Dr.Sujit%20Kumar%20Kar,%20MD

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• Dr.Sujit Kumar Kar, MD
• Lecturer
• Department of Psychiatry
• King Georges 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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Pharmacokinetics

• Drug molecules interact with target sites to
  effect the nervous system
• The 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 effect
• Drugs vary in effectiveness
• Different sites of action
• Different 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 effectiveness
• Tolerance 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 Transmission

• Transmitter substances are
• Synthesized, stored, released, and terminated
• Susceptible 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 receptor
• Indirect 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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Neurotransmitters Go through 7 steps

• Synthesis
• Storage
• Enzymatic destruction if not stored
• Exocytosis
• Termination of release via binding with
  autorecptors
• Binding to receptors
• Inactivated
• Drugs are developed that address these actions as
  an AGONIST (mimic the NT ) or ANTAGONIST (block
  the NT)

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Psychopharmacologic DrugsWork over A Spectrum
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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
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Antipsychotics

• Treat psychotic symptoms.
• Divided into
• Typical/1st generation D2 receptor antagonist
• Effective against ve gt -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

• Atypicals
• Risperidone (4-8)
• Olanzapine (10-20)
• Quetiapine (600-1200)
• Clozapine (100-600)

• Typicals
• Haloperidol (5-15) Thioridazine(100-300)
• Chlorpormazine (50-400)

Lower 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
Remission
Recovery
Normal
Relapse
Recurrence
Response
Relapse
gt 50 STOP Rx
Symptom Severity
65 to 70 STOP Rx
Acute Phase (3 months)
Continuation Phase (6-12 months)
Maintenance Phase (years)
Time
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Potential Adverse Effects ofAntidepressant
Therapy
Central Nervous System Dizziness, cognitive
impairment, sedation, light-headedness, somnolence
, nervousness, insomnia, headache,
tremor,changes in satiety and appetite
Cardiac Orthostasis hypertension heart
block,tachycardia
Gastrointestinal Nausea, constipation, vomiting,
dyspepsia, diarrhea
Urogenital Erectile dysfunction, ejaculation
disorder, anorgasmia, priapism
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 Level 4-12 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 crisis
• Associated with MAOIs.
• Neuroleptic malignant syndrome
• Autonomic instability, severe EPS, delirium, ?CK,
  ARF, myoglobulinuria
• Serotonin syndrome
• Restlessness, myoclonus, ?reflexes, tremors,
  confusion.
• Due to combination of serotenergic agents
• Agranulocytosis
• ( Clozapine, carbamazepine).

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Prescribing a Psychotropic AgentAfter 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?

• 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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Thank you