pharmacology of anxiolytics & anti-psychotics
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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
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