Antipsychotics

Question 1

Antipsychotics are also known as?

Answer 1

neuroleptics
antischizophrenics drugs
major tranquilisers.

Question 2

Antipsychotics are highly effective in what states?

Answer 2

in excited or agitated psychotic states, including acute episodes of:
1. Schizophrenia
2. Hypomania
3. Delirium

Question 3

What do antipsychotics do?

Answer 3

• generally lower the seizure
  threshold and induce extrapyrimidal effects.
• They exert profound effect on the ANS, hypothalamus, reticular formation and the medulla.
  Note: They do not exhibit an addictive potential or anaesthetic properties

Question 4

Most antipsychotics are?

Answer 4

Dopamine Antagonists (D1 and / or D2)
- have side effects

Question 5

Most antipsychotics block?

Answer 5

5-HT, Histamine, Muscarinic (Ach) and alpha-1 receptors
- have side effects and adverse reactions

Question 6

Side effects due to Blockade of D2 receptor?

Answer 6

1. Parkinsonism like symptoms (Extrapyramidal Effects)
2. Tremor /Rigidity
3. Dystonia (grimacing, spastic limbs, eye rolling upwards)
4. Akathisia (Restless, fidgeting, pacing)
5. Tardive Dyskinesia (face, tongue, jaw movements)
6. Also amenorrhoea ♀, loss of libido ♂

Question 7

Side effects due to Blockade of alpha-1 Receptors?

Answer 7

postural hypotension

Question 8

Side effects due to Blockade of Muscarinic (M) Receptors?

Answer 8

Dry mouth, blurred vision, constipation, urinary retention

Question 9

Side effects due to blockade of Histamine (H) Receptors?

Answer 9

Drowsiness, sedation

Question 10

Dosage of antipsychotics?

Answer 10

• Low doses used initially
• Takes 2-3 weeks for drug to work
• The effects on the psychotic ‘episode’ may take 3 weeks
  > Difficult to determine correct dose for an individual
  -Patient compliance a big problem (mainly from side effects)
  > Depot injections or Syrups available

Question 11

Anti-Psychotic Drug Groups
(Classification)?

Answer 11

1. Typical Anti-Psychotic
2. Atypical Anti-Psychotic

Question 12

Typical antipyschotics?

Answer 12

First generation (Typical) antipsychotics - Newer class of Anti-Psychotics

1. Action
   they produce a blockade of Dopamine D2 receptors AND Selective 5-HT2 antagonism
   Examples
   Chlorpromazine, haloperidol, fluphenazine, flupentixol, Clopentixol
2. Side effects
   Minimal extrapyrimidal side effects BUT In some patients causes death through ‘agranulocytosis’ (lack of white blood cells) Monitor WBC count – very important (Clozapine)

Question 13

Atypical antipyschotics?

Answer 13

Second generation (Atypical) antipsychotics - Large class of anti-psychotics

Side effects
Vary in their side effects
e.g.
1. Chlorpromazine: Low potency
- Adverse Side effects (Sedation & Parkinsonism.)
2. Flupenthixol : Used in depot injections
- Rapid onset
- Long Acting.
- Also anti-depressant properties.
- Adverse side effects (Sedation, Parkinsonism. )

Question 14

Distinction between the two groups rests on?

Answer 14

1. Receptor profile
2. Incidence of extrapyrimidal side effects
3. Efficacy in treatment resistant patients
4. Efficacy against negative symptoms

Question 15

Acrions of chlorpromazine?

Answer 15

1. It blocks noradrenaline, dopamine, serotonin, Ach and histamine receptor sites
2. It has an effect on the endocrine glands
3. It is a standard against which other drugs are compared

Question 16

Pharmacological actions of chlorpromazine?

Answer 16

1. Drowsiness and tendency to fall asleep, but arousal can be achieved with little stimulation.
   - Large doses does not induce anaesthesia.
2. Potentiates depressant action of sedative-hypnotics & anaesthetics.
3. Antagonizes the stimulant effects of amphetamine & related drugs that produce steriotyped behaviour.
4. Potentiates actions of analgesics
5. Produces tiredness, sedation & diminution of emotional responsiveness, with indifference to environmental changes. (Ataractic state)
6. Inhibits the CTZ thus has antiemetic properties

Question 17

CPZ vs hypothalamus?

Answer 17

Inhibits hypothalamic function, thus causes
1. temperature control (hypothermia)
2. increased prolactin release leading to galactorrhea, amenorrhea, delayed menstruation and weight gain

Question 18

CPZ vs receptors?

Answer 18

1. Powerful extrapyramidal effects
2. Blocks muscurinic cholinergic 3. receptors, and produces atropine like effects.
3. Blocks histamine H1 receptors
4. Blocks alpha-adrenoreceptors, which plays a part in the production of postural hypotension., which is also due to central impairement of CVS reflexes.

Question 19

Site and mode of action of CPZ?

Answer 19

• CPZ and other phenothiazines exert a relatively selective action on those parts of the CNS that are concerned with alertness and performance.
• Selectivity is due, in part, to the preferential accumulation in the reticular activating system, limbic system, hypothalamus and thalamus.
• Very small amounts are found in the cerebral and cerebella cortices

Question 20

How CPZ decreases alertness?

Answer 20

The decreased alertness is possibly due to the blockade of input into the reticular formation from collaterals of second - order sensory nerves ascending to the cerebral cortex.
In addition, there is inhibition of activity in thalamic nuclei through which impulses from the reticular formation pass to the cortex producing arousal

Question 21

CPZ has antagonistic activity in the following order of potency?

Answer 21

1. Against alpha-receptor agonists
2. Dopamine
3. Histamine
4. Muscurinic agonists
5. Bradykinin
   Note: It is not clear as to what extent the central effects of CPZ are attributable to any one or a combination of these actions.

Question 22

Name and describe the various effects and their causes that CPZ causes?

Answer 22

1. Tranquilizing action of CPZ is due to blockade of central adrenergic transmission.
2. Antischizophrenic activity is due to blockade of serotoninergic dopaminergic transmission
3. Antiemetic effect and extrapyramidal effects are due to blockade of dopaminergic transmission.

Question 23

Antipsychotic drugs produce two
pharmacological actions?

Answer 23

1. Their ability to improve schizophrenia condition
2. Their ability to evoke extrapyrimidal syndromes

Question 24

Pharmacokinetics of CPZ?

Answer 24

1. Orally well absorbed with a 30% bioavailability. (decreased by the presence of food, anticholinergics or antacids)
2. Peak plasma levels reached in 2-3 hours.
3. Half time varies 2 to 24 hours in different people.
4. Plasma steady state is reached in 1 week.
5. A single night time dose is advisable.
6. CPZ undergoes hepatic metabolism & has 168 metabolites by:
7. Demethylation producing active nor1 & nor2 chlorpromazine which are sedative.
8. Oxidation producing inactive sulphoxides and N-oxides.
9. Hydroxylation producing 3-hydroxy and 7-hydroxychlorpromazine and the latter is implicated in skin pigmentation and has more antipsychotic properties than the parent compound.
10. Toxicity is observed at concentrations above 600mg/ml.
11. The rate of excretion is slow.

Question 25

Therapeutic uses of CPZ?

Answer 25

1. Schizophrenia, Mania, Anxiety neurosis, Huntingtons disease 2. Drug induced psychosis 3. Shock, Nausea , Vomiting and Hiccup 4. Withdrawal symptoms 5. Pruritis (itchy skin) 6. Mental retardation 7. Painful terminal illnesses (to reduce emotional response to pain)

Question 26

Adverse effects of CPZ?

Answer 26

- All antipsychotic drugs produce adverse reactions that are extensions of their pharmacological effects. - They are remarkably safe with a wide margin of safety, and overdoses are rarely fatal in adults. - The dose response curve is flat and can be used over a wide dose range

Question 27

Disturbances of the CNS by phenothiazines?

Answer 27

Drowsiness, lethargy & fatigue are common especially in initial therapy

Question 28

Extrapyrimidal effects of phenothiazines?

Answer 28

1. Parkinsonism (tremor & rigidity) 2. Akathesia (aimless motor restlessness) 3. Dystonia (tonic contractions of groups of muscle) 4. Tardive dyskinesia (serious but rare toxicity –faciobucculolinguo-musticatory dyskinesia. Uncontrolled rhythmic, in-&-out movements of the tongue. Spasms of the glottis and respiratory muscle may endanger life 5. Convulsant action They may precipitate epileptyform seizure in susceptible individuals 6. Endocrine effects. These are due to disruption of hypothalamic control over the pituitary, causing suppression of prolactin-inhibitory factor from the hypothalamus, leading to increased blood prolactin levels. (breast enlargement in men – gynaecomastia, & lactation - galactorrhoea in women. 7. False pregnancy tests have also been reported.

Question 29

Disturbances of the ANS function by phenothiazines?

Answer 29

1. Postural hypotension tachycardia (dose related is common during early stages of treatment. 2. Anticholinergic effects Dry mouth, constipation, urinary retention and blurred vision. Tolerence to these side effects may develop and atropine like effects may worsen glaucoma. 3. Nasal congestion. May occur during alpha-adrenoreceptor blockade. 4. Sexual function Failure to ejaculate. Libido is decrease in men and increased in women. 5. Temperature control. Temp control of the thalamus goes out of function

Question 30

Non phenothiazine antipsychotics?

Answer 30

1. Butyrophenones – Haloperidol is an effective alternative to phenothiazines. Less sedative to CPZ, but more potent antiemetic and more prone to produce extrapyrimidal effects. 2. Thioxanthines - Chlorprothixane, an analogue of CPZ. Its side effects and pharmacological effects are similar to phenothiazines. 3. Dihydroindolone – Malindone has a long duration of action and its effects are similar to phenothiazines. Extrapyrimidal incidents are lower. 4. Dibenzodiazepines. – Clozapine, a unique antipsychotic because of low incidence of extrapyrimidal. It resembles CPZ

Question 31

Depot Neuroleptics?

Answer 31

- Fatty acid esters of phenothiazines are increasingly being used for the maintenance therapy in schizophrenics. - Single injections may be effective for 2-4 weeks. - The ester link is broken by tissue esterases to release the free drug, which is then absorbed from the site of injection.