1. Pharmacology Section 10 Neuroleptic Drugs
Pharmacology Section 10 Neuroleptic Drugs. Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz

2. Neuroleptic Drugs = antischizophrenic drugs, antipsychotic drugs or major tranquilizers

3. Schizophrenia

4. Psychosis denotes many mental disorders.
What is the difference?
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
Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance.

5. Schizophrenia
Schizophrenia is characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self

6. Prevalence of schizophrenia
1.1% population over the age of 18
51 mln people worldwide suffer from schizophrenia
12 million people in China (a rough estimate based on the population)
8.7 million people in India (a rough estimate based on the population)
2.2 million people in USA
285,000 people in Australia
Over 280,000 people in Canada
Over 250,000 diagnosed cases in Britain

8. Etiology of Schizophrenia
Idiopathic
Biological Correlates
Genetic Factors
Neurodevelopmental abnormalities.
Environmental stressors.

9. The risk of getting schizophrenia

10. 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.

11. There are 4 major pathways for the dopaminergic system in the brain:
The mesolimbic pathway
from substantia nigra to limbic system, functions of memory, emotion, arousal, and pleasure
The mesocortical pathway
from substantia nigra to neocortex, cognition, social behavior, planning, problem solving, motivation, and reinforcement in learning
The nigrostriatal pathway
from the substantia nigra to the striatum, coordination of involuntary movement
The tuberoinfundibular pathway
from the hypothalamus to the pituitary gland, secretion of certain hormones (prolactin)

12. THE DOPAMINERGIC SYSTEM

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

14. Dopamine Synapse Tyrosine Tyrosine L-DOPA DA
The synapse and synaptic neurotransmission
Describe the synapse and the process of chemical neurotransmission. Indicate how vesicles containing a neurotransmitter, such as dopamine (the stars), move toward the presynaptic membrane as an electrical impulse arrives at the terminal. Describe the process of dopamine release (show how the vesicles fuse with the presynaptic membrane). Once inside the synaptic cleft, the dopamine can bind to specific proteins called dopamine receptors (in blue) on the membrane of a neighboring neuron. Introduce the idea that occupation of receptors by neurotransmitters causes various actions in the cell; activation or inhibition of enzymes, entry or exit of certain ions.

15. Dopamine receptors
There are at least five subtypes of receptors:
D1, D5 dopamine receptors -  cAMP by activation of adenylyl cyclase
D1 – putamen, nucleus acumbens
D5 – hypothalamus, hippocampus
D2, D3, D4 dopamine receptors -  cAMP by inhibition of adenylyl cyclase, inhibits Ca2+ channels and open K+ channels
D2 – caudate–putamen, nucleus acumbens
D3 – frontal cortex, medulla, midbrain

16. Dopamine and the production of cyclic AMP
When dopamine binds to its receptor, another protein called a G-protein (in pink) moves up close to the dopamine receptor. The G-protein signals an enzyme to produce cyclic adenosine monophosphate (cAMP) molecules (in green) inside the cell. [Sometimes the signal can decrease production of cAMP, depending on the kind of dopamine receptor and G-protein present.] Point to the dopamine receptor-G-protein/adenylate cyclase complex, and show how cAMP is generated when dopamine binds to its receptor. Indicate that cAMP (point to the cyclic-looking structures) controls many important functions in the cell including the ability of the cell to generate electrical impulses.

17. The dopamine hypothesis (1):
Most antipsychotic drugs strongly block postsynaptic D2 receptors in the CNS (meso- limbic system)
Drugs that increase dopaminergic activity aggravate schizophrenia and produce psychosis de novo
Increased dopamine receptor density has been found post mortem in brains of schizophrenics

18. The dopamine hypothesis (2):
PET has shown increased dopamine receptor density in schizophrenics
Successful treatment of schizophrenics changes the amount of homovanilinic acid – metabolite of dopamine in cerebrospinal fluid, plasma and urine.

19. SCHIZOPHRENIA Dysfunction of DA-ergic system:
Hyperactivity of DA system
(mesolimbic pathway)
Hypo-activity in frontal cortex (mesocortical pathway)
Dysfunction of 5-HT, GABA and glutamate –ergic systems

20. Onset of schizophrenia
Onset - early adulthood, between the ages of 15 and 25.
Men tend to develop schizophrenia slightly earlier (16 – 25 years old) than women (25 – 30 years old).
The average age of onset is 18 in men and 25 in women

21. The Course of Schizophrenia

22. Early intervention and early use of new medications lead to better medical outcomes for the individual
The earlier someone with schizophrenia is diagnosed and stabilized on treatment, the better the long-term prognosis for their illness
Teen suicide is a growing problem and teens with schizophrenia have approximately a 50% risk of attempted suicide
Anti-psychotic medications are the generally recommended treatment for schizophrenia !!!
If medication for schizophrenia is discontinued, the relapse rate is about 80 percent within 2 years. With continued drug treatment, only about 40 percent of recovered patients will suffer relapses.

23. Outcomes of schizophrenia After 30 years of diagnosed schizophrenia
25% Completely Recover
35% Much Improved, relatively independent
15% Improved, but require extensive support network
10% Hospitalized, unimproved
15% Dead (Mostly Suicide)

24. Symptoms of schizophrenia (1):
Positive
appear to reflect an excess or distortion of normal functions:
* delusions (paranoid, reference, somatic, delusions of grandeur)
* halucinations (visual, auditory, tactile, olfactory, gustatory)
* disorganized speech = „word salad”
*disorganized or catatonic behavior
Negative
appear to reflect a diminution or loss of normal functions:
* lack of emotion * low energy
* affective flattening * low motivation
*inappropriate social skills * alogia

25. The terms "positive" and "negative" may be confusing
The terms "positive" and "negative" may be confusing. They should not be interperated as "good" and "bad" symptoms.

26. Symptoms of schizophrenia (2):
Cognitive
disorganized thinking
slow thinking
difficulty in understanding
poor concentration
poor memory
difficulty with expressing thoughts
difficulty with integrating thoughts, feelings and behavior

27. Symptoms of schizophrenia (3):
Disorganized symptoms (?)
* thought disorder
* confusion
* disorientation
* memory problems
Disorganized symptoms may reflect an underlying dysfunction common to several psychotic disorders, rather than being unique to schizophrenia.

28. Hallucinations and delusions are prominent symptoms
Schizophrenia
Active phase
Hallucinations and delusions are prominent symptoms
Residual phase

29. U.S. diagnostic criteria for schizophrenia (1)
A. Characteristic symptoms: ≥2 during a 1- month period :
delusions
halucinations
disorganized speech
disorganized behavior
negative symptoms

30. U.S. diagnostic criteria for schizophrenia (2)
Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or two or more voices conversing with each other.

31. U.S. diagnostic criteria for schizophrenia (3)
B. Social/occupational dysfunction
work
interpersonal relations
self-care
C. Duration
continuous signs of the disturbance persist for at least 6 months, including 1 month of symptoms from Criterion A and prodromal symptoms)

32. U.S. diagnostic criteria for schizophrenia (4)
D. Schizoaffective and mood disorder exclusion
no major depressive, manic or mixed episodes have occurred with the active-phase symptoms
E. Substance/general medical condition exclusion
F. Relationship to a pervasive developmental disorder

33. Types of schizophrenia
Paranoid schizophrenia
Disorganized schizophrenia (hebephrenic)
Catatonic schizophrenia
Residual schizophrenia
Schizoaffective disorder
Undifferentiated schizophrenia

34. Neuroleptic drugs ANTI-PSYCHOTIC DRUGS TYPICAL NEUROLEPTICS ATYPICAL
PHENOTHIAZINES
THIOXANTHENES
BUTYRO-PHENONES
BENZISOXAZOLES
DIBENZO-
DIAZEPINES

35. Phenothiazines Chlorpromazine Fluphenazine Prochlorperazine
Promethazine
Thioridazine

36. Other groups of typical neuroleptics
Thioxanthene
Thiothixene
Butyrophenone
Haloperidol

37. Typical neuroleptics – mechanism of action

38. Mechanisms of Action of Antipsychotics
conventional antipsychotics
D2 receptor blockade of postsynaptic in the mesolimbic pathway
atypical antipsychotics
D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms;
enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms;
other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia

39. Atypical neuroleptics
Benzisoxazoles
Risperidon
Ziprasidon
Dibenodiazepines
Clozapine
Quetiapine
Olanzapine

40. Atypical neuroleptics - mechanism of action

41. What is the clinical difference between older and newer drugs?
New antipsychotic drugs has been shown to be more effective than older ones for treating negative symptoms

42. Actions of neuroleptic drugs (1)
Dopamine receptor
all, particularly: haloperidol, fluphenazine, thiothixene
Muscarinic receptor
thioridazine, chlorpromazine
 - Adrenergic receptor
chlorpromazine
Serotonin receptor
risperidone, clozapine
H1 - Histamine receptor
promethazine, chlorpromazine

43. Actions of neuroleptic drugs (2)
Antipsychotic actions:
reduce the halucinations
reduce spontaneous physical movement
Occur after 4 – 6 weeks of treatment
Extrapyramidal effects:
Parkinsonian symptoms
akathisia
tardive dyskinesia

44. Actions of neuroleptic drugs (3)
Antiemetic effect (exept thioridazine)
Antimuscarinic effect:
blurred vision, dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle
Other effects:
hypotension, lightheadness

45. Neuroleptic drugs are not curative and do not eliminate the fundamental thinking disorder, but often do permit the psychotic patient to function in a supportive environment

46. Therapeutic uses Schizophrenia Other psychosis
Schizoaffective disorders
Delirium
Prevention of severe nausea and vomiting (vertigo, motion sickness, cancer chemo- and radiotherapy)
Tranquilizers
In combination with narcotic analgesics for treatment of chronic pain with severe anxiety
Intractable hiccups

47. Pharmacokinetics Neuroleptics are absorbed after oral administration
Pass through blood – brain barrier
Bind well to plasma proteins, highly lipid-soluble
Are metabolized in liver by P-450 system

48. Adverse effects (1) Neurologic effects due to D2 receptor blockade
Acute
Acute dystonia
Medium- term
Akathisia
Parkinsonism
Chronic
Tardive dyskinesia
Tardive dystonia

49. Fixed muscle postures with spasm:
Acute dystonia
In the beginning of treatment
Common in young males
Treatment with anticholinergic drugs (procyclidine 5-10mg or benztropine i.m or i.v)
Fixed muscle postures with spasm:
clenched jaw muscles
protruding tongue
opisthotonos
torticollis
oculogyric crisis
(mouth open, head back, eyes staring upwards)

50. Akathisia motor restlessness affect lower limb
very distressing to the patient
Treatment – reduction of the drug dose.

51. Parkinsonism induced by blockade of D2 receptors in the striatum !!!
appear after a few days to weeks
Treatment:
anticholinergic drugs (e.g procyclidine)
reduction of dose
switching to an atypical antipsychotic

52. Tardive dystonia specific movements of the head, neck and trunk.
Tardive dyskinesia orofacial dyskinesia -lip smacking and tongue rotating.
Tardive dystonia specific movements of the head, neck and trunk.
Appear after months to years of drug treatment
Clozapine and Risperidone have a low potential for causing extrapyramidal symptoms and lower risk of tardive dyskinesia
There is no effective treatment !!! They are irreversible.

53. Adverse effects (2):
Anticholinergic effects due to muscarinic blockade:
loss of accomodation, dry mouth, blurred vision, constipation, urinary retention
Ortostatic hypotension due to -adrenergic blockade
Neuroendocrine adverse effects due to D2 blockade in the tuberoinfundibular pathway :
Amenorrhoea-galactorrhoea
Infertility
Impotence, Failure to ejaculate
Drowsiness
Weight gain,
Urticaria, dermatitis, rashes, dermal photosensitivity

54. Adverse effects of clozapine
Bone marrow suppression
Cardiovascular side effects
Diabetes
Adverse effects of chlopromazine
Cholestatic jaundice

55. Neuroleptic Malignant Syndrome
Precise pathophysiology unknown – deranged dopaminergic function ?
It is an idiosyncratic reaction that appears from a few days to weeks after beginning treatment, but can occur anytime.
The mortality – 20% in untreated (bromocriptine – D1/D2 agonist; dantrolene – sceletal muscle relaxant; supportive treatment)

56. Neuroleptic Malignant Syndrome (NMS)
Hyperthermia
Muscle rigidity
Autonomic instability
Fluctuating consciousness
Mortality due to renal failure caused by rhabdomyolysis.

57. Interactions of neuroleptics
Additive effects:
sedatives
 - adrenoreceptor – blocking drugs
anticholinergic drugs
quinidine-like action (thioridazine, ziprasidone)

58. Contraindications Alcohol abuse Seizure disorders (Chlorpromazine)
Epilepsy
Agranulocytosis (Clozapine)

59. Neuroleptics overdose
Rarely fatal
Drowsiness proceeds to coma, with intervening period of agitation
Increased muscular excitability may lead to convulsions
Decreased deep tendon reflexes
Ventricular tachyarrhythmias
Gastric lavage !!!

60. Dosage of neuroleptic drugs
Antipsychotics may be given in divided daily doses initially while effective dosage level is being sought.
2 or more episodes of schizophrenia – therapy for 5 years
Fluphenazine and haloperidol i.m.  slow release drugs (up to 3 weeks)