this ppt is about basic and clinical pharmacology of psychotherapeutic drugs such as antipsychotics, antidepressants, antianxiety and antimanic drugs

2.  has about 100,000,000,000 (100 billion)
neurons
 100,000 miles of blood vessels in the brain.
 Neurons multiply at a rate 250,000
neurons/minute during early pregnancy.

4. MEMORY OF HUMAN BRAIN IS
13367864.5GB

9. PSYCHIATRIC DISORDERS
 2 -3 % of UK national health spending 
schizophrenia
 1 in 6 persons in UK – suffer from depression
 Advances in drug treatment have
revolutionized the practice of psychiatry

10. Prevalance of Psychiatric
Disorder

13. Dr.V. Sathyanarayanan MD
Professor of pharmacology

19.  Excitatory – Glutamate, aspartate
 Inhibitory – GABA, Glycine
 Others –Noradrenaline ,Dopamine, 5- HT
 Acetylcholine
 Histamine
 Adenosine
 Nitric oxide
 Tachykinins
 Opioid peptides and endocannabinoids
CENTRAL NEUROTRANSMITTERS

22. PSYCHIATRIC DISORDERS
 Psychoses
 Neuroses
 Personality disorders
 Organic mental disorders

27. HISTORY
 1952  Introduction of chlorpromazine is a
breakthrough
 Reserpine  lasted only a few years
 1957 – 58 MAO inhibitors, antidepressants
 1957 – Chlordiazepoxide
 1960’s – Other benzodiazepines
 1960’s – Lithium
 1980”s - SSRIs

28. PSYCHOSES
 Organic – delirium, dementia
 Functional
 schizophrenia
 paranoid states
 Mood disorders – depression, Mania

32. SCHIZOPHRENIA
 Schizophrenia is a chronic,
 frequently life-time,
 remitting, and relapsing
 psychotic disorder
 the illness is usually diagnosed in late
adolescence or early adulthood .
 Periodic psychotic exacerbation (relapse)
occurs throughout the course of the illness

34. SCHIZOPHRENIA (Split mind)
 disorder of thought and behavior
 delusions
 hallucinations
 irrational conclusions, interpretations
 patient unable to meet the ordinary
demands of life
 Negative symptoms- apathy

36. RISKS OF SCHIZOPHRENIA
 associated with a high risk of suicide
 (about 10 percent of patients die from
suicide)
 significant impairment in function
 (less than 10 percent of patients are fully
employed and live independently)

38. PATHOPHYSIOLOGY
 Dopaminergic overactivity in limbic system
 Decrease in glutamate
 5- HT, NE also involved
 Complex involvement of multiple
neurotransmitters.

39. Normal
Dopamine Hypothesis
of Schizophrenia
Adapted from Stahl. J Clin Psychiatry. 2001;62:923.
Hyperdopaminergic
pathways
Hypodopaminergic
pathways
Negative symptomsPositive symptoms

40. NEUROCHEMICAL ABNORMALITIES
 Dopamine disregulation
 Glutamatergic hypofunction
 GABAergic hypofunction
 Nicotinic hypofunction

41. TREATMENT APPROACH
 requires a multimodal approach,
 including medication and
 psychosocial interventions,
 such as assistance with routine demands of
life
 as housing,
 financial sustenance,
 and personal relationships

42. broad objective of treatment
 to reduce the overall morbidity and mortality
of the disorder
 decrease the frequency and severity
of episodes of psychotic exacerbation
 and improve the functional capacity and
quality of lives of the individuals
 Most patients require comprehensive and
continuous care
 over the course of their lives.

43. TARGETS OF DRUG THERAPY
 no cure currently exists,
 pharmacological treatment is directed at
 inducing and
 maintaining remission
 of various symptom dimensions.
positive symptoms
 negative symptoms
 cognitive and
 neuropsychological dysfunction

44. GOAL OF THERAPY
 the optimal pharmacotherapy of
schizophrenia
 is one that provides
 the best possible control
 of the various symptoms
 while minimizing side effects
 from such treatment.

45. Antipsychotic Therapy:Antipsychotic Therapy:
Historical Perspective in the U.S.A.Historical Perspective in the U.S.A.
Ziprasidone
1950 1960 1970 1980 1990
2000
Reserpin
e
Chlorpromazin
e Fluphenazine
Thioridazin
e Haloperidol Clozapine
Risperidone
Olanzapine
Quetiapine

46. DRUG THERAPY OF
SCHIZOPHRENIA
 antipsychotic drugs carry the risk of a wide
range of side effects,
 from stiffness and restlessness
 to a form of diabetes,
 these drugs do little or nothing for the
cognitive impairment
 New treatments for psychotic symptoms
 and effective treatments for cognitive
impairment are on the horizon.

47. Ist GENERATION
ANTIPSYCHOTICS chlorpromazine (Thorazine),
 trifluoperazine (Stelazine),
 thioridazine (Mellaril), thio- thixene (Navane),
 haloperidol (Haldol), etc.
 differ from one another in potency and side
effect profile,
 they have similar overall efficacy,
 all cause significant EPS and tardive dyskinesia.

48. Factors in Antipsychotic SelectionFactors in Antipsychotic Selection
Short-Term and Long-TermShort-Term and Long-Term
 Efficacy (general, comparative)
 Safety (likelihood of dangerous side
effects)
and
 Tolerability (various adverse effects)

49. LIMITATIONS OF Ist
GENERATION
 EPS  dysphoria and poor compliance,
 worsening of negative symptoms
 Worsening of cognitive function,
 increased risk of tardive dyskinesia
 lower doses can reduce these adverse
effects….

50. Second-Generation
Antipsychotic Agents
 broader spectrum of efficacy
 and lower risk of neurological adverse
effects,
 greater efficacy in otherwise treatment-
refractory patients,
 clozapine has the best proven track record

51. Adapted from: Jibson MD, Tandon R. J Psychiatr Res. 1998(May-Aug);32(3-4):215-228Jibson MD, Tandon R. J Psychiatr Res. 1998(May-Aug);32(3-4):215-228
Essence of AtypicalityEssence of Atypicality
Less Tardive
Dyskinesia
Less Non-
Compliance
Less
Dysphoria
Better
Cognition
Fewer EPS
Fewer
Negative
Symptoms
EPS
Advantage

52. Comparative PharmacologyComparative Pharmacology
of Atypical Antipsychotic Drugsof Atypical Antipsychotic Drugs
Adapted from: Schmidt et al. Soc Neurosci Abstr. 1998;24(2):2177
5-HT5-HT2A2A
αα11
αα22
DD11
DD22
DD44
HaloperidolHaloperidol RisperidoneRisperidone
HH11
5-HT5-HT2A2A
DD22
5-HT5-HT2C2C
αα11
OlanzapineOlanzapine
5-HT5-HT2A2A
MM11
HH11
5-HT5-HT2C2C
DD22
αα11
ClozapineClozapine
MM11
5-HT5-HT2C2C
αα11HH11
5-HT5-HT2A2A
DD22
5-HT5-HT1A1A
QuetiapineQuetiapine
MM11
αα11
HH11
5-HT5-HT2A2A
DD22
5-HT5-HT1A1A
5-HT5-HT2C2C
ZiprasidoneZiprasidone
5-5-
HTHT1D1D
5-HT5-HT2A2A
DD22
5-HT5-HT1A1A
HH11
αα11 5-HT5-HT2C2C

55. Tandon R, Milner K, Jibson MD. J Clin Psychiatry. 1999;60(suppl 8):21-28Tandon R, Milner K, Jibson MD. J Clin Psychiatry. 1999;60(suppl 8):21-28
Conventional vs. Atypicals: Side-EffectConventional vs. Atypicals: Side-Effect
ProfilesProfiles
Key: 0 = absent; ± = minimal; + = mild; ++ = moderate; +++ =Key: 0 = absent; ± = minimal; + = mild; ++ = moderate; +++ =
severesevere
EPSEPS
Dose-related EPSDose-related EPS
TDTD
Prolactin elevationProlactin elevation
AgranulocytosisAgranulocytosis
AnticholinergicAnticholinergic
AST/ALT elevationAST/ALT elevation
HypotensionHypotension
SedationSedation
QTc prolongationQTc prolongation
Weight gainWeight gain
ZIPZIP THZTHZ HALHAL CLZCLZ RISRIS OLZOLZ QTPQTP
++
±±
±±
++
++
±±
±±
±±
++
++
++
++++
++++
++++++
++++++
+ ++ +
++++++
±±
++
++++++
++
++++++
++++++
++++++
±±
++
++++++
±±
++
++
++
0 to ±0 to ±
00
00
++++++
++++++
++
00
++++
++
++++++
++++++
++++
++++
++++
±±
±±
++
++++
++
++
++
±±
±±
++
++++
++++++
00
++++
±±
±±
++++
++++
±±
0 to ±0 to ±
±± ±±
±± ±±
±± ±±
±± ±± ±±
0 to ±0 to ± 0 to ±0 to ±0 to ±0 to ±

57. Recommended Dosing ofRecommended Dosing of
First-Line AtypicalsFirst-Line Atypicals
 Risperidone 2-6 mg/day
 Olanzapine 10-40! mg/day
 Quetiapine 400-1200! mg/day
 Ziprasidone 80-240! mg/day
!: Above FDA recommended upper
dose
Daily Dose in Acute PhaseDaily Dose in Acute Phase
(Refined After Clinical Experience)(Refined After Clinical Experience)

58. Antipsychotic Treatment OptionsAntipsychotic Treatment Options
 Low-potency conventional antipsychotics
(chlorpromazine, thioridazine)
 High-potency conventional
antipsychotics (haloperidol, fluphenazine,
thiothixene)
 Clozapine
 First-line atypical antipsychotics
 Risperidone
 Olanzapine
 Quetiapine

59. TimeTime
DoseDose
OldOld
agentagent
AtypicalAtypical
Titrate
atypical
Titrate
atypical
to
desired
dosage
to
desired
dosage
Continue oldContinue old
Slowly taper off old
Slowly taper off old
agent
agent
agentagent
Switching Antipsychotics:Switching Antipsychotics:
Recommended StrategyRecommended Strategy

60. Adapted from: Jibson MD, Tandon R. J Psychiatr Res. 1998(May-Aug);32(3-4):215-228Jibson MD, Tandon R. J Psychiatr Res. 1998(May-Aug);32(3-4):215-228
Essence of AtypicalityEssence of Atypicality
Less Tardive
Dyskinesia
Less Non-
Compliance
Less
Dysphoria
Better
Cognition
Fewer EPS
Fewer
Negative
Symptoms
EPS
Advantage

61. Optimizing Outcomes with 2ndOptimizing Outcomes with 2nd
GenerationGeneration AtypicalAtypical AntipsychoticsAntipsychotics
 Maximize improvement
reduce symptoms in various domains
 Minimize impairment by side-effects
 No EPS
 No use of anticholinergic agent
 Minimize other side-effects
 Monitor on ongoing basis and make
necessary adjustments
 INDIVIDUALIZED DOSING IS THE KEY

63. How Antipsychotic TreatmentHow Antipsychotic Treatment
ImpactsImpacts
Life of an Individual with PsychosisLife of an Individual with Psychosis
Antipsychotics
Reduce
symptoms
Causeside effects
o o
o o
Quality
of life

65. ADJUNCTIVE MEDICATIONS
 Anticholinergics
 Mood stabilizers
 Benzodiazepines
 Betablockers
 ECT

66. NEW FORMULATIONS
 Injections of atypical antipsychotics
 depot antipsychotics 
 haloperidol decanoate and
 fluphenazine decanoate

70. CHLORPROMAZINE – PROTOTYPE OF
ANTIPSYCHOTICS

71. PHARMACOLOGICAL ACTIONS - IN
A PSYCHOTIC
 Reduces irrational behavior
 Reduces agitation, aggressiveness
 Normalization of disturbed thought
 Relieves anxiety
 Suppresses delusions, hallucinations, hyperactivity
 Sedation – immediately produced
 Antipsychotic effect  takes weeks to develop.

81. chlorpromazine blocks – D1,
D2, D3, D4 dopamine receptors

82. BLOCKADE OF DOPAMINERGIC
PATHWAYS
 Mesolimbic –Antipsychotic effect
 Nigrostriatal – parkinsonian side effect
 Tuburoinfundibular – hormonal side effects
 CTZ – Antiemetic action

83. MECHANISMS OF ACTION


88. TOLERANCE AND DEPENDENCE
 Tolerance develops to sedation and
hypotension.
 No tolerance for antipsychotic and
extrapyramidal effects.
 No dependence

90. PHARMACOKINETICS
 Unpredictable oral absorption, low
bioavailability
 Highly bound to plasma proteins
 Attains higher concentration in brain
 Cumulates on chronic administration
 Acute effects lasts 6-8 hours

92. ADVERSE EFFECTS
 I. DOSE RELATED SIDE EFFECTS:
 CNS – Drowsiness, mental confusion,
increased appetite , aggravation of seizures
 ALPHA ADRENERGIC BLOCKADE: Postural
hypotension, palpitation, inhibition of
ejaculation

99. ADVERSE EFFECTS
 ANTICHOLINERGIC SIDE EFFECTS
Dry mouth, blurring of vision, constipation, urinary
retention
 ENDOCRINE
Amenorrhea, infertility, gynaecomastia,
galactorrhoea occur infrequently

103. EXTRAPYRAMIDAL DISTURBANCES
PARKINSONISM  rigidity, tremor, hypokinesia,
mask like facies, shuffling gait.
 ACUTE MUSCULAR DYSTONIAS – 2%
 AKATHESIA – desire to move about – 20% ( Tt-
nadolol )
 TARDIVE DYSKINESIA – Purposeless involuntary
movements – 10-20%( tt- vit E, BDZ,
betablockers)
 RABBIT SYNDROME

108. MALIGNANT NEUROLEPTIC SYNDROME
 High doses of potent agents
 Marked rigidity, immobility, tremor, fever,
semi consciousness
 May be fatal
TREATMENT:
 Stop the neuroleptic
 Symptomatically
 I.V dantrolene, bromocriptine

111. OTHER SIDE EFFECTS
 Weight gain
 Rise in blood sugar and lipids
 Blue pigmentation
 Corneal and lens opacities
 Retinal degeneration
 Cardiac arrhythmia

115. HYPERSENSITIVITY REACTIONS
 Cholestatic Jaundice – 2-4%
 Skin rash, urticaria, contact dermatitis,
photosensitivity

118. INTERACTIONS
1. Potentiation of all CNS depressants
2. Block the action of Levodopa
3. Enzyme inducers can reduce blood levels of
neuroleptics

120. THERAPEUTIC USES
 SCHIZOPHRENIA:
 Control positive symptoms better than negative
symptoms
 Afford symptomatic relief
 Do not remove the cause of the illness
 Long term treatment is required
 MANIA  Antipsychotics I.M – CPZ or HALOPERIDOL
 CHRONIC SCHIZOPHRENIA – atypical antipsychotics
are preferred

123. THERAPEUTIC USES
ANXIETY
 Relieve anxiety
 Useful in
 anxiety with a psychotic basis
 and not responding to other drugs

124. HALOPERIDOL
 Extra pyramidal side effects +++
 Sedation+
 Hypotension +
 Few autonomic effects
 Less epileptogenic
 No weight gain
 Jaundice is rare
 Preferred drug for acute schizophrenia

126. TRIFLUPERAZINE AND
FLUPHENAZINE
 Minimum autonomic actions
 Less sedation+
 Less hypotension+
 Less hypersensitivity reactions
 Less likely to precipitate seizures.
 Marked extrapyramidal symptoms
 Fluphenazine decanoate  given as depot
I.M injection every 2-4 weeks

127. ATYPICAL ANTIPSYCOTICS
 Second generation antipsychotics that have weak
D2 blocking and potent 5-HT2 blocking activity
 Minimal EPS
 Improve cognition
 Clozapine, Risperidone, Olanzapine
 Quetiapine, Aripiprazole, ziprasidone

129. CLOZAPINE
 Atypical or second generation antipsychotic
 Selective D4 blocker
 Anti 5HT2
 Weak D2 blocking action
 Produces few extrapyramidal symptoms
 No increase in prolactin level
 Anticholinergic +, alpha blockade+, sedation++
 Suppress both positive symptoms and negative
symptoms
 Useful as a reserve drug in refractory schizophrenia

130. CLOZAPINE - ADR
 Agranulocytosis (0.8%) and other blood
dyscrasias (weekly monitor WBC count)
 High dose induce seizures
 Sedation, tachycardia, weight gain
 Precipitation of diabetes
 Myocarditis

133. RISPERIDONE
 Combination of D2 +5HT2 blockade
 Alpha1, alpha2, H1 blocker
 Less EPS at low doses
 Sedation, postural hypotension +
 Increase prolactin level
 Less epileptogenic than clozapine
 Frequently causes agitation
 CAUTION – stroke in elderly

136. OLANZAPINE
 Blocks D2, 5HT2, alpha1, alpha2, M1, H1
 like clozapine
 Controls positive and negative symptoms
 Broad spectum effect
 covers schizo-affective disorders
 Few EPS
 No agranulocytosis
 Little rise in prolactin
 Long acting
 Potent anti muscarinic – dry mouth, constipation
 More epileptogenic, cause weight gain, diabetes

140. QUETIAPINE
 New, short acting atypical antipsychotic
 Minimal EPS, hyperprolactinemia
 Quite sedating
 Postural hypotension +
 Used in mania/ bipolar disorder
 Interact with macrolides, anticonvulsants

141. ARIPIPRAZOLE
 Partial agonist at D2, 5-HT1A
 Antagonist at 5-HT2
 Minimal sedation
 No EPS, hyperprolactinemia, hypotension
 No weight gain, diabetes
 Long acting

143. ZIPRASIDONE
 Latest atypical antipsychotic
 Same advantages of aripiprazole
 In addition it has anxiolytic, antidepressant
action
 CAUTION – potential to induce serious
arrhythmias
 Also used in mania

145. RESERPINE
 Historical importance in psychiatry
 low efficacy antipsychotic
 Depletes – brain DA, NA, 5-HT
 Cause mental depression, suicidal tendencies

147. FUTURE OF SCHIZOPHRENIA
 Advanced genetic screening technology,
 structural and functional brain imaging,
 sophisticated histological techniques
 will lead to
 greater understanding,
 better treatments,
 and eventually prevention of schizophrenia.

150. AFFECTIVE DISORDERS
 Pathological change in mood state
 Major depression
 Mania

155. MAJOR DEPRESSION
 characterized by symptoms like
1. Sad mood
2. Loss of interest and pleasure
3. Feelings of worthlessness, guilt
4. Loss of appetite, sleep
5. Suicidal thoughts and melancholia

162. MANIA
 Elation or irritable mood
 Racing thoughts
 Accelerated speech
 Increased activity
 Reduced sleep
 Violent behaviour
 Progressive loss of contact with reality

166. BIPOLAR DISORDER
 Cycles of mood swings from mania to
depression occur over time

169. TREATMENT OF DEPRESSION
 Three phases of treatment have been
proposed:
 acute,
 continuation,
 and maintenance treatment phases

170. ACUTE TREATMENT PHASE
 clinical interview,
 diagnostic assessment,
 physical and neurological examination,
 and clinical and laboratory studies
 Lasts 6-12 weeks

171. GOALS
 establishing a diagnosis,
 defining a short-term and long-term
 multidisciplinary treatment plan,
 selecting the most appropriate medication,
 titrating the dose to a therapeutic range,
 monitoring of side effects, compliance,
 and determining the magnitude and quality of
response
 REVIEW  once in 1-2 weeks

172. Maintenance Phase
 prophylactic,
 to maintain the response.
 dosing during this phase should continue at the
same level as during the acute phase
 supportive psychotherapy can help to reduce
the rate of relapse and recurrence
 REVIEW  every 4-12 weeks in the 1st
year
 Then every 6 months to yearly review

173. CONTINUATION PHASE
 Consists of monitoring for completeness of
response and side effects.
 Discontinuation of medication is associated
with a high rate of relapse
 treatment lasts 4 to 9 months
 consolidation phase.

174. ANTIDEPRESSANTS
 Drugs which can elevate mood in depressive
illness.
 Affect monoaminergic transmission

180. TRICYCLIC ANTIDEPRESSANTS
 IMIPRAMINE – Prototype

181. ACTIONS - In depressed
patients
 little acute effects are produced
 Produce sedation
 Mood is gradually elevated after 2 -3 weeks of
continuous treatment
 Make the patients take interest in self and
surroundings
 Make them be more communicative

186. ACTIONS
 Does not produce euphoria but relieves
depression
 Suppress REM sleep
 reduce awakenings during night
 Lower seizure threshold
 More sedative  for patients showing anxiety
and agitation
 Less sedative  for withdrawn and retarded
patients

188. MECHANISM OF ACTION
 Inhibit active uptake of biogenic amines NA and 5-
HT  potentiate them
 Results in increased concentration of the amines in
the synaptic cleft  enhanced nor- adrenergic,
serotonergic transmission
 Uptake blockade occurs quickly but antidepressant
action develops after weeks

191. TOLERANCE AND DEPENDENCE
 Tolerance to the anticholinergic and hypotensive
effects develops gradually
 Psychological dependence is rare
 Physical dependence occur when high doses
used for longer periods
 Gradual withdrawal is recommended
 do not carry abuse potential

193. PHARMACOKINETICS
 Oral absorption is good
 Highly bound to plasma tissue proteins
 Metabolites are excreted urine over 1-2 weeks
 Plasma t ½ 16-24 hours
 Once daily dosing at bed time
in the maintenance phase
 Therapeutic window phenomenon has been
observed

195. ADVERSE EFFECTS
 Sedation, mental confusion
 Postural hypotension
 Anticholinergic: dry mouth, blurred vision
constipation, urinary retention, palpitation
 Cardiac arrhythmias, specially in patients with
ischaemic heart disease
 Increased appetite and weight gain

200. ADVERSE EFFECTS
 Some patients may switch to hypomania or
mania
 Sweating and fine tremors
 Seizure threshold is lowered
 Rashes and jaundice due to hypersensitivity
are rare

203. USES
 1. Endogenous depression
Response takes 2-3 weeks to appear
Therapy continued upto 1 year
SSRIs – mild to moderate depression
TCAs - severe depression
 2. Obsessive compulsive and phobic
states
SSRIs, clomipramine
 3. Anxiety disorders
 4. Neuropathic pain – imipramine

209. USES
 5. Attention deficit – hyperactive disorder in
children
Imipramine, nortriptyline
Less behavioural side effects than
amphetamine like drugs
 6. Enuresis – imipramine 50mg at bed time
is effective in children above 5 years
 7. Prophylaxis of migraine – Amitriptyline
 8. Pruritus – Topical doxepin

213. LIMITATIONS OF TCA’S
 Frequent anticholinergic, cardiovascular and
neurological side effects
 Relatively low safety margin
 hazardous in overdose; fatalities common
 Lag time of 2- 4 weeks before antidepressant
action
 Significant number of patients respond
incompletely and some do not respond

216. MAO INHIBITORS
 Inhibit monoamine oxidase
 MAO –A – deaminates 5 –HT, NA, inhibited
by moclobemide
 MAO- B – deaminates dopamine
 Hit and run drugs
 Cheese reaction

218. MOCLOBEMIDE
 Reversible and selective MAO-A inhibitor
 Cheese reaction less likely
 No side efffects of TCA’s
 Safer in overdose
 Preferred in elderly and heart disease
patients
 Alternative to TCA’s in mild to moderate
depression

222. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
 Since 1980s
 Fluoxetine, Fluvoxamine, paroxetine,
Bupropion, venlafaxine, mirtazapine
 Improved tolerability
 Relatively safe
 Faster onset of antidepressant action

225. ADVANTAGES OF SSRIs
 Little or no sedation,
 Do not interfere with cognitive and
psychomotor function
 Do not produce anticholinergic side effects
 Devoid of alpha adrenergic blocking action –
postural hypotension does not occur
 No seizure precipitating propensity
 Do not inhibit cardiac conduction
 Weight gain is not a problem

227. ADR
 Nervousness, restlessness, insomnia
 Anorexia, NAUSEA
 Dyskinesia
 Headache and diarrhoea
 Interfere with ejaculation
 Impairment of platelet function 
bleeding ( epistaxis)
 Gastric blood loss due to NSAIDs may be
increased

233. DRUG INTERACTION
 The SSRIs inhibit CYP2D6 and CYP3A4
elevate plasma levels of TCAs, haloperidol,
clozapine, terfenadine, astemizole, warfarin,
Beta blockers
 Tolerance
 Serotonin syndrome
 Discontinuation reaction

234. USES
 1st
line drugs in
 Mild to moderate depression
 phobias,
 OCDs
 Panic disorders
 Kleptomania and related disorders
 Preferred for prophylaxis of recurrent depression

238. FLUOXETINE
 Prototype
 Longest acting
 More agitation and dermatological reactions
 More appropriate for poorly compliant
patients
 Less suitable for patients needing rapid effect

240. FLUVOXAMINE
 Shorter acting SSRI
 No active metabolite
 Used in hospitalized patients and in number
of anxiety disorders
 More nausea, agitation, Discontinuation
reactions

243. PAROXETINE
 Short acting SSRI
 Does not produce active metabolite
 A higher incidence of g.i. side effects,
discontinuation reaction

244. SERTRALINE
 Drug interactions due to inhibition of CYP
isoenzymes are less likely to occur
 Produces a longer lasting active metabolite
 Efficacious in juvenile depression

246. CITALOPRAM
 Lower propensity to cause drug interactions
 Should be avoided in patients likely to attempt
suicide

247. OTHER USES OF SSRIs
 Now 1st
choice drugs for OCD, Panic disorder,
social phobia, eating disorders and post
traumatic stress disorder
 Many anxiety disorders, body dysmorphic
disorder, compulsive buying and kleptomania
 Used to improve outlook on life and to feel
good, even in non depressed patients
 post MI and other chronic somatic illnesses

255. ATYPICAL ANTIDEPRESSANTS
 Trazodone
 Mianserin
 Tianeptine
 Amineptine
 Venlafaxine
 Duloxetine
 Mirtazapine

256. TRAZODONE
 Sedative
 Cause bradycardia, less prone to cause arrhythmias
 No anticholinergic side effects
 No seizures
 Nausea is felt, priapism, postural hypotension
 Better suited for elderly depressed patients
 Preferred where heavy sedation is required

258. VENLAFAXINE
 Novel antidepressant
 SNRI
 Like SSRI
 Does not interact with cholinergic,
adrenergic, H1 receptors
 No sedation
 Faster onset
 More nausea, sustained hypertension
 Safer in overdose

261. DULOXETINE
 Similar to venlafaxine
 Cause agitation, rise in BP, insomnia
 Also indicated in
 panic attacks,
 Diabetic neuropathic pain
 Stress incontinence

264. MIRTAZAPINE
 Act by blocking alpha2 autoreceptors (on NA
neurones), heteroreceptors (on 5-HT
neurones)
 Cause sedation, weight gain
 No anticholinergic, sexual side effects
 Efficacy comparable to TCAs

266. BUPROPION
 Inhibit DA, NA uptake
 Excitant
 Available as a Sustained release formulation
for smoking cessation
 No sexual side effects
 Can cause agitation, insomnia, dry mouth,
nausea

268. ACUTE POISONING
 usually self attempted and may endanger life
 Symptoms :Excitement, delirium, anticholinergic
symptoms, convulsions and coma
 Respiration is depressed, BP is low, tachycardia,
ventricular arrhythmias
 Treatment : Primarily supportive
 Propranolol / lignocaine for cardiac arrhythmias
 i.v bicarbonate for acidosis
 i.v diazepam for convulsions

269. INTERACTIONS
 TCAs potentiate directly acting
sympathomimetic amines  rise in BP
 TCAs potentiate CNS depressants including
alcohol and antihistaminics
 Phenytoin, aspirin can displace TCAs from
protein binding sites and cause toxicity
 SSRIs inhibit metabolism of TCAs – dangerous
toxicity can occur
 Hypertensive crisis with MAO inhibitors
 Arrhythmias with thioridazine, pimozide,
amiodarone

270. OTHER TREATMENTS FOR
DEPRESSION

276. ANXIETY
 Unpleasant emotional state associated with
 Uneasiness
 discomfort and
 fear about future threat
 Treatment is needed when anxiety is
excessive

279. TYPES OF ANXIETY
 Cardiac neurosis
 G-I neurosis
 Social anxiety
 Obsessive – compulsive disorder ( OCD )
 Post-traumatic stress disorder
 Phobias
 Panic disorder

286. SLEEP MEDICATIONS

289. ANTIANXIETY DRUGS
 Control the symptoms of anxiety
 Produce a restful state of mind without
interfering with normal mental or physical
functions
 Closely resemble sedative – hypnotics.
 Not effective in schizophrenia
 Do not produce extra pyramidal side effects
 Produce physical dependence
 Carry abuse liability

292. CLASSIFICATION
 Benzodiazepines – Diazepam
Chlordiazepoxide
Oxazepam
Lorazepam, Alprazolam
 Azapirones - Buspirone, Gepirone
Ispapirone
 Sedative antihistaminic – Hydroxyzine
 Beta blocker - Propranolol

293. BENZODIAZEPINES
 One of the most widely used class of drugs
 Little effect on other body systems
 Relatively safe even in gross over dosage
 Higher doses induce sleep and impair
performance
 Potential to produce dependence in long term
use
 Differences between individual BZD  mainly of
pharmacokinetic

297. MECHANISM OF ACTION
 Facilitates inhibitory GABAergic transmission

299. ADR
 Sedation
 Light-headedness
 Psychomotor impairment
 Vertigo
 Confusion in elderly
 Increased appetite, weight gain
 Dependence on long term use

304. CHLORDIAZEPOXIDE
 Ist
BZD to be used clinically
 Slow oral absorption
 Produce smooth long lasting effect
 Preferred in chronic anxiety states
 Active metabolites are produced  extend the
duration of action
 Dosage: 20-100mg/day
 Librium 10, 25mg

306. DIAZEPAM
 Quickly absorbed
 Produces initial phase of strong action, followed
by prolonged milder effect
 Produces active metabolites
 Preferred in acute panic states, anxiety
associated with organic disease
 Valium 2, 5, 10mg
 5 – 30mg

309. LORAZEPAM
 Slow oral absorption
 Less lipid soluble  slow rate of entry to brain
 Good sedative
 Only BZD recommended for I.M use
 Preferred for short lived anxiety states, panic ,
obsessive – compulsive neurosis, tension
syndrome, psychosomatic diseases
 Dose: 1 – 6mg Larpose , Ativan

311. ALPRAZOLAM
 High potency anxiolytic
 In addition has mood elevating action in mild
depression
 Useful in anxiety associated with depression
 Panic disorders with severe anxiety
 Active metabolite is produced
 Cause less drowsiness
 Dose: 0.25-1mg TDS

314. BUSPIRONE
 Ist
Azapirone (non BZD)
 5-HT1A agonist
 No sedation, No cognitive impairment, do not
interact with BZD receptor or (GABA)
 No tolerance
 No physical dependence
 Relieves mild to moderate anxiety
 Slow onset of benefit (maximum benefit delayed
upto 2 weeks)
 Mild mood elevating action

319. PHARMACOKINETICS
 Rapidly absorbed
 t½ 2-3.5 hrs
 Extensive Ist pass metabolism
 BA 5%

320. SIDE EFFECTS
 Dizziness, headache, light headedness
 Does not potentiate CNS depressants
 May cause rise in BP in patients on MAO
inhibitors
 Caution in those operate machinery/motor
vehicles
 Dose: 5-15 mg OD

322. HYDROXYZINE
 H1 antihistaminic
 Sedative, antiemetic
 has antimuscarinic and spasmolytic properties
 Useful in reactive anxiety or
 that associated with marked autonomic
symptoms
 Also effective in pruritus and urticaria
 Atarax 10, 25mg

326. BETA BLOCKERS
 Relieves sympathetic symptoms of anxiety
(Palpitation, rise in BP, shaking, tremor, GI hurrying)
 Produce symptomatic relief
 Do not affect psychological symptoms like worry,
tension, fear
 Useful in acutely stressful situations like public
appearance , exams
 Performance/situational anxiety adjuvant to BZDs

330. TREATMENT OF ANXIETY
DISORDERS Treat when excessive and disabling
 Use BZDs in smallest possible dose for short term
 Individualize the dose
 Longer periods  gradual withdrawal
 Most of the dose given at night to ensure sleep
 Remaining dose divided and given in day to avoid
high peaks
 Low doses of BZD are given in patients with
hypertension, peptic ulcer, ulcerative colitis,
IBW, GERD, angina pectoris  for treating the
anxiety though may not be prominent

331. TREATMENT OF ANXIETY
 SSRIs drug of choice for anxiety disorders
 Monitor for possible ADR
 Treatment effect is often slow  wait 12 weeks
to assess efficacy
 Specific
 Buspirone  nonsedating  less severe forms
 TCA, SSRI  delayed response  combined
with BZD

335. MANIA
 Elation or irritable mood
 Racing thoughts
 Accelerated speech
 Increased activity
 Reduced sleep
 Violent behaviour
 Progressive loss of contact with reality

339. LITHIUM CARBONATE
 Small monovalent cation
 Stabilizes mood
 Used in the prophylaxis of bipolar manic
depressive illness (MDI)
 Standard antimanic, mood stabilizer

341. ACUTE MANIA - TREATMENT
 Lithium – delayed onset of action
 Carbamazepine, volproic acid, divalproex
sodium ( side effects – hepatic failure)
 Typical antipsychotics – highly effective ,
( ADR- tardive dyskinesia)
 Atypical antipsychotics- clozapine ( risk of
agranulocytosis), olanzapine

343. ACTIONS
 On prolonged administration stabilizes mood
 Does not produce sedation or euphoria
 Suppress acute mania in 1 – 2 weeks
 Normalizes sleep time in manic patients
 Continued treatment prevents cyclic mood
changes

345. ACTIONS
 Inhibits the actions of ADH  causes
diabetes insipidus like state
 Has some insulin like action
 Increases WBC count
 Reduces thyroxine synthesis

346. MECHANISM OF ACTION
 Exactly not known
 Inhibits hydrolysis of inositol-1-phosphate 
decrease supply of free inositol  decrease
IP3, DAG  decrease activity of hyperactive
neurones in manic state

347. PHARMACOKINETICS
 Well absorbed orally
 Not protein bound, not metabolized
 Uniformly distributed in total body water
 Eliminated by the kidneys same way as Na+
 On repeated administration steady state
concentration is achieved in
5 – 7 days
 Marked individual variation of elimination

348. MONITORING LITHIUM LEVEL
 Monitoring Li concentration is essential for
optimum therapy  Because margin of safety
is narrow
 0.5 – 0.8 mEq/L – optimum for maintenance
therapy in bipolar disorder
 0.8 – 1.1 mEq/L – for mania
 Above 1.5 mEq/L – toxicity symptoms occur
 Serum Li level measured 12 hours after the
last dose

349. ADVERSE EFFECTS
 Nausea, vomiting and mild diarrhoea
 Thirst and polyuria
 Fine tremors, seizures (rarely)
 Long term use produces renal diabetes
insipidus
 Goiter reported in 4%

353. CONTRAINDICATIONS
 Pregnancy – fetal goiter and cardiac
congenital abnormalities reported
 Sick sinus syndrome

355. LITHIUM TOXICITY
 CNS toxicity appears on higher doses –
 mental confusion
 giddiness, tremors
 ataxia, nystagmus, motor incoordination
 These symptoms seen at concentration above
2mEq/L
 These progress to muscle twitchings, delirium,
convulsions, coma

359. Treatment
 Symptomatic
 no specific antidote
 Osmotic diuretics ( mannitol) , sodium
bicarbonate infusion promote Li excretion
 Haemodialysis is indicated in serum levels
above 4 mEq/L

361. INTERACTIONS
 Diuretics increases lithium level
 Tetracyclines, ACE inhibitors, NSAIDs cause
Li retention
 Sometimes Li potentiates neuroleptic action
of haloperidol
 Li enhance insulin/sulfonylurea induced
hypoglycemia

363. USES
 1. Acute mania – used after the episode is under
control with neuroleptics, diazepam /lorazepam
 2. Prophylaxis in bipolar disorder – used after
measuring risk benefit ratio
 3. Recurrent unipolar depression
 4. Inappropriate ADH secretion syndrome
 5. Cancer chemotherapy induced leukopenia and
agranulocytosis

367. DISADVANTAGES OF LITHIUM
 Intolerance
 Risk of toxicity
 50% of mania, bipolar disorder show poor
response

370. CARBAMAZEPINE
 Equally effective as Li
 Better tolerated than Li
 Preferred by many as first line / adjunctive
treatment for acute mania, bipolar illness
 Efficacy in long term prophylaxis is less
well established

372. SODIUM VALPROATE
 Act faster than Li
 1st
line treatment for acute mania
 Better tolerated
 Useful in those not responding to Li or CBZ
 Also combined with Li in resistant cases
 Shows reduction in manic relapses in bipolar
disorder

374. OTHER DRUGS IN MANIA
 Lamotrigine – specially useful in depressed and
rapidly cycling phases of the illness
 Olanzapine – carries low risk of agranulocytosis,
extra pyramidal side effects  used as
adjuvant/alternative to Li in acute mania,
prophylaxis of cyclic mood swings
 Risperidone
 Clonidine, verapamil, nimodipine are under
investigation

377. TREATMENT
 Psychotic illness ( Schizophrenia, mania, depressive
psychosis )  drugs as first-line treatment ,
psychotherapy adjunctive)
 Depression, anxiety disorders  psychotherapy 1st
line, drugs 2nd
line
 Drugs and psychotherapy combination
 Doctors  Therapeutic relationship with patients
 empathetic, supportive  enhance the
pharmacological efficacy

379. A despondent fellow seeks the advice of the city’s
most fashionable – and expensive – psychiatrist
cum analyst
“You have acute melancholia,” the analyst
informs him. “The circus is in town this week.
Go to it. It may give you some laughs.”
“Your advice is worthless,” mourns the despondent
one. “I’m the top clown there.”

381. “Psychology which explains everything
explains nothing, and we are still in doubt”
Marianne Moore

382. “If the only tool you have is a hammer,
you tend to see every problem as a nail.”
Abraham Maslow (American
Philosopher and Psychologist, 1908-1970)

386. LEVELS OF CONSCIOUSNESS

388. Writing prescriptions is easy!Writing prescriptions is easy!
Understanding people is hard…..Understanding people is hard…..