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

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)

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

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

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

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

Drug Action on Synaptic Transmission

Agonist

Antagonists

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

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

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.

Why Medications ?

Dopaminergic theory of Schizophrenia

Monoaminergic theory of Mood Disorders

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

Psychopharmacologic DrugsWork over A Spectrum

AntipsychoticsAntipsychotics

Mood stabilizing agentsMood stabilizing agents

OthersOthersAnxiolytics/sedativesAnxiolytics/sedatives

AntidepressantsAntidepressants

General principles about adverse effects

• Psychopharmacological agents affect the whole body.

• Remember the common and dangerous side effects.

• They indicate the drug is working.

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

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

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)

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

Potential Adverse Effects ofAntidepressant Therapy

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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

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

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.

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)

Anxiolytics/sedatives

• Benzodiazepines, Trazodone, Zolpidem and others

• Alprazolam, clonazepam, lorazepam, diazepam.

• Risk of dependence & withdrawal.

Other pharmacological agents

Cholinesterase inhibitors:Donepezil, Rivastigmine, Galantamine, (Tacrine has been

withdrawn)

Sympathomimetics:Methylphenidate, Dextroamphetamine.

Anticholinergic agents:Procyclidine, Benztropine

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).

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

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?