2 receptors in nigrostriatal pathway. One form of this is

Acute parkinsonism, in which there is akinesia, bradycardia, tremors and rigidity.

a. Acute dystonias

In this there are muscle spasms in regions of face, neck, back and limbs.

b. Akathesia

Motor restlessness or hyperactivity

c. Peri oral tremors

Tremors in muscles around lips, also known as rabbit’s syndrome.

d. Tardive dyskinesia

Late occurring syndrome seen with chronic administration of antipsychotics. There are chorio athetoid movements, along with orofacial dyskinesias (protruding tongue, smacking lips)

Tardive dyskinesia is important as it is very difficult to be treated, so it is very important to recognize early signs.

All typical antipsychotics should be stopped. Drugs having anticholinergic effects should be withdrawn.

e. Neuroleptic malignant syndrome

Seen in individuals extra sensitive to extrapyramidal side effects of antipsychotics.

There is marked muscle rigidity, altered blood pressure, temperature impaired, with sweating, leading to hyperpyrexia.

Extrapyramidal side effects are most common with piperazine group, far more with butyrophenone. With atypical antipsychotics, extrapyramidal side effects are less.

Dantrolene is given for treatment.

7. Reduced seizure threshold

Antipsychotics decrease threshold of seizures, there are chances of epilepsy, so not given in grand mal epilepsy. If use is inevitable, among atypical antipsychotics, only Molindone can be given in epilepsy.

8. Hypothermia

Antipsychotics decrease the body temperature and bring it below normal as compared to antipyretics, produced by direct effect on thermal regulatory center. In a few surgical procedures this feature is utilized.

9. Autonomic effects

Because of alpha 1 blockage, they produce hypotension.

In response to alpha blockage, reflex tachycardia occurs.

Also block muscarinic receptors, so atropine like effects are seen (dilatation of pupil, blurring of vision, dry mouth, constipation, urinary retention, increased intraocular pressure), so given carefully to elderly, as are more prone.

10. Effects on other receptors

Have some sodium channel blocking property, so have local anesthetic effect.

Have H1 blocking activity, so given in pruritis.

11. Endocrine side effects

Among dopaminergic pathway, tuberoinfundibular pathway may be responsible for hyperprolactenemia, gynecomastia, gonorrhea, galactomastia and infertility.

Clozapine and Olanzapine are notorious for causing weight gain. They precipitate diabetes and hyperlipidemias.

12. Cardiovascular effects; Thioridazine, Ziprasidone

Thioridazine causes T-wave inversion.

Ziprasidone causes prolongation of QT interval.

13. Hypersensitivity reactions; Clozapine, Risperidone

Can produce inflammation of liver cells and obstruction of biliary canaliculi, leading to cholestatic jaundice.

Among atypical antipsychotics, Clozapine can cause agranulocytosis. Incidence is 2%, thus is rare, but is a serious condition.

Risperidone also causes agranulocytosis.

Besides skin rash, articaria, etc. are seen as well.

     14. Ocular complications; Chlorpromazine, Thioridazine

Chlorpromazine gets deposited in cornea.

Thioridazine gets deposited in retina, thus there can be formation of blind spots (scotomas).

15. Pregnancy

Dysmorphogenesis and teratogenesis.

16. Surgery

• Anesthesia
• Anti-emetic effect
• Neuroleptanesthesia
• Hypothermia

 Pharmacokinetics

• Route of administration is mostly oral
• In low compliant patients injectables, solutions, slow release preparations may be used parentally like phenothiazines
• Oral solutions are available mixed with soft drinks.
• Long acting slow release preparations are available, like Fluphenazine.
• Absorption of these drugs is complete
• First pass metabolism – undergo 1^st pass metabolism.
• Bioavailability -35% for phenothiazines and 65% for butyrophenones
• PPB –significant (92-99%)
• Distribution –cross BBB, large volume of distribution (>7 l/kg)
• Metabolism –chlorpromazine is converted into 7 hydroxy metabolite, this increases volume of distribution and remains in body for longer time.

Thioridazine is converted into mesoridazine

Excretion -Piperazine gp. is excreted as such in urine.

Risperidone is converted into 9-hydroxyrisperidone (Paliperidone) which is active metabolite.

Uses

1. Psychotic uses

1. Schizophrenia –control all symptoms of Schizophrenia
2. Manic depressive psychosis –treatment and hypomania
3. Tourette’s syndrome –exact mechanism is not known. Patient talks a lot, talks non-sense, repetitive movements along with

Haloperidol and pimozide are effective in treatment.

4. Paranoid states
5. Huntington’s chorea

Autonomic dominant disorder due to abnormality of chromosome 4.

There is increased dopamine activity

There is decreased cholinergic activity

Haloperidol is effective. Reserpine can also be given.

6. Alcohol induced psychosis –especially after withdrawal
7. Delirium

2. Non psychotic uses

1. Pruritis –due to H1 blocking activity. Promethazine is effective to prevent it.
2. Anti emetic –phenothiazine, butyrophenones, but dose required is much lower than for psychosis.
3. Hypothermia –droperidol
   • For neurolept anesthesia in combination with Fentanyl
   • Where decreased temperature is required
4. Hiccups –chlorproniazine is used. Mechanism is not known.

	Phenothiazines	Butyrophenones
Sedation	More	Less
Anticholinergic effects	More	Less
Hypotension	More	Less
Half life	More	Less
Binding D2 receptors	Less	More strongly
Extrapyramidal side effects	Less	More
Bioavailability	35%	65%
Use		More widely used
Potency	Less	More

	Typical antipsychotics	Atypical antipsychotics
D2 blockage	More strong	Less strong
Extrapyramidal side effects	More	Less
	Decrease threshold seizures	Molindone may be given
Anticholinergic effects	More	Less
Antiemetic effects	More	Less
Alpha blockage	More	Less
Ocular effects	More	Less
		Endocrine adverse effects Clozapine, olanzapine not given
		CVS adverse effects –QT prolongation
		Allergic manifestations
Potency	Less	More
Action	Mainly at dopamine receptors	At various receptors: Histamine, alpha 1 and M1
Hyperprolactinemia	More	Less
Tardive dyskinesia	More	Less
Use	For positive symptoms	For negative symptoms
Cost	Cost effective	Expensive
Agranulocytosis	Absent/less	More esp. Clozapine
Weight gain	Less/absent	More esp. Olanzapine

Adverse effects of antipsychotics

1. Behavioral effects

Older typical are unpleasant to take. May cause:

• sedation and drowsiness –remedy being minor dose during day, major at bed time
• pseudodepression due to drug induced akinesia –remedy being anti-parkinsonism drugs
• toxic confusional state because of muscarinic blockage.

a. Early occurring

I. Typical Parkinson’s syndrome

Characterized by:

Rigidity

Hypokinesia

Tremors

Dystonia

The mechanism being blockage of D2 receptors.

Remedy is to use antiparkinson drugs of antimuscarinic type or amantadine.

L-dopa is never used because:

• D2 receptors are already covered by antipsychotic drugs
• Administration of L-dopa will aggravate the symptoms

II. Akathasia

Patient moves his arms all the time.

Remedy is to give sedating antihistamines and anticholinergic property drugs (diphenhydramine) PO or PE.

III. Acute dystonia

Spasm of skeletal muscles especially of face, neck and tongue. i.e.

Spastic torticollis

Spastic retrocollis

Seen in emergencies and outdoor patients.

The cause is that when metoclopramide is taken parentally, it causes spasms.

Remedy is:

1. Withdraw phenothiazines
2. Diphenhydramine
3. Central acting anticholinergics (Benzhexol in tablet form not I/V)

IV. Perioral tremors (rabbit’s syndrome)

Tremors around mouth. These are very rare.

b. Late occurring

I. Tardive dyskinesia

Most important side effect with chronic use. Features include:

1. Slow in onset
2. Choreoathetoid movements
3. Orofacial dyskinesia
4. Protrusion of tongue
5. Smacking of lips
6. Jerky purposeless movements (Quasipurposive) which appear purposeful.

Mechanism

Chronic treatment leads to super sensitivity of dopamine receptors. This increases inhibition of cholinergic neurons, increasing dopaminergic and decreasing cholinergic effects. There is relative deficiency of acetyl choline leading to tardive dyskinesia.

Remedy

Should be prevented because once developed, it is very difficult to treat. Patient is strictly monitored. Drug is stopped if symptoms appear.

Treatment

1. Stop the drug
2. Decrease the dose
3. Switch to newer antipsychotics
4. Diazepam (30-40 mg/day) which increases GABA activity

II. Seizures

Seen with Clozapine and Chlorpromazine.

Mechanism

Antipsychotics decrease the threshold for seizures

Denovo seizures occur in 2% of patients treated with Clozapine.

Remedy is molindone (least likely to cause seizures)

III. Neurolept malignant syndrome

Occurs in patients who are extremely sensitive to extrapyramidal effects of D2 blocking antipsychotics.

Features

1. Marked muscle rigidity
2. Hyperthermia
3. Fever
4. Leukocytosis induced by stress
5. Autonomic instability with altered blood pressure and  pulse rate
6. Increased creatine kinase levels due to muscle damage

Remedy

1. Stop the drug
2. Maintain vitals
3. Muscle relaxants (diazepam)
4. Vigorous treatment of EPS by antiparkinsonism drugs.
5. Dantrolene (directly acting muscle relaxant)
6. Bromocriptine (D2 agonist)
7. Cooling by  physical measures (fever)

IV. ANS

1. Antimuscarinic –switch to less anticholinergic agent
2. Failure of ejaculation
3. Impotence
4. Orthostatic hypotension due to alpha 1 blockage (Chlorpromazine and mesoridazine)

Metabolic

a. Weight gain (newer antipsychotics)

Clozapine and Olanzapine cause increase in weight. Mechanism involved is the blockage of dopamine receptors in medullary periventricular pathways, leading to increased apetite.

b. Hyperglycemia

Weight gain associated insulin resistance

Hyperprolactinemia

D2 blockage causes loss of dopamine mediated inhibition of prolactin secretion.

In women

1. False positive pregnancy tests
2. Decreased libido
3. Infertility
4. Amenorrhea, galactorrhea

In men

1. Loss of libido
2. Impotence
3. Gynaecomastia
4. Infertility

Remedy

1. Dose adjustment
2. Clozapine is safer
3. Olanzapine and quetiapine are safer

Other effects

Increased conversion of androgens to estrogens peripherally.

VII. Ocular Complications

1. Deposits in anterior portion of eye (cornea and lens) –chlorpromazine metabolites deposit in anterior chamber of  eye, leading to browning of vision and aging of lens.
2. Retinal deposits of thioridazines, in advanced cases leading to retinitis pigmentosa and scotomata (blind spot) formation.

Remedy being the daily dose should not exceed 800 mg/day.

VIII. Cardiac toxicity

Among older antipsychotics, thioridiazines cause:

1. In doses >300 mg/day minor abnormalities of T wave
2. In overdoses; ventricular arrhythmias and conduction blockage

Among newer antipsychotics, ziprasidone causes QT prolongation producing torsades de pointes.

Combination of these drugs with others having QT prolongation activity are contraindicated:

1. Pimozide
2. Quinidine
3. Thioridazine should not be combined with ziprasidone

IX.  Hypersensitivity

I. Agranulocytosis

Most common adverse effect of Clozapine therapy, develops between 6^th and 18^th weeks (in 1-2% of patients). This is due to hypersensitivity reactions producing leucopoenia and disturbance in other blood cells, leading to agranulocytosis.

Prevention includes blood counts every week for first 6 months and every 3 weeks thereafter.

II. Cholestatic jaundice

Due to hypersensitivity reactions, obstruction of bile duct occurs, leading to jaundice.

III. Skin rashes

Photosensitive dermatitis

X. Teratogenicity

Dysmorphogenesis

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