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Drug interactions in psychiatry
Drug interactions are an important consideration in psychiatry. Several types of interactions can occur, including pharmaceutical, pharmacokinetic, and pharmacodynamic. Pharmacokinetic interactions can affect absorption, distribution, metabolism, and excretion of drugs. Many psychiatric medications are substrates, inhibitors, or inducers of cytochrome P450 enzymes, particularly CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Recognition of interactions is important to avoid adverse effects or lack of efficacy. Management may require dosage adjustments or choosing alternative medications.
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Drug interactions in psychiatry
- 1. Drug Interactions InPsychiatry PRESENTER: DR.PJ.CHAKMA,PGT,AMCH MODERATOR: DR.R.U.ZAMAN,ASSOC. PROF. AMCH 21/06/2013
- 2. Plan of presentation •Introduction • Importance of drug interaction • Risk factor • Type of interaction • Different drug interaction in psychiatry • Clinical consequences • Management • Conclusion • bibliography
- 3. introduction • A druginteraction, defined as the modification of the action of one drug by another, can be beneficial or harmful, or it can have no significant effect.This action can be synergistic or antagonistic • The risk that a pharmacological interaction will appear increases as a function of the no of combinations of drugs administered to a patient at the same time
- 4. importance Recognition of beneficialeffects and Recognition and prevention of adverse drug interactions Basic principles of drug-drug interactions in planning a therapeutic regimen.
- 5. Risk factor – Oldage – Polydrug misusers – Polypharmacy – Psychiatric patients taking high doses ofmedication – people in developing countries in which there is a high prevalence of self-medication – Irresponsible dispensing by a small minority of pharmacists
- 6. Role of Genetics •An individual's genetic makeup can alter their response to a drug. • A common example is the metabolism of ethanol .There are ethnic differences in the metabolism of ethanol by alcohol dehydrogenase.
- 7. Presentation of druginteractions A multitude of different types of serious adverse events (SAEs), such as sudden death, seizures,cardiac rhythm disturbances,delirium Poor tolerability (ie, patient is “sensitive” to adverse drug effect) Lack of efficacy (ie, patient is “resistant” to beneficial drug effect) Symptoms that mimic or lead to a misdiagnosis of a new disease The apparent worsening of the disease being treated Withdrawal symptoms or drug-seeking behavior on the part of the patient
- 8. Epidemiology of DrugInteractions • The overall prevalence of drug interactions is 50% to 60%. • Those that affect pharmacodynamics or pharmacokinetics have a prevalence of approximately 5% to 9%. • About 7% of hospitalizations are due to drug interactions.
- 9. Challenges in AnticipatingInteractions Drug potency, strength, dose Drug purity – contaminants, adulterants Research studies lacking, inconclusive, unethical Drug interaction information based on unproven theory or case reports with incomplete data Clients not forthcoming Over-the-counter drugs, herbal products and grapefruit juice not often reported by clients
- 10. Drug Interaction: DrugEffects in the Body
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- 15. Pharmaceutical When drugs aremixed outside the body prior to administration. For example, mixing chemically incompatible drugs before intravenous infusion can result In precipitation or inactivation.
- 16. Pharmacokinetic Interactions • Onedrug changes how the body handles other drugs, either increasing or decreasing blood levels of one or both drugs Absorption: (gut,skin) – drug movement from administration site to bloodstream (P-Glycoproteins, protein binding) Distribution – drug movement from bloodstream to the rest of the body – psychotropics must cross the blood brain barrier to reach their site of action Metabolism – transformation of drug by chemical processes(phase 1 metabolism= CYP450) PHASE II= conjugation Excretion or Elimination(urine,bile,gut) – routes of leaving the body for drug and drug metabolites
- 17. Effect of interactionat absorption • Delay n the rate of absorption- Antacid can decrease the rate of absorption of chlordizapoxide by increasing the pH • Alteration of dissolution of tablets • Elevation of gastric PH with antacids above the Pka of chlordiazepoxide (4.8) may reduce the dissolution rate • Change in the amount of drug absorbed – Decreased serum concentration – Increased serum concentration – Precipitation of the drug
- 18. • Precipitation :Ironmay decrease the antibacterial efficacy of tetracycline by chelation • Enzymatic reaction : Monoamine oxidase inhibitor and tyramine.(drugs-food interactions)
- 19. Pharmacodynamic Interactions: • Basedon the way the drug works on the body Additive / Synergistic - two drugs with the same effect – increased drug effects (e.g. euphoria, relaxation) – increased side effects (e.g. drowsiness, nausea, overdose) Opposing – two drugs with opposite effects – do not necessarily ‘cancel each other out’ Counterproductive – drug exacerbates underlying condition; more of a disease/drug interaction than true drug interaction
- 20. Pharamacodynamics: Where Drugs Act Foursites of action Receptors (those sites to which a neurotransmitter can specifically adhere to produce a change in the cell membranes) Ion channels Enzymes carrier Proteins Biological action depends on how its structure interacts with a receptor
- 21. Receptors Types of Action Agonist:same biologic action Antagonist: opposite effect Interactions with a receptor Selectivity: specific for a receptor Affinity: degree of attraction Intrinsic activity: ability to produce a biologic response once it is attached to receptor
- 22.
- 23. Protein Binding • Notas clinically relevant as previously believed. • Properties of a drug that predict clinically relevant displacement by protein binding: – Low clearance drugs – Low therapeutic index – Small volume of distribution – Examples: warfarin, tolbutamide, phenytoin
- 24. Protein Binding andUrinary Excretion of SRIs The Pharmacological Basis of Therapeutics; Goodman & Gilman; 10th Edition; 2001 *From Physician’s Desk Reference; 2004; page 1302
- 25. Protein Binding ofAtypical Antipsychotics 2005 Physicians’Desk Reference
- 26. Distribution of drug Whenthe drug leaves the systemic circulation and moves to various parts of the body • Drugs in the bloodstream are often bound to plasma proteins; only unbound drugs can leave the blood and affect target organs • Low serum albumin can increase availability of drugs and potentiate their effects
- 27. Factors affecting volumeof distribution Lipid solubility Degree of plasma protein binding Affinity for different tissue eg duration of action of thiopental, first dose lorazepam and diazepam.
- 28. Drug metabolism • Primarilyin the liver; cytochrome P-450 enzyme system facilitates drug metabolism; metabolism generally changes fat soluble compounds to water soluble compounds that can be excreted – Enzyme mediated biotransformation – Cytochrome P450
- 29. Elimination Clearance: Total amountof blood, serum, or plasma from which a drug is completely removed per unit time Half-life: Time required for plasma concentrations of the drug to be reduced by 50% kidneys (responsible for excreating all water soluble substances) Some excreted via the liver,urine,faeces,saliva& sweat,milk, bile and delivered to the intestine may be reabsorbed in intestine and “re-circulate” (up to 20%)
- 30. Elimination Interactions – Glomerularfiltration: Chloral derivatives – Tubular re-absorption: • Alkalizing agent may enhance the excretion of Lithium or Tranylcypromine • Urinary acidifier such as may enhance excretion of imipramine, amitriptyline or amphetamines • (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs) should be used cautiously, if at all, in patients already receiving lithium.
- 31. Cytochrome P450 – Oxidasesystem – Metabolize endogenous compounds such as steroids and neuropeptides – Contain red pigmented heme – Absorb light at a wave length of 450 nm if bound to CO – Encoded by one particular gene – Grouped into families and subfamilies on the basis of amino acid sequences
- 32. Cytochrome P450 • Largestclass of enzymes catalyzing oxidation of organic substances in all living things 11,550+ identified ; 57 in humans High affinity for fat-soluble drugs Involved in metabolism of most psychiatric medications Inactivate drugs (or in some cases activate them) Chemicals may increase or decrease CYP activity Example: SSRIs inhibitors of the subfamily CYP2D6 Compounds in grapefruit juice inhibit CYP3A4 Tobacco induces CYP1A2
- 33. Cytochrome P450 Category meaningExamples Family numeral CYP450 1 Subfamily numeral + capital letter CYP450 1A Single gene or protein Arabic numeral + capital letter + numeral for individual gene CYP450 1A2
- 34. contd Iso enzymes >200 P450enzymes in nature at least 40 enzymes in humans
- 35. cytochrome p450 • Substrate –any drug metabolized by P450 enzymes • Inhibitor – any drug that inhibits the metabolism of a P450 substrate (strong, moderate, weak) • Inducer – anything that increases the amount of P450 enzymes (strong, moderate, weak)
- 37. P450 Variations • Somepeople have more than normal amounts of certain P450 enzymes (ultra-rapid metabolizers) • Some people have normal amounts (extensive metabolizers) • Some people have less than normal amounts (poor metabolizers
- 38. Effects of DrugInteraction Different types of serious adverse effects Poor tolerability Lack of efficacy Symptoms that mimic or lead to a misdiagnosis of a new disease The apparent worsening of the disease being treated Withdrawal symptoms or drug-seeking behavior on the part of the patient
- 39. Cytochrome P450 1A2 Antidepressant fluvoxamine Antibiotics ciprofloxacin fluoroquinolones furafylline Other cimetidine amiodarone interferon omeprazole tobacco Insulin Modafinil broccoli brusselsprouts char-grilled meat methylcholanthrene nafcillin INHIBITOR INDUCER
- 40.
- 41. Inhibitors and Inducersof 2C9
- 42.
- 43. Cytochrome P450 3A4 HIVAntivirals indinavir nelfinavir ritonavir Antibiotics clarithromycin itraconazole ketoconazole nefazodone saquinavir telithromycin erythromycin fluconazole Antidepressant Fluvoxamine Other verapamil,cimetidine amioderon nevirapine barbiturates carbamazepine oxcarbazepine glucocorticoids modafinil phenobarbital phenytoin pioglitazone rifabutin rifampin St. John's wort INHIBITOR INDUCER
- 44. Interaction of antipsychotics Clozapine 1A2 3A4 2D6 Fluoroquinolones, Fluvoxamine,sertraline Erythromycin, ketoconazole,ritonavir, cimetidine Ritonavir, quinidine, risperidone, fluoxetine, sertraline Smoking, Rifampin, carbamazepine, phenytoin, barbiturates Drug & CYP450 Inhibitor Inducer
- 45. contd Risperidone (2D6) Olanzepine( 1A2,2D6) Quetiapine(3A4) Ziprasidone (3A4) Aripiprazole (3A4,2D6) FLUOXETINE, PAROXETINE Fluvoxamine Ketoconazole, Erythromycin NONE NONE Rifampin, carbamazepine Phenytoin,PHB. Smoking,Carbamazepine Rifampin, carbamazepine, phenytoin, Barbiturates NONE NONE Drug & CYP450 Inhibitor Inducer
- 46. contd • others commoninteraction antacids dopamine agonists or antiparkinson”s Rx CNSdepressants such as analgesics, anxiolytics, and hypnotics
- 47. Antidepressants and theCytochrome 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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- 50. TCA • Phenytoin,valproate,carbamazepine • Verapamil,diltiazem,ketoconazole,cimetadine. smokingInhibit P450-3A4 • Adrenergic receptor blockade can worsen the orthostatic hypotension • antiarrhythmics and anticholinergic medications
- 51. Monoamine Oxidase Inhibitors •The combination of MAOIs and narcotics, particularly meperidine may cause a fatal interaction • With SSRIs can cause the serotonin syndrome.
- 53.
- 54. Drug Interactions withLithium • (ACE) inhibitors • Alprazolam • Amiloride • Antipsychotic agents • Fluoxetine • Ibuprofen • Indomethacin • Mefenamic acid • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Phenylbutazone • Thiazides diuretics • Spironolactone • Tetracycline, aminophyline Increase lithium level
- 55. contd • Caffeine • Carbonicanhydrase inhibitors • Laxatives • Osmotic diuretics • Theobromine • Theophylline Decrease lithium level
- 56. Increase Adverse Reactions •Atracurium • ECT • Carbamazepine • Fluoxetine • Fluvoxamine • Methyl DOPA • Verapamil • Succinyl choline
- 57. Benzodiazepine Drug Interactions Increasedmetabolism Decreased metabolism Carbamazepine Rifampin Corticosteroids,phenobarbitone, phenytoin Cimetidine Azole antifungals (ketoconazole, miconazole, itraconazole) Erythromycin Disulfiram Oral contraceptives,Fluvoxamine Fluoxetin isoniazide
- 58. Phenytoin • carbamazapine, phenobarbitalwill decrease plasma levels; • Isoniazide,cimetadine,warfarin, alcohol, diazapam, methylphenidate will increase plasma levels--- precipitate toxicity • Induces microsomal enzymes failure of ocp,digitoxin,doxycycline,theophyline
- 59. Valproate Drugs increased valproatelevel aspirin Cimetidine Erythromycin Fluoxetin Fluvoxamine ibuprofen Drugs that decreased valproate level Carbamazepine Phenobarbitone Rifampin ethosuximide
- 60. Carbamazepine Phenobarbital Primidone Phenytoin Cimetidine Diltiazem Erythromycin Fluoxetine Fluvoxamine Isoniazid Propoxyphene Valproic acid Verapamil increased decreased Reduce efficacy of haloperidol,ocp,& other antiepileptics drugs
- 61. Lamotrigine • Carbamazepine • Oxcarbazepine •Phenobarbital • Phenytoin Fluoxetin,valproate,erythromycin
- 62. Drug interaction withECT Drugs seizure duration threshold TCA”s Increased decreased MAOIs minimal effect no effect Lithium increased combination may lead delirium BZD”s Reduced raised SSRIs mild increase safe Venlafaxine minimal epileptogenic Propofol decrease increase Antipsychotics some increase decrease
- 63. Drug Interactions ofHerbal Medicines
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- 65.
- 66. Drug interactions withgrape fruit
- 67. Psychostimulants interactions MPH =Methylphenidate AMP= amphetamine
- 68. MPH = Methylphenidate DEX=Dextroamphetamine
- 71. Drug-Drug Interactions: approach •Take a medication history • Remember high risk patients • Evaluate therapeutic alternative – Dose spacing – Decreasing dose – Discontinue the drug – Add another agent to counter the interaction
- 72. Management of DrugInteractions • Inform all prescribers about current medications - GP’s, psychiatrists, dentist • When possible take all prescriptions to one pharmacy so there is one computer record • Ask pharmacist about OTC meds & check ingredient list on combination products (will sometimes change!!) • Scheduling different dosing times can sometimes minimize interaction (but not always) • Some interactions cannot be avoided, so close monitoring and dosage adjustment is essential
- 73. contd • Some websiteshave drug interaction programs, but significance of each interaction needs to be assessed and put in proper context by MD or pharmacist • Some interactions are more theoretical, and may not have clinical significance • Some drug interactions are good – Using a 2nd drug to decrease a “bad” metabolite of the first drug • Not all combinations can be anticipated or tested, so new drug interactions are being discovered every day!!
- 74. How to avoiddrug interaction • Beware and follow good clinical practice • Avoid multi target medication • Use available literature • When in doubt start low and go slow • Monitor for adverse out come
- 75. conclusions • Drug Interactionsare inevitable .There is also a lack of knowledge of the size of the problem and of the many pharmacological and host factors that determine whether or not an individual will have a particular interaction • Future research has been carried out into potentially hazardous interactions with different drugs, yet there is much that remains unknown.
- 76. bibliography • Kaplan andSadock’s Comprehensive Textbook of Psychiatry vol.1 by Benjamin J. Sadock and Virginia A Sadock 9th edition 2005, Williams and Wilkins • Textbook of Postgraduate Psychiatry, Vol.1 by J.N. Vyas and Niraj Ahuja, 2nd edition 2003 Jaypee Brothers Medical Publishers (P) Ltd • The south london and maudsley NHS foundation trust prescribing guidelines 10th edition • Jerald kay,Allan Tasman,wiley essentials of psuchiatry,2006 Richard A Harvey, Pamela C. Champe (2006) Lippincott’s Illustrated Reviews: Pharmacology: 3rd Edition. Lippincott Williams & Wilkins
- 77. contd • New OxfordTextbook of Psychiatry vol.1 by M.G. Gelder, Juan J. Lopez-Ibor Jr, Nancy C. Andreasen • Dr. Brunton, Parker, and Lazo: Goodman Gillman’s The Pharmacological Basis of Therapeutics, 10th edition. McGraw Hills • B.J.Sadock”s,V.A.Sadock”s,Kaplan & sadock”s synopsis of psychiatry,10th edition • Psychopharmacology treatment of psychiatric disorders,(late) jambur anant,2007,jaypee publisher • Wikipedia • Googleimages.com
- 78.