Antipsychotics drug therapy

1. DRUG TREATMENT OF
PSYCHOSIS

2. Psychosis
Psychosis is a thought disorder characterized
by disturbances of reality and perception,
impaired cognitive functioning, and
inappropriate or diminished affect (mood).
Psychosis denotes many mental disorders.
Schizophrenia is a particular kind of psychosis
characterized mainly by a clear sensorium but a
marked thinking disturbance.

3. Psychosis-Producing Drugs
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine

4. Schizophrenia
• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens -
early ‘20s.
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1% of the population worldwide.
• May or may not be present with anatomical
changes.

5. Schizophrenia
• Athought disorder.
• The disorder is characterized by a divorcement
from reality in the mind of the person
(psychosis).
• It may involve visual and auditory hallucinations,
delusions, intense suspicion, feelings of
persecution or control by external forces
(paranoia), depersonalization, and there is
attachment of excessive personal significance to
daily events, called “ideas of reference”.

6. Schizophrenia
Positive Symptoms.
Hallucinations, delusions, paranoia, ideas of reference.
Negative Symptoms.
Apathy, social withdrawal, anhedonia, emotional blunting,
cognitive deficits, extreme inattentiveness or lack of
motivation to interact with the environment.
These symptoms are progressive and non-responsive to medication.

7. Etiology of Schizophrenia
Idiopathic
Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.

8. Etiology of Schizophrenia
Characterized by several structural and
functional abnormalities in the brains of
schizophrenic patients:
1) Enlarge cerebral ventricles.
2) Atrophy of cortical layers.
3) Reduced volume of the basal ganglia.

9. Dopamine Theory of Schizophrenia
Many lines of evidence point to the aberrant
increased activity of the dopaminergic
system as being critical in the
symptomatology of schizophrenia.
There is a greater occupancy of D2 receptors
by dopamine => greater dopaminergic
stimulation

10. Dopamine Theory of Schizophrenia
Dopamine Correlates:
• Antipsychotics reduce dopamine synaptic activity.
• These drugs produce Parkinson-like symptoms.
• Drugs that increase DA in the limbic system cause
psychosis.
• Drugs that reduce DA in the limbic system
(postsynaptic D2 antagonists) reduce psychosis.
• Increased DA receptor density (Post-mortem, PET).
• Changes in amount of homovanillic acid (HVA), a DA
metabolite, in plasma, urine, and CSF.

11. Pharmacodynamics
Anatomic Correlates of Schizophrenia...
Areas Associated with Mood and Thought Processes:
Frontal cortex
Amygdala
Hippocampus
Nucleus accumbens
Limbic Cortex

12. Dopamine Theory of Schizophrenia
Evidence against the Theory?
• Antipsychotics are only partially effective in most
(70%) and ineffective for some patients.
• Phencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in non-
schizophrenic subjects than DA agonists.
• Atypical antipsychotics have low affinity for D2
receptors.
• Focus is broader now and research is geared to
produce drugs with less extrapyramidal effects.

13. Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
I. The Nigro-Stiatal Pathway.
II. The Mesolimbic Pathway.
III. The Mesocortical Pathway.
IV. The Tuberoinfundibular Pathway.

14. THE DOPAMINERGIC SYSTEM

15. Catecholamines
Tyrosine
Tyrosine hydroxylase
L-Dopa
Dopadecarboxylase
Dopamine (DA)
Dopamine hydroxylase
Norepinephrine (NE)
(Noradrenaline)Phenylethanolamine-
 -N-methyltransferase
Epinephrine (EPI)
(Adrenaline)

16. Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine

17. Dopamine System
• DOPAMINE RECEPTORS
– There are at least 5 subtypes of receptors:
– D1 and D5: mostly involved in postsynaptic
inhibition.
– D2, D3, and D4: involved in both pre-and
postsynaptic inhibition.
D2: the predominant subtype in the brain:
regulates mood, emotional stability in the limbic
system and movement control in the basal
ganglia.

20. Dopamine Reuptake System

22. Antipsychotic treatments
SCHIZOPHRENIA IS FOR LIFE
There is no remission

23. Antipsychotic treatments
Schizophrenia has been around perhaps, since the
beginning of humankind, however, it was not until
the last century that it was established as a
separate entity amongst other mental disorders.
Many treatments have been devised:
 Hydrotherapy:
“The pouring of cold water in a stream, from a height of
at least four feet onto the forehead, is one of the most
certain means of subsiding violent, maniacal excitement
that we have ever seen tried”... wrote an anonymous
physician in the early 1800’s.

24. Antipsychotic treatments
 Lobotomies (EgazMoniz).
 In 1940’s Phenothiazenes were isolated and were
used as pre-anesthetic medication, but quickly
were adopted by psychiatrists to calm down their
mental patients.
 In 1955, chlorpromazine was developed as an
antihistaminic agent by Rhône-Pauline Laboratories
in France. In-patients at Mental Hospitals dropped
by 1/3.

25. Antipsychotics treatment
Antipsychotics/Neuroleptics
• Antipsychotics are the drugs currently used in
the prevention of psychosis.
• They have also been termed neuroleptics,
because they suppress motor activity and
emotionality.
** These drugs are not a cure **
• Schizophrenics must be treated with
medications indefinitely, in as much as the
disease in lifelong and it is preferable to
prevent the psychotic episodes than to treat
them.

26. Antipsychotics/Neuroleptics
Although the antipsychotic/neuroleptics are drugs
used mainly in the treatment of schizophrenia,
they are also used in the treatment of other
psychoses associated with depression and
manic-depressive illness, and psychosis
associated with Alzheimer’s disease. These
conditions are life-long and disabling.

27. Antipsychotics/Neuroleptics
NON-compliance is the major reason for relapse.

28. Antipsychotic/Neuroleptics
Three major groups :
1) Phenothiazines
2) Thioxanthines
3) Butyrophenones
OLDER DRUGS

29. Antipsychotics/Neuroleptics
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
• Old antiphsychotics
/neuroleptics are D2
dopamine receptor
antagonists.
Although they are
also effective
antagonists at ACh,
5-HT, NE receptors.
dopamine
receptor
antagonist
D2

30. Antipsychotics/Neuroleptics
• It appears that the specific interaction of
antipsychotic drugs with D2 receptors is
important to their therapeutic action.
• The affinities of most older “classical” agents
for the D2 receptors correlate with their
clinical potencies as antipsychotics.

31. Antipsychotic/Neuroleptics
Correlations between therapeutic potency
and affinity for binding D2 receptors.
Clinical dose of drug [mg d-1]
haloperidol
clozapine
thiothixene
chlorpromazine
promazine
spiroperidole

32. Antipsychotics/Neuroleptics
• Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus
accumbens.
• Clozapine has a higher affinity for the D4 receptors
than for D2.
• Recently it has been found that most antipsychotic
drugs may also bind D3 receptors (therefore, they
are non-selective).

33. Antipsychotics/Neuroleptics
• Antipsychotics produce catalepsy (reduce motor
activity).
– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
• Antipsychotics reverse hyperkinetic behaviors
(increased locomotion and stereotyped behavior).
– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
• Antipsychotics prevent the dopamine inhibition of
prolactin release from pituitary.
– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia

34. Pharmacokinetics
Absorption and Distribution
• Most antipsychotics are readily but incompletely
absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-65%.
• Most are highly lipid soluble.
• Most are highly protein bound (92-98%).
• High volumes of distribution (>7 L/Kg).
• Slow elimination.
**Duration of action longer than expected, metabolites are present
and relapse occurs, weeks after discontinuation of drug.**

35. Pharmacokinetics
Metabolism
• Most antipsychotics are almost completely
metabolized.
• Most have active metabolites, although not
important in therapeutic effect, with one
exception. The metabolite of thioridazine,
mesoridazine, is more potent than the parent
compound and accounts for most of the
therapeutic effect.

36. Pharmacokinetics
Excretion
• Antipsychotics are almost completely metabolized
and thus, very little is eliminated unchanged.
• Elimination half-lives are 10-24 hrs.

37. Antipsychotic/Neuroleptics
1) Phenothiazines
ChlorpromazineThioridazineFluphenazine
TrifluopromazinePiperacetazinePerfenazine
MesoridazineAcetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
• Aliphatic PiperidinePiperazine*
* Most likely to cause extrapyramidal effects.

38. Antipsychotic/Neuroleptics
[Drug dose]
Piperazine
Aliphatic
Piperidine

39. Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
Closely related to phenothiazines

40. Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*
*Not marketed in the U.S.

41. Antipsychotic/Neuroleptics
[Drug dose]
Phenothiazine
Thioxanthene
Butyrophenone

42. Antipsychotics/Neuroleptics
• Newer drugs have higher affinities for D1, 5-
HT or -AR receptors.
• NE, GABA, Glycine and Glutamate have also
been implicated in schizophrenia.

43. Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why
their therapeutic effects are not evident until 4-8
weeks of treatment.
Blockade of D2 receptors

Short term/Compensatory effects:
 Firing rate and activity of nigrostriatal and
mesolimbic DA neurons.
 DA synthesis, DA metabolism, DA release

44. Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 receptors

Compensatory Effects
 Firing rate and activity of nigrostriatal and mesolimbic DA
neurons.
 DA synthesis, DA metabolism, DA release.
Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.

Receptor Supersensitivity

45. Antipsychotic/Neuroleptics
Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Ziprasidone
Olindone
Newer Drugs

46. Antipsychotic/Neuroleptics
ClinicalEx. Py.
Drug Potency toxicity Sedation Hypote.
Chlorpromaz. Low Medium Medium High
Haloperidol High Very High Very High Low
Thiothixene High Medium Medium Medium
Clozapine Medium Very low Low Medium
Ziprasidone Medium Very Low Low Very low
Risperidone High Low Low Low
Olanzapine High Very Low Medium Very low
Sertindole High Very Low Very low Very Low

47. Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2= D2>D1 >M>2
Haloperidol: D2>D1= D4>1>5-HT2 >H1>M = 2
Clozapine: D4 = 1>5-HT2 = M>D2 = D1 = 2;H1
Quetiapine: 5-HT2 = D2 = 1 = 2; H1
Risperidone: 5-HT2 >>1 >H1 >D2 >2>>D1
Sertindole: 5-HT2>D2=1

48. Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect
2) Significant toxicity
a) Parkinson-like symptoms
b) TardiveDyskinesia (10-30%)
c) Autonomic effects
d) Endocrine effects
e) Cardiac effects
3) Poor Concentration

49. The Nigro-Striatal Pathway
Inhibition
of
Motor Activity
DA
neuron ACh
neuron
GABA
neuron
GABA
neuron
Substantia
Nigra
+
-
-
-
-
Striatum

50. Antipsychotic/Neuroleptics
 Some antipsychotics have effects at
muscarinicacetylcholine receptors:
• dry mouth
• blurred vision
• urinary retention
• constipation
Clozapine
Chlorpromazine
Thioridazine

51. Antipsychotic/Neuroleptics
 Some antipsychotics have effects at -
adrenergic receptors:
• orthostatic hypotension
Chlorpromazine
Thioridazine
 Some antipsychotics have effects at H1-
histaminergic receptors:
• sedation
Risperidone
Haloperidol

52. Antipsychotic/Neuroleptics
 Blockade of D2 receptors in lactotrophs
in breast increase prolactin
concentration and may produce breast
engorgement and galactorrhea.

53. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Is a rare but serious side effect of neuroleptic
(antipsychotic) therapy that can be lethal. It
can arise at any time in the course of
treatment and shows no predilection for age,
duration of treatment, antipsychotic
medication, or dose.

54. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
• Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
• Due to excessively rapid blockade of postsynaptic
dopamine receptors.
• The syndrome begins with marked muscle rigidity.
• If sweating is impaired, a fever may ensue. The
stress leukocytosis and high fever associated with
this syndrome may be mistaken for an infection.
• Autonomic instability with altered blood pressure
and heart rate is another midbrain manifestation.
• Creatinekinaseisozymes are usually elevated,
reflecting muscle damage.

55. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Treatment
Vigorous treatment with antiparkinsonian drugs is
recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or
bromocriptine may be helpful.

56. Antipsychotic/Neuroleptics
Drug Interactions
• Additive effects with sedatives.
• Additive effects with anticholinergics.
• Additive effects with antihistaminergics.
• Additive effects with -AR blocking drugs.
• Additive effects with drugs with quinidine-like
action (thioridazine).