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Dr.Sujit Kumar Kar, MDLecturer
Department of Psychiatry
King George’s Medical University
Lucknow, U.P
Dr.Sujit Kumar Kar, MDLecturer
Department of Psychiatry
King George’s Medical University
Lucknow, U.P
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Psychopharmacology
Psychopharmacology is the study of the effects of drugs on affect, cognition, and behavior
The term drug has many meanings:• Medication to treat a disease• A chemical that is likely to be abused• An “exogenous” chemical that significantly alters the
function of certain bodily cells when taken in relatively low doses (chemical is not required for normal cellular functioning)
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PharmacokineticsDrug molecules interact with target sites to effect the
nervous systemThe drug must be absorbed into the bloodstream and then
carried to the target site(s)Pharmacokinetics is the study of drug absorption,
distribution within body, and drug elimination– Absorption depends on the route of administration– Drug distribution depends on how soluble the drug
molecule is in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)
– Drug elimination is accomplished by excretion into urine and/or by inactivation by enzymes in the liver
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Drug Effectiveness
Dose-response (DR) curve: Depicts the relation between drug dose and magnitude of drug effect
Drugs can have more than one effectDrugs vary in effectiveness
Different sites of actionDifferent affinities for receptors
The effectiveness of a drug is considered relative to its safety (therapeutic index)
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Routes of Drug Administration
Routes of drug administration into the body– Intravenous (IV): into a vein (rapid absorption)– Intraperitoneal (IP): into the gut (used in lab
animals) – Subcutaneous (SC): under the skin– Intramuscular (IM): into a muscle– Inhalation of the drug into the lungs– Topical: absorbed through the skin– Oral (PO): via the mouth
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Tolerance and Sensitization
Repeated administration of a drug can alter its subsequent effectivenessTolerance: Repeated drug administration results in
diminished drug effect (or requires increased dosage to maintain constant effect)
• Withdrawal effects are often the opposite of the drug effect and often accompanies tolerance
• Tolerance can reflect decreased drug-receptor binding or reduced postsynaptic action of the drug
Sensitization: Repeated drug administration results in heightened drug effectiveness
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Synaptic TransmissionTransmitter substances are
Synthesized, stored, released, and terminatedSusceptible to drug manipulation
Definitions:Direct agonist: a drug that binds to and activates a
receptor Antagonist: a drug that binds to but does not
activate a receptorIndirect antagonists are drugs that interfere with the
normal action of a neurotransmitter without binding to its receptor site
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Drug Action on Synaptic Transmission
Agonist
Antagonists
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Presynaptic Drug Actions
Presynaptic autoreceptors regulate the amount of NT released from the axon terminal– Drugs that activate presynaptic autoreceptors
reduce the amount of NT released, an antagonistic action
– Drugs that inactivate presynaptic autoreceptors increase the amount of NT released, an agonistic action
Presynaptic heteroreceptors are sensitive to NT released by another neuron, can be inhibitory or facilitatory
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Neuromodulators
Neurotransmitter binding to receptors produces either EPSPs or IPSPs– Glutamate produces EPSPs – GABA produces IPSPs
Neuromodulators alter the action of systems of neurons that transmit information using either glutamate or GABA
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Objectives
• Classification of psychotropic medications.
• Mechanism of action of psychotropic medications.
• Choose a psychotropic medication rationally.
• Know common & dangerous adverse effects.
• Manage failure of response to a therapeutic trial.
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Why Medications ?
Dopaminergic theory of Schizophrenia
Monoaminergic theory of Mood Disorders
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1. Synthesis2. Storage 3. Enzymatic destruction if not stored4. Exocytosis5. Termination of release via binding with autorecptors6. Binding to receptors7. Inactivated
Drugs are developed that address these actions as an AGONIST (mimic the NT ) or ANTAGONIST (block the NT)
Neurotransmitters Go through 7 steps
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Psychopharmacologic DrugsWork over A Spectrum
AntipsychoticsAntipsychotics
Mood stabilizing agentsMood stabilizing agents
OthersOthersAnxiolytics/sedativesAnxiolytics/sedatives
AntidepressantsAntidepressants
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General principles about adverse effects
• Psychopharmacological agents affect the whole body.
• Remember the common and dangerous side effects.
• They indicate the drug is working.
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Antipsychotics
• Treat psychotic symptoms.• Divided into:Typical/1st generation = D2 receptor antagonist Effective against +ve > -ve Atypicals/2nd generation = Serotonin-dopamine antagonists Effective against both +ve & -ve sx • Requires ~ one month for significant antipsychotic effect
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AntipsychoticsAverage Daily Doses in mg
Typicals
Haloperidol (5-15) Thioridazine(100-300)
Chlorpormazine (50-400)
Atypicals
Risperidone (4-8) Olanzapine (10-20)
Quetiapine (600-1200) Clozapine (100-600)
Lower numbers indicate higher potencyLower numbers indicate higher potency
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Antidepressants
• Used in many psychiatric disorders other than Depression.
• Full clinical response in 6-8 weeks in major depression, up to 6/12 in obsessive compulsive disorder.
Examples: Fluoxetine & Paroxetine (20-60 mg/d)Fluovoxamine & Sertraline (50-200 mg/d)Imipramine(200-300 mg/d)
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THREE PHASES OF TREATMENT
Time
Sym
pto
m S
ever
ity
Normal
AcutePhase (3 months+)
ContinuationPhase (6-12 months)
MaintenancePhase (years)
Response
RemissionRemission
Relapse
Relapse Recurrence
> 50% STOP Rx
65 to 70% STOP Rx
RecoveryRecovery
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Potential Adverse Effects ofAntidepressant Therapy
04/19/23 36
Cardiac
Orthostasishypertensionheart block,tachycardia
Urogenital
Erectile dysfunction,ejaculation disorder,anorgasmia, priapism
Central Nervous System
Dizziness, cognitive impairment,sedation, light-headedness,somnolence, nervousness,insomnia, headache, tremor,changes in satiety and appetite
Gastrointestinal
Nausea, constipation,vomiting, dyspepsia,diarrhea
Autonomic Nervous System
Dry mouth, urinary retention,blurred vision, sweating
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Antidepressants and the Cytochrome P450 System
• Antidepressants and mood stabilizers may be inhibitors, inducers or substrates of one or more cytochrome P450 isoenzymes
• Knowledge of their P450 profile is useful in predicting drug-drug interactions
• When some isoenzymes are absent of inhibited, others may offer a secondary metabolic pathway
• P450 1A2, 2C (subfamily), 2D6 and 3A4 are especially important to antidepressant metabolism and drug-drug interactions
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Mood Stabilizers
• Lithium, Valproic acid, Carbamazepine, Lamotrigine, Gabapentine, Topiramate.
• Used in the treatment of Bipolar affective disorder and similar conditions associated with impulsivity.
• Drug level measurements are available for many of them.
• Mechanism of action is not clearly understod.
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Common Mood Stabilizers
Carbamazepine Valproic Acid Lithium
Therapeutic Level4-12 mg/ml
40-100 mg/ml 0.5-1.2 mEq/L
Common S/E
Dizziness, sedation, ataxia, leukopenia,
rash,
nausea, diarrhea, ataxia, dysarthria, weight gain, slight
elevation of hepatic transaminases
nausea, hypothyroidism,
tremors, dysarthria, ataxia
Dangerous S/E
Agranulocytosis, teratogenicity (neural tube defect), induction of hepatic metabolism
teratogenic (neural tube defects)
sinus node dysfunction, T-wave
changes,
teratogenic (cardiac anomalies)
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Anxiolytics/sedatives
• Benzodiazepines, Trazodone, Zolpidem and others
• Alprazolam, clonazepam, lorazepam, diazepam.
• Risk of dependence & withdrawal.
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Other pharmacological agents
Cholinesterase inhibitors:Donepezil, Rivastigmine, Galantamine, (Tacrine has been
withdrawn)
Sympathomimetics:Methylphenidate, Dextroamphetamine.
Anticholinergic agents:Procyclidine, Benztropine
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Dangerous Side Effects
Hypertensive crisisAssociated with MAOIs.
Neuroleptic malignant syndromeAutonomic instability, severe EPS, delirium, ↑CK, ARF, myoglobulinuria
Serotonin syndromeRestlessness, myoclonus, ↑reflexes, tremors, confusion.Due to combination of serotenergic agents
Agranulocytosis ( Clozapine, carbamazepine).
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Prescribing a Psychotropic Agent
After Diagnostic Assessment
• Choose a medication based on FDA approval• Family or personal hx of response• Adverse effects vs. key symptoms• Starting dose• Monitor side effects & clinical response• Adjust dose if needed
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Failure of ResponseWhat to do?
Failure of ResponseWhat to do?
• Check Compliance & availability
• Review the diagnosis
• Is the dose appropriate?
• Is the duration of treatment long enough?
• Any ongoing substance abuse?
• Other drugs/preparation causing drug-drug Interaction?
• Individual Variation?
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