2. Psychiatric disorders
1. Psychosis
Sever psychiatric disorder with distortion of;
Behavior
Thought
Capacity to recognize reality
Perception (delusions & hallucinations)
2
3. 2. Neurosis
Abnormal behavior that the patient knows but unable to
correct
A mental or personality disturbance not attributable to any
known neurological or organic dysfunction;
Anxiety/generalized
Phobias
Obsessive compulsive
Reactive depression
Post traumatic stress
Psychiatric disorders
3
4. Psychiatric disorders
3. Affective disorders
I. Mania
• Elation or irritable mood, reduced sleep, hyperactivity,
uncontrollable thought & speech
II. Depression
• Sadness, loss of interest & pleasure, worthlessness, guilt, physical
& mental slowing, melancholia, self destructive idea
III. Bipolar (manic depressive)
• Cyclic occurrence of manic & depressive phases
4
7. Anti-psychotics are those drugs that primarily affect psyche
(mental process) & useful in psychiatric disorders
Are used to produce calmness or tranquility in patients with
schizophrenia and other psychiatric disorders
Antipsychotics
7
8. One particular kind of psychosis
Geek words: Skhizo (to split) & Phern (mind) which
means the split between the emotions & the intellect
Clinical presentations have two components
-Positive symptoms
-Negative symptoms
Schizophrenia
8
9. Symptoms of Schizophrenia
Positive symptoms: the presence of inappropriate behaviors
- Delusions: thoughts
- Hallucinations: auditory >>> visual > other
- Disorganized talking
- Movements
Negative symptoms: the absence of appropriate behaviors
- Flat affect: joy, anger, disgust
- Anhedonia; without pleasure
- Catatonia: waxy flexibility
9
10. 10
Cognitive symptoms: Some patients, the cognitive symptoms of schizophrenia
are subtle, but for others, they are more severe and patients may notice changes in
their memory or other aspects of thinking.
Symptoms include:
- Poor “executive functioning” (the ability to understand information and use it
to make decisions)
- Trouble focusing or paying attention
- Problems with “working memory” (the ability to use information immediately
after learning it)
Symptoms of Schizophrenia
11. Schizophrenia
A group of severe disorders characterized by atypical:
1. Cognition
2. Behavior
3. Emotions
NOT Multiple Personality Disorder
11
12. Etiology & Pathogenesis
1.Genetic & environmental factors
• Number of susceptibility genes are identified which show strong
but incomplete hereditary tendency (gene for neuregulin-1, a gene involved
with synaptic development and plasticity, with effects on NMDA receptor expression.
• Transgenic mice that underexpress neuregulin-1 show a phenotype resembling human schizo
phrenia in certain respects).
• Some environmental factors have been identified as possible
predisposing factors (E.g. maternal viral infections, cannabis)
2. Neurochemical theories
• A change in amine NTs especially DA has been proposed as a
cause of psychosis
• The main neurochemical theories center on DA & glutamate
• However, 5-HT & other NTs are also involved 12
15. Representative dopaminergic synapse. The above illustration is a representative
dopaminergic synapse.
The signaling pathways in the postsynaptic neuron are only representative of D1-
like receptor signaling (which increases cAMP).
D2-like receptors are known to have opposite affects on cAMP activity, and thus
slightly different downstream signaling cascades.
Dopaminergic signaling effects on ion channels and membrane permeability are not
shown however, may be important in the regulation of behavior such as physical
activity.
Abbreviations: AC5 - adenylate cyclase 5; ATP - adenylyl tri-phosphate; CREB -
cyclic AMP response element binding protein; DARPP-32 - dopamine and cyclic
AMP-regulated phosphoprotein (thought to be important in positive feedback
signaling); D1 - dopamine receptor 1; MAPK - mitogen-activated protein kinase;
PKA - protein kinase A; PKC - protein kinase C; PLC - phospholipase C; VMAT --
vesicular monoamine transporter; c-fos - downstream early gene.
Etiology & Pathogenesis
15
16. Mentions:
•Expression levels of the dopamine receptors may be important in mediating downstream
behavioral responses including voluntary activity.
•Dopamine receptor expression can be affected by the levels of dopamine in the system, level
and length of treatment of pharmacological agents, as well as other external stimuli mediated
through rewarding behavior such as sexual activity, or exercise.
•However, overall dopaminergic responses and signaling are also dependent on other factors
such as the electrical response produced (dopamine signaling can act in both an excitatory
manner, as well as an inhibitory manner depending on the circumstance), as well as interactions
with other neurotransmitters and signaling molecules. For example, the dopamine system has
been shown to interact with glutamate, GABA, acetylcholine, and serotonin.
•Only possible signaling pathways for the D1-like receptors are illustrated. Possible signaling
pathways in the dopaminergic neurons are extensively reviewed by Neve and colleagues, and
these downstream signaling pathways may be important in future investigations of the role of
the dopamine system and regulation of voluntary physical activity.
Etiology & Pathogenesis
16
17. I. Dopamine theory
The theory suggests that schizophrenia is caused by excess DA
activity in the mesolimbic DA pathway…DA excess
Drugs like
• Levodopa (DA precursor)
• Amphitamine (DA releaser)
• Apomorphine & bromochriptine (DA agonists)
either aggravate or produce psychosis de novo in some
patients
Etiology & Pathogenesis
17
18. • After successful treatment with antipsychotics, there is change
in the amount of homovanillic acid in the CSF, plasma & urine
• Most antipsychotic drugs act by blocking D2 receptors
• An increase in DA receptor density was found in treated &
untreated schizophrenics when compared with normal control
• DA receptor density has been found to be increased in the brains
of schizophrenics who have not been treated with antipsychotic
drugs (postmortem)
Etiology & Pathogenesis
18
19. Evidence against DA theory
1.Drugs which block DA should bring complete cure ……practically
not true
2.Phencyclidine (NMDA receptor antagonist) produce much more
schizophrenia like symptoms than do DA agonists when
administered to non-psychotic individuals
3.Atypical antipsychotics have less affinity for D2 receptor
Etiology & Pathogenesis
19
20. II. Glutamate theory
NMDA receptor antagonists (phencyclidine, ketamine )
produce psychotic symptoms
Reduced glutamate concentrations & glutamate receptor
densities have been reported in postmortem schizophrenic
brains
Etiology & Pathogenesis
20
21. III. Other theories
Many effective antipsychotic drugs, in addition to blocking
DA receptors also act as 5-HT2A receptor antagonists
5-HT modulates dopamine pathways
Whether 5-HT2A receptor blockade accounts directly for
their antipsychotic effects, or merely reduces undesirable
side effects associated with D2-receptor antagonists remains
controversial.
In conclusion, the dopamine hyperactivity theory of schizop
hrenia remains attractive.
Etiology & Pathogenesis
21
28. Neurotransmitters in Schizophrenia
Dopamine Hypothesis
Dopamine Hyperactivity in Mesolimbic pathways
Hypofunction in Mesocortical pathways
Glutamate Hypothesis
NMDA hypofunction
The role of Serotonin
Dysfunction in DA release
28
29. 29
In animal tests, all antipsychotic drugs initially increase and later decrease the electrical
activity of midbrain dopaminergic neurons in the substantia nigra and ventral tegmentum,
and also the release of dopamine in regions containing dopaminergic nerve terminals
(see O'Donnell & Grace, 1996). These changes are possibly associated with changes in
dopamine receptor expression (see later). Effects on the mesolimbic/mesocortical
dopamine pathways are believed to correlate with antipsychotic effects,
whereas effects on the nigrostriatal pathways are responsible for the unwanted
motor effects produced by antipsychotic drugs (see below).
Thus haloperidol , a first-generation drug with marked unwanted motor effects,
acts on both sets of dopamine neurons, whereas clozapine and other drugs
(see Table 38.1) that have much less tendency to cause adverse
motor effects affect mainly the ventral tegmental neurons.
30. Classification of antipsychotic drugs
I. Phenothiazines
•Chlorpromazine (CPZ)
•Triflupromaizne
•Thioridazine
•Mesoridazine
•Piperacetazine
•Fluphenazine
•Trifluoperazine
Phenothiazines nucleus
30
31. II. Butyrophenones
• Haloperidole
• Trifluperidole
• Penfluperidole
III. Thioxanthenes
• Chlorprothixene
• Flupenthixol
Classification of antipsychotic drugs
31
33. Antipyschotic drugs are categorized into two
Typical antipsychotics (1st generation)
Atypical antipsychotics (2nd generation)
The two groups show differences in terms of;
Receptor selectivity
Incidence of extrapyramidal side effects
Efficacy in 'treatment-resistant' patients
Efficacy against negative symptoms
EPS are more common with typical antipsychotics
Metabolic ADRs and weight gain are common with atypical antipsychotics
Antipsychotic drugs
33
34. 1. Central nervous system
A. Extrapyramidal syndromes
1. These adverse effects are related to a dopamin
e-receptor blockade in the basal ganglia (and
elsewhere in the CNS) that leads to an imbalan
ce in dopamine and acetylcholine actions in the
nigrostriatal pathway.
2. These effects are a major cause of noncomplia
nce.
35. 3. Extrapyramidal effects are:
• most likely to occur with high-potency conventional antipsychotic dr
ugs that have a high affinity for postjunctional dopamine D2-receptors i
n the basal ganglia.
• occur with few atypical drugs like risperidone.
4. These effects can sometimes spontaneously re
mit.
36. Extrapyramidal syndromes include the following:
1. Acute dystonia: sustained muscle contractions cause twis
ting and repetitive movements or abnormal postures
• This condition is often elicited during the first
week of therapy.
2. Akathisia is the irresistible compulsion to be in m
otion.
• This condition can develop as early as the first 2 weeks o
f treatment or as late as 60 days into therapy.
3. Parkinsonian-like syndrome
• Parkinsonian-like syndrome is characterized by tremors,
bradykinesia, rigidity, and other signs of parkinsonism.
• This syndrome can develop from 5 days to weeks into tr
eatment.
38. b. Tardive dyskinesia (10—20%)
• CNS disorder characterized by:
•twitching of the face and tongue
•involuntary motor movements of the trunk and lim
bs
• More likely with conventional antipsychotic agents.
• Tardive dyskinesia generally occurs after months t
o years of drug exposure; it may be exacerbated o
r precipitated by the discontinuation of therapy.
40. • Tardive dyskinesia is often irreversible.
• more likely to occur in the elderly or in institutionaliz
ed patients who receive long-term, high-dose therapy
.
• The only effective treatment for tardive dyskinesia is t
he discontinuation of treatment.
41. Atypical antipsychotics
Have broad spectrum of activity than traditional antipsychotics
but less affinity for D2
Has some efficacy for treatment resistant schizophrenia &
negative symptoms
’’atypical’’ is used to describe antipsychotic drugs which don’t
cause EPS
‘typical’ antipsychotic drugs associated with anticholinergic,
sedation, & cardiovascular side effects in addition to EPS
Antipsychotic drugs
41
43. Depot antipsychotics
• Esterification of the antipsychotic with long chain fatty acid
• The drug will be released at constant rate for long time
• Reduce compliance problem
• However reduced flexibility of dosage, pain at site of administration, high
incidence of EPS & weight gain
Some antipsychotic available as Depot
Haloperidol, Flupenthixol, Zulcopenthioxol, Fluphenazine, pipothiazine
43
Antipsychotic drugs
44. Antipsychotic action has shown good correlation with the
capacity to bind to D2 receptor
There is no clear correlation with antipsychotic activity &
the capacity to bind with D1, D3, & D4
Activities on other NT receptors may determine side effect
profile
44
Antipsychotic drugs
46. Antipsychotic: Pharmacological action
1. ANS
• Varying degree of α-adrenergic blocking activity
• More potent drugs have lesser α blocking activity
• Anticholinergic property is generally weak
2. Local anesthetic
• CPZ is a potent local anesthetic activity
3. CVS
• Antipsychotics produce postural hypotension by central &
peripheral action adrenergic receptors
46
47. 4. Endocrine effects
Increase prolactine secretion by blocking the inhibitory
effect of DA
• Galactorrhoea
• Gynaecomastia
• Decreased libido
Antipsychotic: Pharmacological action
47
48. Clinical uses of antipsychotics
1. Schizophrenia
2. Anxiety
• Antipsychotic are used in patients who fail to benefit from benzodiazepines
• Widespread ADRs limit their routine use as anxiolytics
3. Emesis
• Antipsychotics are used to control wide range of drug & disease induced
vomiting at doses much lower than those needed for psychosis
• Ineffective in motion sickness
4. Other uses
• Potentiate hypnotics, analgesics, & anesthetics
• Intractable hiccough (involuntary spasm of the diaphragm and respiratory organs)
may respond to parental CPZ
• In tetanus, CPZ is secondary drug to achieve skeletal muscle relaxation
48
49. ADRs associated with antipsychotics
I. CNS
• Drowsiness, lethargy, mental confusion
• Increased appetite & weight gain
• Aggravation of seizures in epileptics
• Non epileptics may develop seizure at high dose of some antipsychotics such
as clozapine & olanzapine
II. CVS
• Postural hypotension
• Palpitation
III. Anticholinergic actions
• Dry mouth, blurred vision
IV. Endocrine
• Hyperprolactinemia
• Atypical antipsychotics don’t raise prolactin level
49
50. V. Extrapyramidal disturbances
a. Pseudo parkinsonism
• Rigidity, tremor, hypokinesia, mask like face
• Appears between 1- 4 weeks of therapy & persist unless dose is reduced
• Anticholinergic, anti PD drugs can be given together with antipsychotics
b. Acute muscular dystonias
• Muscle spasm mostly in facial muscles
• Torticollis (neck muscle cause head to tilt down), locked jaw
VI. Malignant neuroleptic syndrome
1.Rarely occurs with potent antipsychotics
2.Patient develops marked rigidity, immobility, tremor, fever, semi consciousness,
fluctuating BP & HR
3.Lasts 5 – 10 days after withdrawal & may be fatal
4.Anticholinergics are of no help rather large dose of bromocriptine may be useful
ADRs associated with antipsychotics
50
51. d. Tardive dyskinesia
Involuntary rolling of the tongue and twitching of the face or
trunk or limbs
Purposeless involuntary facial & limb movements like constant
chewing, pouting, puffing of cheeks & lip licking
More common in elderly women
May subside months or yrs after withdrawal of the treatment or
may be life long
No satisfactory solution found
• D2 super-sensitivity in the DA pathway
• Other dopamine antagonists
ADRs associated with antipsychotics
51
53. c. Neuroleptic malignant syndrome
• Due to excessively rapid blockade of postsynaptic
dopamine receptors.
• This syndrome is characterized by:
• altered blood pressure and heart rate.
• muscle rigidity
• diaphoresis
• profound hyperthermia
• This condition occurs, often explosively, in 1% of p
atients; it is associated with a 20% mortality rate.
54. • This condition is treated by:
1.discontinuing drug therapy
2.initiating supportive measures, including the use o
f bromocriptine to overcome the dopamine recept
or blockade
3.muscle relaxants such as dantrolene and diazepa
m to reduce muscle rigidity.
55. d. Sedation
• More likely with low-potency antipsychotic age
nts and with the atypical agents, are due to a cent
ral histamine H1-receptor blockade.
• These effects may be mild to severe.
• The elderly are particularly at risk.
• May be temporary
56. 2. Autonomic Nervous system
1. α-Adrenoceptor blockade
More likely to occur with:
• conventional low-potency
• atypical antipsychotic agents.
• Postural hypotension- phenothiazines
when a person moves to a more vertical position: from sitt
ing to standing or from lying down to sitting or standing.
• Orthostatic hypotention – atypical drugs
symptoms: dizziness, faintness or lightheadedness which appear on
ly on standing, and which are caused by low blood pressure.
• Failure to ejaculate -phenothiazines
57. b. Muscarinic cholinoceptor blockade
• More common with:
conventional low-potency antipsychotic agents
atypical agent clozapine.
• Muscarinic receptor blockade, atropine-like effects (
dry mouth, constipation, urinary retention, and visu
al problems)
• Elderly patients are more at risk
• The effects may be temporary.
58. 3. Endocrine and metabolic disturbanc
es
• Most likely with
• most conventional antipsychotic agents
• atypical agent risperidone
• Due to dopamine (D2)-receptor antagonist activity i
n the pituitary, resulting in hyperprolactinemia.
59. In women, these disturbances include:
galactorrhea
loss of libido
delayed ovulation and menstruation or amenorr
hea.
In men, these disturbances include:
gynecomastia
impotence.
60. Weight gain, which is likely with:
most conventional
atypical antipsychotic agents, except aripiprazol
e and ziprasidone, may be due in part to hista
mine H1-receptor antagonist activity.
61. 4. Other adverse effects
a. Withdrawal-like syndrome
1. Symptoms: nausea, vomiting, insomnia, and hea
dache
• in 30% of patients, especially those receiving low-pot
ency antipsychotic drugs.
2. Symptoms may persist for up to 2 weeks.
3. Symptoms can be minimized with a tapered red
uction of drug dosage.
62. b. Cardiac arrhythmias
• More likely with thioridazine and ziprasidone, whi
ch
• Can prolong the Q-T interval and lead to conducti
on block and sudden death.
63. c. Cholestatic jaundice, which is caused primarily
by chlorpromazine
d. Photosensitivity
1. The effect is specific to chlorpromazine
• it includes dermatitis (5%), rash, sunburn, and pigmentati
on, and it may be irreversible.
2. Chlorpromazine and high-dose thioridazine also
produce retinitis pigmentosa
64. f. Overdose.
• rarely fatal, except when caused by thioridazine or
mesoridazine (and possibly ziprasidone), which may
result in drowsiness, agitation, coma, ventricular arr
hythmias, heart block, or sudden death.
65. 1. Neuroleptics potentiate all CNS depressants
Hypnotics, anxiolytics, alcohol, opioids, antihistamines &
analgesics
2. Neuroleptics block the action of levodopa & DA
agonists in parkinsonism
3. Antihypertensive effect of clonidine & methyldopa is
reduced
Drug interaction
65
66. Drug selection……..
1)Individual patients differ in their response to different
antipsychotics
2)There is no way to predict which patient will respond better to
which drug
3)However drug selection should consider state of the patient & side
effect profile of the drug
Eg. If the patient is aggressive, sedating drugs such as CPZ would be
drug of choice
• Haloperidol is drug of choice if postural hypotension is a problem
• If there is difficulty in frequent administering of the drug go for
depot antipsychotic drugs
66
72. Diazepam (A
Benzodiazepine that
probably facilitates the
actions of GABAA in the
CNS)
Baclofen (GABAB agonist )
Primarily used in the
treatment of spasticity
associated with spinal cord
injury
Spasmolytic Drugs
72
73. Centrally Acting muscle relaxant
•Baclofen
• GABAB agonist
•Diazepam
•Dantrolene
• It interferes with the release of calcium from its stores in sk. muscles
(sarcoplasmic reticulum).
• It inhibits excitation-contraction coupling in the muscle fiber.
• Used in malignant hyperthermia & spastic states.
73
