. 1 1 Classify antipsychotics & describe mechanism of action of various drugs/group of drugs Describe pharmacokinetics, clinical uses, adverse effects & interactions of typical antipsychotics Outline the neurological adverse effects of typical antipsychotics & their t/t Describe pharmacokinetics, clinical uses, adverse effects & interactions of atypical antipsychotics Write important differences between typical & atypical antipsychotics and mention advantages of atypical antipsychotics over typical antipsychotics Describe drug t/t of schizophrenia & selection of drug in schizophrenia in special situations & with associated disease 2 • Drugs having primary effects on Psyche (mind) and – osis (diseased or abnormal condition) – overall the mental process and used for treatment of Psychiatric disorders 3 Psychiatric illness Psychoses Neuroses (Insight absent) (Insight present) OCD Schizophrenia Affective disorder Phobia Anxiety PTSD Bulimia Mania Depression Bipolar disorder 4 Antipsychotics are used in treating psychoses, mainly Schizophrenia Psychosis means a major psychiatric disorder with loss of insight like Schizophrenia. So, antipsychotics were earlier called as Major tranquilizers. Neurosis means a minor psychiatric disorder with insight intact like anxiety. So, anxiolytics were earlier called as Minor tranquilizers. 5 – Delusion: These are fixed, false beliefs that are outside patient’s culture firmly held. Types – grandeur/persecutory etc. – Hallucinations: Abnormal sensations. It is a sensory perception without a source in the external world. May be visual, auditory, olfactory and tactile etc. – Illusion: It is a mistaken or false interpretation of a real sensory experience 6
Transcript
.
1
1
Classify antipsychotics & describe mechanism of action
of various drugs/group of drugs
Describe pharmacokinetics, clinical uses, adverse
effects & interactions of typical antipsychotics
Outline the neurological adverse effects of typical
antipsychotics & their t/t
Describe pharmacokinetics, clinical uses, adverse
effects & interactions of atypical antipsychotics
Write important differences between typical & atypical
antipsychotics and mention advantages of atypical
antipsychotics over typical antipsychotics
Describe drug t/t of schizophrenia & selection of drug in
schizophrenia in special situations & with associated
disease2
• Drugs having primary effects on Psyche (mind) and
– osis (diseased or abnormal condition) – overall
the mental process and used for treatment of
Psychiatric disorders
3
Psychiatric illness
Psychoses Neuroses
(Insight absent) (Insight present)
OCD
Schizophrenia Affective disorder Phobia
Anxiety
PTSD
Bulimia
Mania Depression Bipolar disorder
4
Antipsychotics are used in treating psychoses, mainly
Schizophrenia
Psychosis means a major psychiatric disorder with
loss of insight like Schizophrenia. So, antipsychotics
were earlier called as Major tranquilizers.
Neurosis means a minor psychiatric disorder with
insight intact like anxiety. So, anxiolytics were
earlier called as Minor tranquilizers.
5
– Delusion: These are fixed, false beliefs that are outside patient’s culture firmly held. Types –grandeur/persecutory etc.
– Hallucinations: Abnormal sensations. It is a sensory perception without a source in the external world. May be visual, auditory, olfactory and tactile etc.
– Illusion: It is a mistaken or false interpretation of a real sensory experience
6
.
2
False Belief Delusion of Persecution
7
Pic. 1 Pic. 2
8
Little Voice Inside My Brain.
9
The real shadow of the hallucinating person transforms into the corporal image.
10
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.
11
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine
12
.
3
SCHIZOPHRENIA
13
SCHIZOPHRENIA IS FOR LIFE
There is no remission
14
DOPAMINERGIC SYSTEM:
There are four major pathways for the
dopaminergic system in brain :
I. The Nigro-Striatal Pathway
II. The Mesolimbic Pathway
III. The Mesocortical Pathway
IV. The Tuberoinfundibular Pathway
15 16
Schizophrenia results from excess activity of
dopamine neurotransmission in Mesolimbic and
Mesocortical Pathways because:
➢ All antipsychotic drugs block dopamine receptors.
➢ Higher levels of dopamine receptors measured in brains
of schizophrenics by PET.
➢ Stimulant drugs which act through dopamine can
produce schizophrenic-like behavior
(eg.amphetamines).
17
➢ Dopaminergic activity in the brain
➢ Drugs ing dopaminergic activity cause psychosis
e.g. Levodopa
➢ Drugs ing dopaminergic activity treat psychosis
e.g. Dopamine receptors blockers like
Chlorpromazine
➢ But drugs ing dopaminergic activity cause
Parkinsonism & other extrapyramidal side-effects
➢ Not seen with the newer antipsychotics.
18
.
4
19
POSITIVE
SYMPTOMS:
➢ Delusions
➢ Hallucinations
➢ Combativeness
➢ Insomnia
20
NEGATIVE SYMPTOMS:
➢ Affective Flattening
(blunt)
➢ Alogia
➢ Avolition
➢ Amotivation
➢ Apathy
➢ Asocial Behavior
21
DISORGANIZED
SYMPTOMS:
➢ Disorganized
thought, speech,
behavior.
➢ Poor Attention.
22
23
More
Anti-psychotic Drugs
(Neuroleptics)
Butyrophenones
Haloperidol
Trifluperidol
Penfluridol
Thioxanthenes
Flupenthixol
Newer Atypical
Antipsychotics
•Risperidone
•Ziprasidone
•Clozapine
•Olanzapine
•Quetiapine
•Aripiprazole
Older Typical
AntipsychoticsLess
Extrapyramidal
Side-effects
Phenothiazines Other drugs (High potency)
Aliphatic
(Low potency)
Chlorpromazine
Triflupromazine
Piperazines
(High potency)
Trifluperazine
Fluphenazine
Piperidines
(Medium potency)
Thioridazine
Others
Pimozide
Loxapine24
.
5
Distinction between ‘typical’ and ‘atypical’
groups is not clearly defined, but rests on:
➢Incidence of extrapyramidal side-effects (less
in ‘atypical’ group)
➢Efficacy in treatment-resistant group of
patients
➢Efficacy against negative symptoms.
25 26
➢ There are many type of DA-receptors.
➢ The antipsychotic drugs probably owe their
therapeutic effects mainly to blockade of D2
receptors.
➢ The main groups, phenothiazines, thioxanthines
and butyrophenones, show preference for D2 over
D1 receptors; whereas clozapine is relatively non-
selective between D1 and D2, but has high
affinity for D4.
27
DOPAMINE RECEPTORS
Receptor 2nd Messenger System
D1 ↑cAMP
D2 ↓cAMP,↑K+ ch.,↓Ca2+ch.
D3 ↓cAMP, ↑K+ ch., ↑Ca2+ch.
D4 ↓cAMP
D5 ↑ cAMP
28
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.
29
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
30
.
6
Differ in Normal and psychotic individuals
In Normal: (Neuroleptic syndrome)
Effects are appreciated as neutral or unpleasant
(different from typical Barbiturate action)
Indifference to surroundings, paucity of thoughts,
psychomotor slowing, emotional quietening, and
tendency to go off to sleep (easily aroused)
Minimized spontaneous movements, but no ataxia or
slurring of speech
31
In psychotics:
Typical Psychotic patients – less agitated, more communicative and responsive
Aggressive and impulsive behavior diminishes
Over a period of days – hallucinations/delusions and others come to normal
Neuroleptics – emotional quietening with neurological effects – tremor, rigidity, bradykinesia etc.
Ataxia and dysarthria do not develop in normal doses
32
All phenothiazines, Butyrophenones and Thioxanthenes have same antipsychotic efficacy – but potency differs in equieffective doses Low potency (Aliphatic and piperidines) and high
Dose reduction or central anticholinergics Rabbit syndrome – years after therapy
Acute muscular dystonia (acute onset- within hrs) –grimacing, tongue thrusting, torticollis and locked jaw etc. – initial therapy – resolve spontaneously
Akathisia (1-8 weeks, m.common EPS): 20% cases-restlessness, agitation, compulsive desire to move about
Anticholinergics/Propranolol - stoppage
Tardive dyskinesia: constant chewing, pouting, lip licking etc. – accenuated by anticholinergics –uncommon with newer ones
Malignant neuroleptic syndrome – Rare, high doses of potent agents – rigidity, tremor, immobility, semiconsciousness, fluctuation in BP and Myoglobinemia – must stop, Dantrolene
42
.
8
43 44
6. Weight gain: risk of diabetes worsening – clozapine,
less with Haloperidol. Blue pigmentation of exposed
skin, lenticular opacities and degeneration
7. Hypersensitivity reactions:
Cholestatic jaundice – common with CPZ
Skin rash, urticaria, photosensitivity etc.
Agranulocytosis – clozapine
Myocarditis - clozapine
45
1. Approximately one-third of patients with
schizophrenia fail to respond
2. Limited efficacy against Negative symptoms
3. High proportion of patients relapse
4. Side effects and compliance issues
5. Atypical/New generation Antipsychotics are
preferred for the treatment of various
psychotic disorders.
46
47
➢ Effective in treating some patients with psychosisunresponsive to standard neuroleptic drug.
➢ 1st FDA approved drug for anti-suicide indication
➢ Relative high selectivity for D4 and 5-HT2 receptors
➢ Lacks EPS
➢ Must monitor the granulocyte counts due to higherincidence of agranulocytosis and other blooddyscrasias.
➢ Convulsions – dose dependent
➢ Myocarditis – C/I in severe heart disease
➢ Potentially severe ileus & sialorrhea
48
.
9
Cognitive, affective and Motor disturbances –relieved overall
Little improvement in judgment, memory and orientation
Some patients do not respond (90% responds)
Only symptomatic relief, does not remove the cause – lifelong treatment may require
Choices of Drugs: Patient dependent, empirical and guided by presenting symptoms
Individual patients differ in response to different drugs
49 50
Symptoms Drugs
Agitated and violent CPZ, Thioridazine and
Haloperidol
Withdrawn and apathetic Trifluperazine and
Fluphenazine
Negative symptoms Clozapine, Olanzapine,
Risperidone and
Aripiprazole
Mood elevation Haloperidol,
Fluphenazine and
Olanzepine
51
➢ Mania: CPZ or Haloperidol – IM or IV
➢ Organic Brain Syndromes:
➢Not very effective, used as short term therapy in
acute cases to control aggression
➢ Antiemetic and anti-anxiety
➢ Other Uses:
• Potentiation of anaesthetics
• Intractable Hiccough
• Tetanus
• Alcoholic hallucinosis
• Huntington’s disease – DOC is Haloperidol
• Gilles de la Tourette’s syndrome
52
▪ ANTI – Anti emetics
▪ PSY - Psychosis
▪ CHO – Chorea
▪ TIC – Tic disorders ( Gilles de la Tourette
syndrome)
53
Asenapine – used sublingually for
schizophrenia & acute mania
Paliperidone
Iloperidone – AM of Paliperidone. It has less
risk of EPS but causes orthostatic
hypotension & QT interval prolongation
54
.
10
55 56
A Antipsychotic effect in psychotic patients (therapeutic effect).
N Neuroleptic syndrome in normal persons (unpleasant effect).
Neuroleptic malignant syndrome in few persons extremely sensitive to EPS
T Temperature control is disturbed.
I Inhibit CTZ so have an antiemetic effect
P Prolactin release increases – galactorrhoea and gynecomastia.
S Side effects- Extrapyramidal & Autonomic; Extrapyramidal e.g. Parkinsonism, dystonias, akathisia, dyskinesia. Autonomic e.g.anticholinergic, alpha-blocking
Y Yellowness i.e. Cholestatic jaundice by Chlorpromazine
C Convulsions can be caused by Chlorpromazine & Clozapine
Clozapine causes agranulocytosis
H Hiccups not responding to other measures are relieved by Chlorpromazine
O Obesity or weight gain by newer atypical ones like Olanzapine
T Tics of Tourette’s syndrome are relieved by Pimozide
I Itching is relieved because of their antihistaminic effects; Specially Promethazine is used
C Corneal & lens deposits can occur with Chlorpromazine while retinal deposits can occur with Thioridazine
Cardiac arrhythmias can be caused by high doses of Thioridazine and Ziprasidone
