PSYCHOPHARMA COLOGY Dr Sujit Kumar Kar MD Lecturer

PSYCHOPHARMA COLOGY Dr. Sujit Kumar Kar, MD Lecturer Department of Psychiatry King George’s Medical University

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 q Agonist q Antagon ists

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/1 st generation = D 2 receptor antagonist Effective against +ve > -ve Atypicals/2 nd 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 Symptom Severity 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 11/6/2020 Nausea, constipation, vomiting, dyspepsia, diarrhea Autonomic Nervous System Dry mouth, urinary retention, blurred vision, sweating 36

Antidepressants and the Cytochrome P 450 System • Antidepressants and mood stabilizers may be inhibitors, inducers or substrates of one or more cytochrome P 450 isoenzymes • Knowledge of their P 450 profile is useful in predicting drug-drug interactions • When some isoenzymes are absent of inhibited, others may offer a secondary metabolic pathway • P 450 1 A 2, 2 C (subfamily), 2 D 6 and 3 A 4 are especially important to antidepressant metabolism and 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 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 m. Eq/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 • • • 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? • 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?