Psycho pharmacology

Anxiolytics and Anti psychotics

Dr.U.P.Rathnakar
MD. DIH. PGDHM
Psychotropic drugs
 Psychoses
• Severe mental illness
• Not in touch with reality
• Hallucinations
• Delusions
• Abnormal behaviour
Eg: Schizophrenia.,
Affective-Mania&Dep
Others-Alzheimers, Sub.abuse, Pers.disorder
 Neuroses
 Less severe(Extreme
suffering)
 In touch with reality
 Eg: Dep without
psychoses, Panic
disorder, GAD, OCN,
Phobias, PTSD, Eating
disoders, Sleep disorder
Psychoses and Neuroses
 A psychotic thinks that two and two are
five.

 A neurotic knows two and two are four

-- but he hates it.
Neurotic builds castles in air
But does not live in it [In touch with reality]

Psychotic too builds castles in air but…

Moves in and happily lives there!

[Not in touch with reality]

Psychiatrist collects rent from both!

Psychotropics

 Anti psychotics ( Neuroleptics,

Major tranqulizers)
 Anxiolytics ( Minor
tranquilizers)
 Anti depressants
 Mood stabilizers*
 Anxiety and Anxiolytics
 Flight-Fright-Fight-Response to threat→
ANXIETY→Normal behaviour
 Symptoms- Defensive behaviour,
Autonomic reflexes, Alertness,
Corticosteroid secretion

 Extremes→Interfere with productive

activity →Anxiety neurosis
 Symptoms: Occur in anticipatory manner
Anxiety

Anxiety neurosis
 Bilogical basis of anxiety

 3 NT systems-implicated
2) GABA-BNZDP Receptor
complex
3) NA system-Locus coeruleus
4) Serotonin ( 5HT)*
GABA

GABA inhibitory
Cl- Channels, GABA- A
BNZDP facilitates*
 Nor epinephrine
 NA Cell bodies in Locus Coeruleus.
 Over active in anxiety states
 Responsible for subjective
responses.
 Clonidine, Beta blockers reduce
subjective/ emotional aspects.*
 Anxiety
Dilated pupils

Tachycardia Tremors

Sweating

Over activity of NA system

Serotonin (5HT)
 Excess→ Anxiety
 Defeciency → Depression
 Partial agonists → Modulate →Effective in
both Anxiety
S
E
R
O
T ← Partial agonists
O
N
I
N
Depression
 Switch analogy-Serotonin hypothesis
Anxiety Depression

Switch on Switch off

TOO BRIGHT TOO DARK

5HT-Excess Normal
5 HT-Defeciency

5 HT 5 HT
Partial agonist EQUALLY
LIGHTED Partial agonist

Partially on/off
Anti anxiety drugs
 Benzodiazepines: Alprazolam.
Chlodiazepoxide, Oxazepam,
Lorazepam, Diazepam
 Azapirones: Buspirone,
Gepirone, Ispapirone
 Beta blockers
 Others: Meprobomate,
Hydroxyzine, SSRIs*
 Benzodiazepines
 Muscle relaxant
 Sedative hypnotics
 Anticonvulsant
 Anesthetic

Anxiolytic
 Earlier agents-Crudely masked anxiety by
sedation
 BZDP-Sp.antianxiety action*
BNZDP-Advantages
 Less effect on CVS and RS
 Lower dependence
 Milder withdrawal symptoms
 Safe in gross over dosage

MOA: GABA fecilitation

Site: Limbic system*
Adverse effects
 Sedation
 Psychomotor impairment
 Confusional state
 Hypersensitivity

Individual Drugs: Difference is PK.*

FUTURE
Antagonist

Part.agonist Part.inv.agonist

Agonist Inv.agonist

No
Anxiolytic clinical Promnistic
ONLY effect Anxiogenic
Pro conv.
Anxiolytic
Sed.Hypn Promnistic
Musc.relax. Anxiogenic
Anit conv. Pro conv
Amnestic
Dependenc
y

Spectrum of activity of agonists at BZDP

receptor
 Azapirones
 5HT1A partial agonist
 No sedation
 No physical dependence
 [Also effective in depression-Not used]
 No drug interaction

Disadvantages
 Slow onset*
Anxiety disorder

 Panic Disorder
 Obsessive-Compulsive Disorder
 Post-Traumatic Stress Disorder
 Social Phobia (Social Anxiety Disorder)
 Specific Phobias
 Generalized Anxiety Disorder (GAD) *
Anxiety Disorders

Panic Disorder
 My heart pounds really hard,
 I feel like I can’t get my breath,
 and there’s an overwhelming feeling
that things are crashing in on me.
 In between attacks there is this dread
and anxiety that it’s going to happen
again*
Obsessive-Compulsive Disorder

 I couldn’t do anything without rituals

 I would wash my hair three times as
opposed to once because three was a
good luck number
 I knew the rituals didn’t make sense,
 I was deeply ashamed of them,
 But I couldn’t seem to overcome them*
Post-Traumatic Stress Disorder

 “I was stabbed when I was 25 years old

 For a long time, I spoke about it as
something that happened to someone
else.
 Then I started having flashbacks.
 They kind of came over me like a splash
of water.
 I would be terrified *
Social Phobia (Social Anxiety Disorder)

 In any social situation, I felt fear

 I would be anxious before I even left
the house
 When I would walk into a room full of
people, I’d turn red
 It was humiliating. I felt so clumsy, I
couldn’t wait to get out.” *
Generalized Anxiety Disorder (GAD)

 “I always thought I was just a worrier.

 I’d feel keyed up and unable to relax.
 At times it would come and go, and at
times it would be constant.
 It could go on for days.
 “I’d have terrible sleeping problems.
 There were times I’d wake up wired in
the middle of the night. *
Specific phobias
Treatment of Anxiety Disorders

 Anti-Anxiety Drugs
 Antidepressants
 Beta-Blockers –Propranolool
 Cognitive-Behavioral Therapy
 Adjunctive treatments
 Antihistaminics-Produce sedation rather
than sp.anxiolysis
 Betablockers- Social phobias, reduce
symptoms, situational anxiety.
 Clonidine- Useful in anxiety associated
hyperadrenergic crisis
 Future:

• CCK antagonists
• CRF antagonists*
 Contradiction!
 Excess of 5HT→Anxiety.OCN←SSRIs ?
 Hypothesis only hypothesis. Nothing more.
 SSRIs effective in OCN = 5HT dysfunction(def)
 40% do not respond. Neuroleptic+SSRI give
relief =DA dysfunction (DA excess)
 Action of antidepressant independent of ‘AD’
action-Not reducing dep.elements in OCN
 Dose of SSRIs more for anxiety
 Effect more delayed
Antipsychotics
Neuroleptics

Antischizophrenics ×
Major tranquilizers ×
 Psychoses
 Difficult to define
 Word is misused

}
 Mental illness,
 psychotic killers,

Psychosis
 psychotic rage,
 crazy,
 madness
Symptoms- Psychoses
 Positive
• Delusions
• Hallucinations
• Disorganized
speech/behaviour
 Negative
• Emotional withdrawal
• Poor rapport
• Social withdrawal

Allogia- Decreases fluency of speech

Anhedonia-Lack of pleasure
Biological basis of Psychosis

Dopamine
hypothesis
Glutamate theory
Serotonin theory
DA hypothesis- Excessive DA activity
 For:
• PET→ ↑DA receptor density in Schizo.
• PM → ↑ Receptor density
• Levodopa(DA precursor), Apomorphine
(DA agonist) → ↑DA activity →
Aggravate Schizo
• Most antipsychotics block D2 receptors
• Metabolites of DA(HVA) ↑in Schizo and
↓ after treatment*
DA hypothesis-
 Against:
• Antipsychotics not always effective
• Atypical antipsychotics do not have
much action on D2 receptors*
DA receptors
 D12345
 D1 like---- D1 and D5
 D2 like---- D2 D3 and D4

 D2 agonists→Psychoses
 D2 antagonists → Antipsychotics
• Nigrostriatal
• Mesolimbic
• Mesocortical 4 DA pathways in brain
• Tuberoinfundibular
 DA pathways
 Meso-limbic→Brain stem to Limbic area →
Over activity → Delusions & Hallucinations
 Nigro-striatal → Controls movements →
Antipsychotics block → Parkinsonism like
symptoms[Neuroleptics] →Tardive
dyskinesia
 Mesocortical →Role not established-+ve
symptoms
 Tubero-infundibular → Hypo →Pitutary
→Controls prolactin secretion*
 Nigrostriatal EPRs

Mesolimbic Relief of psychosis

Increase in
Mesocortical
Negative symptoms

Tubero-infundibular ↑ prolactin

Effect of DA rec.block by neuroleptics in DA pathways

 Glutamate theory
 GABA-ergic neurones → Sensory gate

↑ ↑
Glutamate DA
[Excitatory] [Inhibitory]
Too little Too much

Psychoses
Others
 Serotonin theory
 NA theory
Early Tt
 Sigmund Freud-Neurosis
 Isolation
 Restraint
 Sleep therapy
 Insulin shock
 ECT
 1950-CPZ*
Mentally ill in chains in a 'mental
home’
Twenty-seven mentally ill people died in
the early hours of August 6,2001
when a fire engulfed the thatched roof of the
Moideen Badusha Mental Home at Erwadi,
 Antipsychotics
 Classical:  Atypical
2. Phenothiazines • Clozapine
 Aliphatic---Chlorpromazine • Risperidone
Triflupromazine • Olanzapine
 Piperidine---Thioridazine • Quetiapine
 Piperazine—Trifluperazine, • Aripiprazole
Fluphenazine • Ziprasidone
 Butyrophenones—
Haloperidol, Trifluperidol,
Penfluperidol,
 Thioxanthines—Flupenthixol
 Others—Pimozide, Loxapine
Pharmacological actions[CPZ]
 CNS
 In Normal person:

• Indifference to surroundings,
• Psychomotor slowing,
• Drowsiness,
• Unpleasant effects-
• Neuroleptic syndrome*
 In Psychotics:
 Reduces irrational behaviour
 ↓Aggression and agitation
 ↓Psychotic symptoms
 Sedation-Tolerance develops
 Antipsychotic effect take longer to
manifest-No tolerance
 ↓Seizure threshold
 Antiemetic
 CAR avoided-Not unconditional response*
 ANS:
• α Blockade & Anticholinergic
• LA- irritant
• CVS: Hypotension, QT prolongation
 Endocrine:
• Increase prolactin release
• Gynecomastia, Galactorrhea
• Amennorhea, infertility-Gn secretion↓
PK
 Oral—BA is low
 Protein bound
 Large vol of dist.
 Metabolism-CYP2D6*
Th.action & side effects-Classical antipsychotics
SDA
Atypical-Weak D2 block & Potent 5HT2
antagonism
 Clozapine most complicated drug in
psychopharmacology
 Interacts with 9 NT receptors
 3- α`1, H1, M1, Blockade-ADE
 6- with DA and 5HT receptor subtypes-
Probably useful
 None explains agranulocytosis
 EPRs less
 Improve negative functions*
Atypical
 Risperidone:
 EPRs less only in low doses
 Less epileptogenic
 Rise In BP with SSRIs
 Olanzapine
 Resembles clozapine, Antimuscaranic,
 Both +ve & -ve symptoms
 Less EPRs, epileptogenic
 Wt.gain
 Others: Quetiapine, Aripiprazole, Ziprasidone
 What is Atypical about “Atypical”?

 Unique receptor affinity-5HT2 Not D2

 Effective against +ve & -ve
symptoms
 Effective in Pts refractory to
classical
 Less liability to cause EPRs
Ad.Effects

 Dystonia?
 -----Distorted tone
 Dyskinesia?
 -----Distorted movement
 Tardive?
 ----Late appearance of symptoms
 Akathisia ?
 Motor restlesness*
Adverse effects of antipsychotics

Type Manifestations Mechanism

Loss of accomodation, dry M1Blockade
mouth, constipation
ANS Post.Hypoten., Impotence, Alpha blockade
failure to ejaculate
EPRs, dystonias, akathesia DA rec.blockade

CNS Tardive dyskinesia Supersensitivity

of DA rec.
Toxic-confusional state Muscarinic
blockade
Endocrine Amenorrhea-galactorrhea, DA rec block &
infertility, impotence Hyperprolactinemi
a
Others Weight gain H1 & 5HT2 block
 Acute muscle dystonia:
• Common –children
• Muscle spasm, facial, neck, lock
jaw
• Self limiting
• Tt.Promethazine*
 Akathisia:

• Restlessness(Inner),leads to
moving about
• 1-8 weeks
• No effective tt
• Reduce dose*
 Tardive dyskinesia:
• Serious
• Disabling & irreversible
• Gets worse when antipsychotic stopped
• Involuntary movements of face, tongue,
limbs
• Less with Atypical
• Supersensitivity of DA rec.
• May be due to excitotoxicity*
 TD appears years of antipsychotic
drug use,
 Tongue protrusion
 Grimacing
 Rapid eye blinking
 Lip smacking, pursing, or puckering
 Rapid movement of the arms or legs
 Other involuntary movements of the
head, face, neck and tongue muscles
Tardive dyskinesia
 Hyperthermic syndromes
Syndrome Precipitated by drug Clinical.present. Tt

Serotonin SSRIs, MAOIs, HTN, BZDP, Paralysis,

syndrome Linezolid, Tramadol, II Hyperthermia, intubation, 5HT2
gen.antidep, Fentanyl, tremor, block with
Ondansetron, mydriasis, Cyproheptadine
Sumatriptan, LSD, diarrhea
Ginseng etc.
Malignant Vol.anesthetics, Hyperthermia, Dantrolene,
hyperthermi Sch HTN, cooling`
a Tachycardia
Malignant Classical Severe Stop drug,
Neuroleptic antipsychotics, Parkinsonism, Diphenhydramine
syndrome High doses of HTN, (Parenteral),
potent drugs Hyperthermia cooling,
BZDP,Dantrolene
Bromocricptine
 Other ADE
 Wt.gain(Atypical)
 Retinal detachment
 Cholestatic jaundice
 Skin rashes
 Agranulocytosis
 Myocarditis*
Characterstic Adverse effects

 Clozapine→
Agranulocytosis(Metabolite)
 Thioridazone → Card.arrhythmia
 Ziprasidone →QT prologation
 Quitiapine → Cataract*
Overview of adverse effects

Typical Atypical
 EPRs, TD, Dystonia  DM
 Akathesia  Hypercholesterolemia
 Hyperprolactinemia  Agranulocytosis(Cloz)
 Sedation  Seizures
 Mod wt gain  Wt.gain(Cloz.Olanza.)
 Post.hypo.  Prolonged QT
 Neuro.Malig.synd (Ziprasidone)
 QT, Arrhythmia
(Thioridazone)
 Drug interactions
 Neuroleptics  CNS depressants
Potentiate (Alcohol, opioids,
 Neuroleptics antihistaminics)-
Block  Levodopa actions &
 Neuroleptics DA agonists in Park.
Reduce  Anti hypertensive
action of Clonidine,
 Reduce blood levels Methyldopa
Of Neuroleptics  Enzyme
inducers(Barb)
 ????????
 Metoclorpropamide&
CPZ
 Antipsychotics- uses
 Psychoses
 Schizophrenia
 Mania
 Organic brain syndromes
 Anxiety
 Antiemetic, Hiccoughs
 Neuroleptanesthesia
 Tetanus
 Alcoholic hallucinosis*
 Schizophrenia
 Treatment is life long
 Pt can lead fairly normal life
 Some do not respond
 Controls positive symptoms better
 Choice of drug is empirical
 Clozapine is the reserve drug in resistant
cases
 Atypical –less toxic
 Atypical-for long term use*
In Mania
 Li takes longer time to take effect
 For rapid control-CPZ or Haloperidol
used –i.m or i.v.
Anxiety
 Not routinely
 Only resistant/psychotic basis
General principles
 Dose individualized by titration
 Takes 2-4 months for effect
 Aggressive symptoms controlled by
parenterals quickly
 Antidepressants or anxiolytics may be
needed
 Depot injections-once in 2-4 weeks*
Therapeutic overview
Typical Atypical
 +ve symptoms  +ve & -ve
 Affinity for D2 Rec  Less affinity for D2

 Blocks 5HT2A Rec.

 Resistance cases
 Less ad.effects
Outcome
 Patients with early onset of schizophrenia are
more often male-worse outcome
 Patients with later onset are more likely to
be female -more hopeful prognoses
 30% of patients diagnosed with schizophrenia
recover completely
 Majority experience some improvement
 Stressful life events and a hostile or
emotionally intense family environment-
Adverse outcome
 Most important component of long-term care
of schizophrenia is compliance for
antipsychotic medications
 Antidep & Antipsych
Antidep[TCA] Antipsycho[CPZ]
 5HT, NA, DA reuptake  DA, 5HT, receptor
inhibition antagonism
 [Therapeutic effect]  [Therapeutic effect]

 M1, α1, H1, Antagonism  M1, α 1, H1, Antagonism

 [Toxicity]  [Toxicity]
Primary use of antipsychotics is

A. Schizophrenia
B. Epilepsy
C. Depression
D. Alchoholism

 A
Other uses of antipsychotics include all of the
following except

A. Acute mania
B. Siezures
C. Alcoholic hallucinosis
D. Inntractable hiccough

 B
Antipsychotic drugs may react with any of the
following receptors EXCEPT
A. D1
B. D2
C. α adrenergic
D. β adrenergic

D
Therapeutic benefit of antipsychotics results from
blockade of which of the following receptors?
A. α Adrenergic
B. β Adrenergic
C. Cholinergic
D. D2 Dopamine

D
EPRs of antipsychotics result from blockade of
which receptors?

A. Dopaminergic
B. Adrenergic
C. Cholinergic
D. Histaminergic

A
Sedation results from blockade of which receptors?

A. Histaminergic
B. Dopaminergic
C. Serotonin
D. Adrenergic

A
Postural hypotension results from
blockade of which receptors?
A. α Adrenergic
B. β Adrenergic
C. D1 Dopaminergic
D. D2 dopaminergic

A
Tardive dyskinesia
A. After prolonged treatment with
Antipsychotics
B. May be irreversible
C. Involves abnormal movements
D. All of the above
D
Antipsychotic induced gynecomastia occurs due to
blockade of which receptors?

A. α Adrenergic
B. β Adrenergic
C. D1 Dopaminergic
D. D2 dopaminergic

D
Antipsychotics do not include
A. Buspirone
B. Butyrophenones
C. Phenothiazines
D. Thioxanthines

A
Which drug has the lowest
incidence of EPRs?
A. Chlorpromazine
B. Haloperidol
C. Clozapine
D. Thiothixene

C
Which of following drugs used as
anxiolytic?
A. Phenobarbitone
B. Buspiron
C. Risperidone
D. Clozapine