Transcript Psychopharmacology Dr. Sujit Kumar kar

PSYCHOPHARMACOLOGY
Dr.Sujit Kumar Kar, MD
Lecturer
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)
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
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
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
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
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
Neurotransmitters Go
through 7 steps
1.
2.
3.
4.
5.
6.
7.
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)
Psychopharmacologic Drugs
Work over A Spectrum
Antipsychotics
Antidepressants
Anxiolytics/sedatives
Mood stabilizing agents
Others
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
Antipsychotics
Average 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 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
Normal
Remission
Relapse
Recovery
Recurrence
Response
Relapse
> 50%
STOP
Rx
65 to 70%
STOP
Rx
Acute
Continuation
Maintenance
Phase (3 months+) Phase (6-12 months) Phase (years)
Time
Potential Adverse Effects of
Antidepressant Therapy
Cardiac
Orthostasis
hypertension
heart block,
tachycardia
Central Nervous System
Dizziness, cognitive impairment,
sedation, light-headedness,
somnolence, nervousness,
insomnia, headache, tremor,
changes in satiety and appetite
Gastrointestinal
Urogenital
Erectile dysfunction,
ejaculation disorder,
anorgasmia,
priapism
4/7/2016
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 drugdrug 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
Therapeutic Level
Common S/E
Dangerous S/E
4-12 mg/ml
Dizziness, sedation,
ataxia, leukopenia,
rash,
Agranulocytosis,
teratogenicity (neural
tube defect), induction
of hepatic metabolism
Valproic Acid
Lithium
40-100 mg/ml
0.5-1.2 mEq/L
nausea, diarrhea,
ataxia, dysarthria,
weight gain, slight
elevation of hepatic
transaminases
teratogenic (neural
tube defects)
nausea,
hypothyroidism,
tremors, dysarthria,
ataxia
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 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).
Prescribing a Psychotropic Agent
After Diagnostic Assessment
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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 Response
What to do?
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Check Compliance & availability
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Review the diagnosis
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Is the dose appropriate?
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Is the duration of treatment long enough?
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Any ongoing substance abuse?
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Other drugs/preparation causing drug-drug Interaction?
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Individual Variation?