Drugs for Schiezophrenia by Rebira Workineh.pptx

WALLAGA UNIVERSITY
INSTITUTE OF HEALTH SCIENCE
DEPARTMENT OF NURSING
PROGRAM OF MSC FOR AHN
INDIVIDUALASSIGNMENT OF ADVANCED CLINICAL PHARMACOLOGY
TITLE: PHARMACOLOGY OF SCHIZOPHRENIA
SET BY: REBIRA WORKINEH
APRIL, 2023
NEKEMTE, ETHIOPIA
19/4/2024 Set by: Rebira W. 1

Pharmacology of Schizophrenia
Student Name ID No
Rebira Workineh WU1500418
Instructor: Mr. Tekle. D. (Assistant Professor)
April, 2023
Nekemte, Ethiopia

Outlines
Introduction
Symptoms of schizophrenia
Dopamine system
Drugs used in schizophrenia
Classification of antipsychotics
Indication
Mechanism of actions

Outlines
Pharmacological action of antipsychotics
Therapeutic uses of antipsychotics
Adverse effects of antipsychotics
Common typical antipsychotics
Common atypical antipsychotics
Summary
References

Introduction
Schizophrenia
Is one of the most important forms of psychiatric illness.
 Is a chronic psychotic illness which affects people during late
adolescence or early adulthood.
Schizophrenia has strong genetic component and probably due to
biochemical abnormality that is dysfunction of dopaminergic neurons.
There is some evidence for involvement of 5-HT pathways.

…
Schizophrenia is a thought disorder characterized by divorcement from reality in
mind of patient.
It may involve hallucinations, delusions , intense suspicion, paranoia (felling of
persecution or control by external forces).
Patients with schizophrenia have problems with seeing things, hearing voices,
imagining things, and having terrifying thoughts are positive symptoms
Apathy, blunted emotions, anhedonia and reduced ability to react with people, i.e.
social withdrawal are negative symptoms.

…

Symptoms of Schizophrenia
Positive Symptoms
Hallucination
Delusion
Thought disturbances
Paranoia
 Feeling of control by external forces
Negative Symptoms
Blunted emotion
Anhedonia
 Absence of pleasure
Social withdrawal
Loss of motivation
Impaired personal hygiene

Dopamine System
Note
 Dopamine is the naturally occurring agonist that interacts with D1 and D2
receptors
 Both of these receptors are found in high density in the corpus striatum
and nucleus accumbens.
 Most striatal neurons have D1 responses and most accumbens neurons have
D2 responses.

…
Schizophrenia has a strong genetic component and probably reflects too
much dopamine activity in the mesolimbic system which is the part of
brain that controls seeing, hearing, imagining, etc.
Drug that increase dopamine may produce psychotic symptoms, for
example, cocaine and amphetamine.
All known antipsychotic drugs capable of treating positive psychotic
symptoms block the dopamine receptors (D2).

…
Dopaminergic pathways in the brain: Four dopamine pathways are there
in the human brain.
Dopamine pathways are used to control movements, overactivity of these
pathways produces delusion and hallucination
Schizophrenia drugs affect all the pathways
Blocking dopamine receptors in mesolimbic pathway is useful.
But, blocking dopamine receptors in the other three may be harmful

…
1. Mesolimbic-mesocortical pathway (behavior)
 Schizophrenia drugs have therapeutic effect only on this pathway
2. Nigrostriatal pathway
 Co-ordination of voluntary movements
3. Tuberoinfundibular pathway
 Endocrine effects
4. Medullary-periventricular pathway
 Metabolic effects

…
 Most of schizophrenia drugs side effects come from blocking D2
receptors in pathways other than mesolimbic-mesocortical.
 If we avoid blocking D2 so, we avoid these side effects
 There are at least five subtypes of dopamine receptors: D1, D2, D3, D4, D5
 D2 is the classical dopamine receptor

…

Drugs Used in Schizophrenia
 Originally tested as an antihistamine & then proposed as anthelminthic
 E.g. chlorpromazine emerged as antipsychotics in the 1950s
 Also known as:
Pharmacology of schizophrenia
Drugs used in schizophrenia
Antipsychotic drugs
Neuroleptic drugs (Its oldest name)

…
Definition
Antipsychotic drugs, which are also known as neuroleptic or anti-
schizophrenic drugs are used mainly to treat schizophrenia, mania, and
depressive psychosis.
Antipsychotic drugs are group of drugs used in the treatment of
schizophrenia.

Classification of Antipsychotics
More than 20 different antipsychotic drugs are available for clinical use,
but with certain exceptions the differences between them are minor
Antipsychotic drugs are broadly classified into two main groups: the
typical ( classical) = First generation and the atypical= Second generation
antipsychotics
Atypical antipsychotic drugs are preferred to as first line treatment because:
 Fewer side effects
Additional benefits for “ negative symptoms of schizophrenia”
Can treat resistant cases

Indication
• For prophylaxis and acute treatment of psychotic illnesses
o Schizophrenia
o Psychoses associated with depression & mania
• Alternative or adjunct to BDZ to manage acutely disturbed patient
o Tranquillization & sedation
• Used short-term in severe anxiety but are now given only as a last resort.
• As antidepressant effect that is different from psychosis-depression
o But, now many options are available for treating depression

Mechanism of Actions
All antipsychotic drugs block D2 receptors in the brain and periphery
The main groups, phenothiazines, thioxanthines and butyrophenones show
preference for D2 over D1 receptors
Some newer agents for example remoxipride is highly selective for D2
receptors
Clozapine is relatively non-selective between D1 and D2 , but has high
affinity for D4.

…
Atypical antipsychotic drugs exert part of their action through blocking
of 5-HT2A receptor.
Antipsychotics take days to weeks to work, suggesting that secondary
effects ( e.g. increase in numbers of D2 receptors in limbic structure)
may be more important than direct effect of D2 receptor block.
Many antipsychotics block other receptors such as acetylcholine (M),
noradrenaline (α1) and histamine (H1).

Typical Antipsychotics
1. Phenothiazine derivatives
 Chlorpromazine
 Prochlorperazine
 Promethazine
 Fluphenazine
 Promazine
 Thioridazine
2. Butyrophenone derivatives
 Haloperidol
 Droperidol, Benperidol
3. Thioxanthines
 Flupentixol, Zuclopenthixol
4. Others
 Pimozide, Loxapine

Atypical Antipsychotics-Better!
Atypical antipsychotics commonly refer to the diminished tendency of some
newer compounds to cause unwanted motor side-effects.
The pharmacological profile of atypical antipsychotics is somewhat different
from that of typical Antipsychotics
Clozapine, Olanzapine, Quetiapine, Risperidone, Ziprasidon, Amisulpride,
Zotepine, Sertindole, Aripiprazole, and etc. are examples of atypical
antipsychotic drugs.

Advantages of Atypical Drugs
 Blocking both dopaminergic & serotonergic receptors
 Effective in refractory cases of schizophrenia
 Less extrapyramidal effects
 Efficacy (particularly clozapine) in treatment of resistant group of
patients
 Efficacy against negative symptoms

Pharmacological Action of Antipsychotics
1. Antipsychotic Effects
Though blocking D2 receptors in the mesolimbic system, antipsychotic
drugs relieve hallucination, improve thoughts.
The additional blocking effects of atypical antipsychotics on 5-HT2A
receptors can treat the negative symptoms of schizophrenia.
2. Autonomic Effects
Anticholinergic effects: dry mouth, urinary retention, constipation and
blurred vision

…
3. Extrapyramidal Effects
Blocking of D2 receptors in the nigrostriatal pathway causes unwanted
parkinsonian-like symptoms, rigidity, and tremors.
Clozapine and risperidone exhibit a low incidence of these symptoms.
4. Antiemetic Effects
Blocking of D2 receptors both centrally in the CTZ of the medulla and
peripherally in the stomach.
This process interrupts the communication between the chemoreceptor trigger
zone and the vomiting center to initiate vomiting.

…
5. Endocrine Effects
Amenorrhea-galactorrhea, false positive pregnancy tests in women
Decreased libido and gynecomastia in men
This is due to blockage of D2 receptors in the pituitary leading to an increase in
prolactin release resulting in hyperprolactinemia
6. Antiadrenergic Effects
Blockage of alpha1-adrenergic receptors results in postural hypotension, impotence,
and failure of ejaculation
NOTE: None of the atypical group causes antiadrenergic effect

…
7. Antipsychotics block H1 receptors causing sedation and constipation.
8. Antipsychotics depress the hypothalamus affecting thermo-regulation resulting in
hypothermia.
Resulted from
Blocking dopamine receptors at different areas in the brain
Blocking muscarinic receptors
Blocking α-adrenergic receptors
Blocking H1 receptors

Therapeutic Uses of Antipsychotics
Pharmacokinetics
Incompletely absorbed
Highly lipid soluble (So it can cross BBB)
Highly bound to plasma proteins
Undergo extensive first-pass hepatic metabolism
Excretion by the kidney
Note: Therapeutic uses of antipsychotics are both psychiatric & non-
psychiatric

…
1. Treatment of schizophrenia
 Typical antipsychotics are the most effective in treating positive symptoms.
 Atypical antipsychotics with serotonin blocking activity are effective in many
patients resistant to the traditional agents, especially in treating -ve symptoms.
2. Treating of other psychotic disorder
 Example mania and mood (bipolar) disorder, depressive psychosis

…
3. Prevention of severe nausea and vomiting
Drug-induced nausea haloperidol
4. Droperidol is used in combination with fentanyl in neuroleptanalgesia
5. Due its antihistaminic effects, promethazine is used in cases of
pruritus and as preoperative sedative.
6. To induce hypothermia in certain major operations – chlorpromazine
7. Chlorpromazine is used to treat intractable hiccough

Adverse Effects of Antipsychotics
Antipsychotic drugs have a wide range of side effects
1. Sedation (Drowsiness) is a common side effect of antipsychotic drugs
2. Movement disorders
 Extrapyramidal side effects are common with the typical antipsychotics
i.e. haloperidol and include dystonia, akathisia, parkinsonian-like
syndrome.
 Treatment- Anticholinergic drugs-benztropine

Extrapyramidal Symptoms ( EPS)
Dopamine versus Acetylcholine
 Dopamine (inhibitory) and acetylcholine (excitatory) have a reciprocal
relationship in the Nigrostriatal pathway.
 A delicate balance allows for normal movement
 Dopamine blockage by antipsychotics result in relative increase in cholinergic
activity causing EPS.
 When high potency antipsychotics are chosen, we often prescribe anticholinergic
medication like benztropine

Tardive Dyskinesia
Is the most important adverse effect of long-treatment with typical drugs
Characterized by excessive movement of lips, tongue, jaw, and limbs
May be irreversible and is postulated to result from increased number of
dopamine receptors that are synthesized in response to long term dopamine
receptor blockage, which leads to neuronal super-sensitivity to dopamine
Atypical drugs have lower incidence of EPS and tardive dyskinesia as they
block 5-HT2A receptors and have less D2 receptors blocking effect

…
3. Autonomic Effects
Orthostatic hypotension-alpha- adrenergic blockage
The concomitant use of antihypertensive agents must be noticed and
anticholinergic adverse effects.
4. Endocrine and metabolic effects
 Hyperprolactemia in the form of galactorrhea, amenorrhea in women,
gynecomastia and changes in libido and impotence in men

…
5. Allergic Reactions
Agranulocytosis is common with clozapine
Cholestasis jaundice and skin eruptions are common with chlorpromazine
6. Ocular Complications
Chlorpromazine may cause retinal pigmentation, corneal and lens opacities
7. Clozapine and chlorpromazine tend to lower an individual’s seizure
threshold.

Neuroleptic Malignant Syndrome
An idiosyncratic: Life-threatening neurological disorder associated with
antipsychotic drugs
Idiosyncrasy is an unusual to a particular food or drug. It is determined
genetically and may be due to a biological deficiency
Clinical manifestation include:
 Encephalopathy, hyperpyrexia, delirium
 Autonomic instability (Vital instability)
 Rigidity of muscles

Common Typical Antipsychotics
1. Chlorpromazine
Phenothiazine class
Increased prolactin-gynecomastia
Hypothermia
Anticholinergic effects
Hypersensitivity reactions
Obstructive jaundice
Ocular complications
High EPS
2. Fluphenazine
Phenothiazine class, but
Causes more EPS
Does not cause jaundice
Causes less hypotension
3. Haloperidol
Butyrophenone class
As chlorpromazine but does not cause
jaundice
Significant anticholinergic side effects
Strong EPS tendency
Hypotension

Common Atypical Antipsychotics
1. Risperidone
 Largely replaces clozapine-no risk of agranulocytosis
 Low incidence of EPS and minimal sedation
 Weight gain
 Approved for the treatment of autism and bipolar depression
2. Aripiprazone
 Is recently approved antipsychotic drug
 Long-acting (plasma half-life = 3 hours)

…
 Unusual D2 partial agonist profile may be account for paucity of s/e.
 No effect on prolactin secretion
 No weight gain
 Less incidence of dystonia and tardive dyskinesia
3. Clozapine
 Benzodiazepine class
 Potent antagonist at D4 receptors

…
 Selectively blocks 5-HT2A receptors
 Sedation
 Minimal EPS
 Low incidence of tardive dyskinesia
 Increased risk for seizure (2-3 %)
 Agranulocytosis in 1%.

…
 Agranulocytosis increases when co-administered with carbamazepine anticonvulsant
and mood stabilizing drug used in the treatment of epilepsy and bipolar disorder.
 Anticholinergic side effects
 Weight gain
 Effective against negative and positive symptoms
 Used in the treatment of resistant patients-more effective than classical agents for
resistant cases
 Lowest cause of EPS and rare tardive dyskinesia

Disadvantage of Atypical Drugs
Clozapine has the risk of inducing agranulocytosis
Clozapine tends to lower an individual’s seizure threshold
Atypical dugs cause weight gain
Atypical drugs may exacerbate diabetes and hyperlipidemia
Are more expensive than typical antipsychotics

Summary
Drugs used in schizophrenia are classified according to chemical structures.
Typical Antipsychotics →affect D2 mainly except cariprazine on D3 → treat
the positive symptoms.
Atypical Antipsychotics are better than typical →Affect both dopamine & 5-
HT2A receptors →treat positive & negative symptoms.
Atypical drugs are effective in refractory cases of schizophrenia-to reduce the
risk of recurrent suicidal behavior

References
1. H.P.Rang, M.M.Dale, J.M.Ritter, & Churchill Livingstone, (2001).
Pharmacology, 4th Edition.
2. T.Brody, J.Larner, K.Minneman, & Mosby, (1998). Human Pharmacology.
Molecular to Clinical, 3rd Edition.
3. B.G.Katzung, (2001). Basic & Clinical Pharmacology. A Lange Medical
Book, 8th Edition.
4. P. N. Bennett, & M. J. Brown, (2003). Clinical Pharmacology, 9th Edition.

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