Psycho pharmacologyAnxiolytics and Anti psychotics

Dr.U.P.RathnakarMD. DIH. PGDHM

Psychotropic drugs

Psychoses• Severe mental illness• Not in touch with reality• Hallucinations• Delusions• Abnormal behaviour

Eg: Schizophrenia.,

Affective-Mania&Dep

NeurosesNeuroses Less severe(Extreme Less severe(Extreme

suffering)suffering) In touch with realityIn touch with reality Eg: Dep without Eg: Dep without

psychoses, Panic psychoses, Panic disorder, GAD, OCN, disorder, GAD, OCN, Phobias, PTSD, Eating Phobias, PTSD, Eating disoders, Sleep disoders, Sleep disorderdisorder

Others-Alzheimers, Sub.abuse, Pers.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

Psychotic too builds castles in air but…

But does not live in it [In touch with reality]

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 depressantsMood 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-implicated1) GABA-BNZDP Receptor

complex2) NA system-Locus coeruleus3) Serotonin ( 5HT)*

GABA

GABA inhibitoryCl- Channels, GABA- ABNZDP facilitates*

Nor epinephrine

NA Cell bodies in Locus Coeruleus.

Over active in anxiety statesResponsible for subjective

responses.Clonidine, Beta blockers reduce

subjective/ emotional aspects.*

Anxiety

Tachycardia

Dilated pupils

Tremors

Sweating

Over activity of NA system

Serotonin (5HT) Excess→ Anxiety Defeciency → Depression Partial agonists → Modulate →Effective in

bothSEROTONIN

Anxiety

Depression

← Partial agonists

Anxiety

TOO BRIGHT

Depression

TOO DARK

Normal

EQUALLY LIGHTED

5HT-Excess 5 HT-Defeciency

5 HTPartial agonist

5 HTPartial agonist

Switch analogy-Serotonin hypothesis

Switch on Switch off

Partially on/off

Anti anxiety drugs

Benzodiazepines: Alprazolam. Chlodiazepoxide, Oxazepam, Lorazepam, Diazepam

Azapirones: Buspirone, Gepirone, Ispapirone

Beta blockersOthers: 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 fecilitationSite: Limbic system*

Adverse effects

Sedation Psychomotor impairment Confusional state Hypersensitivity

Individual Drugs: Difference is PK.*

Part.inv.agonist

Inv.agonist

Antagonist

Part.agonist

Agonist

Anxiolytic Sed.Hypn Musc.relax. Anit conv. Amnestic Dependency

Anxiolytic ONLY

No clinical effect

Promnistic Anxiogenic Pro conv.

Promnistic Anxiogenic Pro conv

Spectrum of activity of agonists at BZDP receptor

FUTURE

Azapirones

5HT1A partial agonist No sedation No physical dependence [Also effective in depression-Not used] No drug interactionDisadvantages 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

AntipsychoticsNeuroleptics

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 speechAnhedonia-Lack of pleasure

Biological basis of Psychosis

Dopamine hypothesis

Glutamate theorySerotonin 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

1. Nigrostriatal2. Mesolimbic3. Mesocortical4. Tuberoinfundibular

4 DA pathways in brain

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

MesocorticalIncrease inNegative 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 6,2001when a fire engulfed the thatched roof of theMoideen Badusha Mental Home at Erwadi,

Antipsychotics Classical:1. Phenothiazines Aliphatic---Chlorpromazine

Triflupromazine Piperidine---Thioridazine Piperazine—Trifluperazine,

Fluphenazine2. Butyrophenones—

Haloperidol, Trifluperidol, Penfluperidol,

3. Thioxanthines—Flupenthixol4. Others—Pimozide, Loxapine

Atypical• Clozapine• Risperidone• Olanzapine• Quetiapine• Aripiprazole• Ziprasidone

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

ANS

Loss of accomodation, dry mouth, constipation

M1Blockade

Post.Hypoten., Impotence, failure to ejaculate

Alpha blockade

CNS

EPRs, dystonias, akathesia DA rec.blockade

Tardive dyskinesia Supersensitivity of DA rec.

Toxic-confusional state Muscarinic blockade

Endocrine

Amenorrhea-galactorrhea, infertility, impotence

DA rec block & Hyperprolactinemia

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 syndromesSyndrome Precipitated by

drugClinical.present.

Tt

Serotonin syndrome

SSRIs, MAOIs, Linezolid, Tramadol, II gen.antidep, Fentanyl, Ondansetron, Sumatriptan, LSD, Ginseng etc.

HTN, Hyperthermia, tremor, mydriasis, diarrhea

BZDP, Paralysis, intubation, 5HT2 block with Cyproheptadine

Malignant hyperthermia

Vol.anesthetics, Sch

Hyperthermia, HTN, Tachycardia

Dantrolene, cooling`

Malignant Neuroleptic syndrome

Classical antipsychotics,High doses of potent drugs

Severe Parkinsonism, HTN, Hyperthermia

Stop drug, Diphenhydramine(Parenteral), cooling, BZDP,DantroleneBromocricptine

Other ADE

Wt.gain(Atypical) Retinal detachment Cholestatic jaundice Skin rashes Agranulocytosis Myocarditis*

Characterstic Adverse effects

Clozapine→ Agranulocytosis(Metabolite)

Thioridazone → Card.arrhythmia

Ziprasidone →QT prologationQuitiapine → Cataract*

Overview of adverse effects

Typical EPRs, TD, Dystonia Akathesia Hyperprolactinemia Sedation Mod wt gain Post.hypo. Neuro.Malig.synd QT, Arrhythmia

(Thioridazone)

Atypical DM Hypercholesterolemia Agranulocytosis(Cloz)

Seizures Wt.gain(Cloz.Olanza.) Prolonged QT

(Ziprasidone)

Drug interactions

Neuroleptics Potentiate

Neuroleptics Block

Neuroleptics Reduce

Reduce blood levels Of Neuroleptics

????????

CNS depressants (Alcohol, opioids, antihistaminics)-

Levodopa actions & DA agonists in Park.

Anti hypertensive action of Clonidine, Methyldopa

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 +ve symptoms Affinity for D2 Rec

Atypical +ve & -ve 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]

5HT, NA, DA reuptake inhibition

[Therapeutic effect]

M1, α1, H1, Antagonism [Toxicity]

Antipsycho[CPZ]

DA, 5HT, receptor antagonism

[Therapeutic effect]

M1, α 1, H1, Antagonism

[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

B