Drug interaction .pptx
- 2. 2 Content Definition Epidemiology Risk factor Out come of interaction Mechanism ofinteraction Pharmacokinetic Pharmacodynamic Drug-Food interaction Drug-Disease interaction Reference
- 3. Definition • Drug interaction occur when the response of a patient to a drug is changed by the presence of another drug, food, drink, herb or by some environmental chemical agent. • A drug whose activity is affected by such interaction OBJECT DRUG • The agent which precipitates such a interaction PRECIPITANTS 3
- 4. Drug interaction includes Drug –drug interaction Food – drug interactions •e.g. inhibition of several drugs by grapefruit juice Drug – disease interactions • e.g. worsening of disease condition by the drug 4
- 5. 5 Epidemiology • Drug–drug interactions resulting in about 2.8% of all hospitalizations • In 2007, a meta-analysis of 23 clinical studies from around the world revealed that drug–drug interactions cause approximately 0.054% of emergency room visits, 0.57% of hospital admissions, and 0.12% of rehospitalizations • There are 136.1 million emergency room visits and 34.1 million hospital admission in USA each year
- 6. Risk Factor • Poly pharmacy • Multiple pharmacies • Multiple prescribers • Genetic make up • Specific populationlike e.g. females, elderly, obese, critically ill patient, transplantrecipient • Specific illness E.g. Hepatic disease, Renaldysfunction • Narrow therapeutic index drug - Cyclosporine, Digoxin, Lithium, Antidepressant, Warfarin 6
- 7. Outcomes of drug interactions Synergism or additive effect of one or more drugs Antagonism or reduction of the effects of one or more drugs Alteration of effect of one or more drugs or the production of idiosyncratic effects or toxicity 7
- 9. 9 INTERACTIONS OUTSIDE THE BODY • Interactions may occur outside the body even before it is administered and is usually chemicalinteraction • E.g. mixing the drugs in same syringe such as thiopentone and succinylcholine interact – administered separately • Carboxipenicillin inactivate aminoglycosides when mixed in same syringe or infusion • Quinupristin and dalfoprisin combination used as i.v. infusion which is incompatible with N-saline – use 5% dextrose • Ampicillin, amoxicillin, phenytoin, sulphonamides, heparin are unstable in acidic pH of 5% dextrose – avoided
- 10. Drug interactions inside the body Pharmacokinetics Pharmacodynamics 10
- 11. Pharmacokinetic interaction Absorption Distribution Metabolism Excretion 11
- 14. 14 ABSORPTION
- 15. • Changes in GITpH • Complex and chelate formation in theGIT • GIT motility • Toxic effects on the GIT • Changes in gutflora Altered Gastro- intestinal tract absorption 15
- 16. Changes in gastrointestinal pH • Non-ionized > Ionized form Antacids Decrease the absorption of Ketoconazole, Itraconazole (acidic) Proton pump inhibitors Histamine H2-antagonists 16
- 17. Alkalinizing effects of antacids on the gastrointestinal tract aretransient The potential for interaction decreased by leaving an interval of 2–3 hours between antacid and potentially interacting drug 17
- 18. 18 Complex formation in the gastrointestinal tract • Certain drugs are liable to react with other drugs in the gastrointestinal tract and form chelates and complexes that are not absorbed
- 20. • Interaction can be prevented if the antibacterialis not given until at least 6 hours after theantacid • reduce the absorption of antibacterials – azithromycin, quinolones, rifampicin, tetracyclines Antacids • Reduce the absorption of bisphosphonates – alendronate, clodronate, etidronate Calcium 20
- 21. 21 •Most chelation and adsorption interactions can be prevented by separating doses of the interacting drugs by a period of several hours
- 22. 22 Gastrointestinal motility •Drugs that influence gastric emptying or gastrointestinal motility can affect the absorption of other drugs
- 23. bioavailability of levodopa by as much as 50% Anticholinergic • Delay gastric emptying andreduce drugs • Increases gastric emptying and increases absorption rate of paracetamol • Also accelerates absorption propranolol, mefloquine, lithium and cyclosporin Metoclopramide 23
- 24. Toxic effects on the gastrointestinal tract Absorption of some drugs may be reduced due to damage of the small intestine Absorption of phenytoin and verapamil can be reduced by 20–35% in patients taking cytotoxic drugs such as methotrexate, carmustine, or vinblastine for treatment of malignant disease 24
- 25. Changes in gut flora Large bowel Small bowel Stom- ach 25
- 26. 26 • Drugs that are metabolised to some extent by the gut flora include sulfasalazine and levodopa • Evidence suggest that ampicillin may reduce the effects of sulphasalazine by reducing the gut bacteria that act on sulphasalazine to release sulphapyridine and 5-aminosalicylic acid
- 27. DISTRIBUTION 27
- 28. Main mechanism behind such interactions is displacement from protein binding sites Drug displacement interaction is defined as a reduction in plasma protein binding of one drug caused by presence of another which competes for the same binding sites, resulting in an increased free or unbound concentration of displaced drug 28
- 29. 29 • Displacement makes more unbound (free) drug available for metabolism of glomerular filtration, displaced drug can normally distribute out of the plasma compartment, increased unbound drug concentrations are usually only transient, and, do not give rise to altered pharmacological effects in the patient
- 30. Phenylbutazone, Salicylates, Sulphonamides Displace Tolbutamide from binding site Cause hypoglycaemia Salicylates, Indomethacin, Phenytoin and Tolbutamide Displace warfarin Cause haemorrhage 30
- 31. METABOLISM 31
- 32. METABOLIC PROCESS PHASE I REACTIONS Oxidation, hydrolysis or reduction Hepatic mixed function oxidase system cytochrome P450is most important PHASE II REACTIONS Conjugation ofdrug (or productof phase I metabolism) with substances such as glucuronic acid, sulphate, orglycine 32
- 33. 33 • Sub-families of P450 isoenzymes are responsible for most of the metabolism of commonly used drugs CYP1, CYP2, and CYP3 in humans • Isoforms (CYP1A2, CYP2C9, CYP2C19,CYP2D6, CYP2E1, and CYP3A4) are involved in the metabolism of a large proportion of drugs • Importance of these enzymes for drug interactions is enzyme inducers and inhibitors and may affect the metabolism of selected drugs
- 34. Enzyme induction Enzyme induction usually develops over a period of several days or weeks Effect generally persists for a similar period following withdrawal of the enzyme-inducing agent 34
- 35. • Rifampicin • Tobacco smoke • Phenytoin • Rifabutin • Ethanol (chronic) • Griseofulvi n • Barbiturate s • Carbamaze pine Some enzyme are inducers 35
- 36. 36 • Enzyme induction usually results in a reduced pharmacological effect of the induced drug but where active metabolites are responsible for a drug’s effect the reverse may occur
- 37. Barbiturates, phenytoin, carbamazepine and rifampicin CYP2C9 WARFARIN If phenytoin administered Anticoagulant effect over To maintain the the same effect to patient the period the dose of stabilised on warfarin of several weeks warfarin If enzyme inducing drug is withdrawn enzyme activity returns to normal, with a risk of haemorrhage unless the warfarin dose is correspondingly reduced 37
- 38. 38 Examples of interactions due to enzyme induction Drug affected Inducing agent Clinical outcome Carbamazepin e Lamotrigine Increased concentrationsof epoxide metabolite leading totoxicity Hormonal contraceptives Rifampicin Therapeutic failure ofcontraceptive Rifabutin Additional contraceptive precautionsrequired Carbamazepine Ciclosporin Phenytoin Decreased ciclosporin levels with possibility of transplant rejection Carbamazepine Paracetamol Alcohol (chronic) In overdose, hepatotoxicitymay occur at lower doses Corticosteroids Phenytoin Increased metabolism with possibilityof therapeuticfailure Rifampicin
- 39. Enzyme inhibition Inhibition of drug metabolism may result in exaggerated and prolonged responses and increased risk of toxicity inhibition is more rapid than induction as soon as sufficient concentrations of the inhibitor appear in theliver 39
- 40. • Antiviraldrugs • Indinavir • Ritonavir • Saquinavir 40 • Antifungal drugs • Fluconazole • Itraconazole • Ketoconazole • Miconazole • Antidepressants • Fluoxetine • Fluvoxamine • Paroxetine • Antibacterials • Ciprofloxacin • Erythromycin • Isoniazid some enzyme are inhibitors
- 41. • Other • Disulfiram • Dextropropoxyphe ne 41 • Rheumatological drugs • Allopurinol • Azapropazone • Phenylbutazone • Gastrointestinal drugs • Cimetidine • Cardiovascular drugs • Amiodarone • Diltiazem • Quinidine • Verapamil some enzyme are inhibitors
- 42. Cimetidine reduces theophylline clearance serious convulsions and cardiac arrhythmias dose of theophylline may need to be reduced 42
- 43. • Cimetidine prolongs the t1/2 phenytoin, nitrazepam, diazepam, warfarin, and theophylline • enzyme inhibitors, including macrolides cause the accumulation of drugs, prolong the QT interval and cause arrhythmias most characteristic is torsades de pointes oxidative drug -- -- metabolism 43
- 44. 44 Drugs that can prolong the QT interval • Mechanism is drug-induced blockade of the repolarizing potassium channels Antiarrhythmic drugs Amiodarone, sotalol, quinidine, disopyramide Antihistamines Terfenadine, astemizole Antiinfectives Erythromycin (especially intravenous use), halofantrine, some quinolones Psychiatric drugs Amisulpride, haloperidol, sertindole, thioridazine, pimozide Others Cisapride
- 45. metabolism of cyclosporin is inhibited by diltiazem, verapamil, azole antifungal agents, erythromycin and clarithromycin Interactions have been used as a cost saving device in organ transplant patients, aim of using a lower dose of cyclosporin to achieve immunosuppression 45
- 46. EXCRETION 46
- 47. Most interactions involving elimination or excretion occur in kidneys Interactions can occur when drugs interfere with kidney tubule fluid pH, active transport systems, or blood flow to the kidney thereby altering the excretion of other drugs 47
- 48. Changes in urinary pH • Passive reabsorption of drugs depends on the extent towhich the drug exists in the non-ionised lipid-soluble form At alkaline pH weakly acidic drugs, exist as un-ionised lipid insoluble molecules unable to diffuse and lost in the urine clearance of these drugs is increased if the urine is made more alkaline 48
- 49. Urine alkalinisation may be used as increasing drug elimination in salicylate poisoning Acidification of urine has been used to increase amphetamine elimination 49
- 50. Changes in active renal tubule excretion Drugs which use the same active transport system in kidney tubules can compete with one another for excretion Onset and offset of this inhibitory effect is rapid and concentration dependent, due to its competitive nature Probenecid may be given to increase the serum concentration of penicillins by delaying their renal excretion 50
- 51. Changes in renal blood flow Blood flow through the kidney is partially controlled by the production of renal vasodilatory prostaglandins mechanism underlying this interaction is not entirely clear 51
- 52. If an NSAID is prescribed for a patient takinglithium synthesis of prostaglandinsis inhibited renal excretion of lithium is reduced with a rise in serum levels serum levels should be closely monitored 52
- 53. Drug-Transporter Proteins Drugs cross biological membranes by passive diffusion and by transporter proteins most well known is P-glycoprotein, an efflux pump found in cell membranes pumping actions of P-glycoprotein can be induced or inhibited by some drugs 53
- 54. Induction of intestinal P-glycoprotein by rifampicin causes digoxin to be ejected into the gut more, resulting in reduced digoxin levels Verapamil inhibit activity of P-glycoprotein, andincrease digoxin levels P-glycoprotein inhibition may have a greater impact on drug distribution than on drug absorption. 54
- 56. • Antagonistic or Opposing Interactions • Additive Effect/Potentiation/Synergy • Interactions Due to Changes in Drug Transport Mechanisms • Interactions Due to Disturbances in Fluid and Electrolyte Balance • fairly common but may not always be recognised Pharmacodynamic interactions generally involve 56
- 57. Antagonistic or Opposing Interactions drug with an agonist action at a particular receptor type will interact with antagonists at that receptor Specific antagonists may be used to reverse the effect of another drug at receptor sites opioid antagonist naloxone and the benzodiazepine antagonist flumazenil 57
- 58. Additive Effect/Potentiation/Synergy • If two drugs with similar pharmacological effects are given together, the effects can be additive Additive or synergistic interactions Interacting drugs Pharmacological effect NSAID and warfarin Increased risk of bleeding ACE inhibitors and K-sparing diuretic Increased risk of hyperkalemia Verapamil and beta-adrenergicantagonists Bradycardia andasystole Neuromuscular(NM) blockers and aminoglycosides Increased NM blockade Alcohol andbenzodiazepines Increased sedation Thioridazine andhalofantrine Increased risk of QT interval prolongation Clozapine andcotrimoxazole Increased risk of bone marrow suppression
- 59. Interactions Due to Changes in Drug Transport Mechanisms One drug may interfere with the uptake and transport of another to intracellular sites ofaction Antihypertensive effects of adrenergic neurone blocking drugs such as guanethidine is prevented or reversed by tricyclic antidepressants 59
- 60. Interactions Due to Disturbances inFluid and Electrolyte Balance Potentiation of the effects of digoxin by diuretics which decrease plasma potassium concentrations ACE inhibitors have a potassium-sparing effect, and concurrent use of potassium supplements or potassium sparing diuretics lead to hyperkalaemia 60 •Changes in electrolyte balance may alter the effects of drugs, acting on myocardium, neuromuscular transmission and kidney
- 61. 61 DRUG - HERB INTERACTIONS • Most well-known and documented example is the interaction of St John’s wort (Hypericum perforatum) with different drugs • Herb can induce CYP3A4, and can also induce P-glycoprotein
- 62. Effect of St John’s wort (Hypericum perforatum) on ‘conventional drugs’ Drug Effect Buspirone Additive CNS effects Carbamazepine Reduced levels of single-dose carbamazepine, no significant effect on multiple doses of carbamazepine Digoxin Reduced digoxin levels; digoxin toxicity seen in onepatient when St John’s wortstopped Hormonal contraceptives Breakthrough bleedingand contraceptive failures reported Indinavir Marked reduction in indinavirlevels Irinotecan Decreased levels of the active metabolite of irinotecan SSRIs Cases of the serotonin syndrome reported Verapamil Reduced verapamil bioavailability Voriconazole Reduced voriconazolelevels Warfarin Moderate reductionin the effects of warfarin reported 62
- 63. 63 DRUG FOOD INTERACTIONS • Due to presence or absence of food and simultaneous consumption of food items, several interactions have occurred • Most of them are not clinically relevant while some may be serious(cheese reaction)
- 64. 64 1. Presence of food: • Fatty food reduces the absorption of many drugs due to reduced gastric emptying e.g. Thyroxine , Rifampicin • Absorption of alendronate is reduced by orange juice, tea, or coffee • Therefore should be taken empty stomach 2. Milk: • Reduces absorption of certain drugs e.g iron and tetracycline due to presence ofcalcium 3. Grape fruit juice: • Increases the absorption of cyclosporine • Inhibits metabolism of phenytoin, terfenadine and amiodarone leading to toxicity
- 65. 65 4. Cheese reaction: • Severe hypertension may occur if a patient on MAO inhibitor and consumed the food item prepared by fermentation as they contain tyramine • Cheese also contains tyramine and same reaction occurs with cheese as well and this is called cheese reaction 5. Fruits rich in potassium: • Sweet lime and mango may cause hyperkalemia when used with potassium diuretics or ACE inhibitors or patients of chronic renal failure
- 66. 66 DRUG DISEASE INTERACTIONS • Presence of disease or in pathological states a drugmay aggravate or precipitate thedisease 1.Hepatic disease: Drugs which are completely metabolized, their concentration increases in hepatic damage depending on the degree of liver dysfunction 2.Renal disease: Drugs which are eliminated unchanged, their concentration increases in renal damage depending on the degree of renal dysfunction
- 67. 67 3.Cardiovascular diseases: a)Variant angina: Non-selective beta blockers may aggravate the variant angina because they cause vasoconstriction of coronary blood vessels b)MI: Cardiac dysrhythmia may occur due to digoxin and sympathomimetics 4.Respiratory diseases: a)Asthmatic patients: Non selective beta blockers , aspirinand indomethacin may precipitate the attack of bronchialashtma
- 68. 68 5. Endocrine diseases: a)Diabetes mellitus: glucocorticoids cause hyperglycemia and thus difficult to control diabetes mellitus b)Thyroid disease: drug metabolism is reduced in hypothyroidism while enhanced in hyperthyroidism 6.Other diseases: a)Myasthenia gravis: made worse by quinine and quinidine. Myasthenics are intolerant to competitive neuromuscular blockers(d-tubocurarine) and aminoglycosides(gentamicin) b)Migraine: during acute attack of migraine the delayed gastric emptying and reduced intestinal motility lead to reduced absorption of drugs
- 69. 69 CONCLUSION • Drug interaction causes morbidity and occasionally mortality • It is impossible to remember all known important interactions, but keeping basic principles in mind can help clinicians minimise their occurrence • Drugs with a narrow therapeutic window (e.g. anticoagulants, digoxin, lithium, immunosuppressives) are oftenimplicated • pharmacokinetic interactions involved drugs which can induce or inhibit hepatic cytochrome P450 enzymes; vigilance is required when these areprescribed