ADVERSE DRUG REACTION (ADR) BIOMEDIK ADVERSE DRUG REACTION (ADR) Prof Dr dr Jazanul Anwar SpFK Fakultas Kedokteran USU Dept Farmakologi dan Terapi pROF jAZANUL aNWAR

Obat (O) + reseptor obat (R)  OR  stimulus  Efek Kebanyakan obat membangkiitkanbanyak efek, biasanya hanya satu efek dimanfaatkan untuk efek terapi, efek yag dimanfaatkan untuk mengobati suatu gangguan kesehatan. Efek-efek lainnya bisa dianggap tak diinginkan baik yang meusak atau tidak. Umpamanya antihistaminika tertentu menyebabkan ngantuk atau hoyong Obat (O) + reseptor obat (R)  OR  stimulus  Efek Ox + R1  OR1  Efek1 Ox + R2  OR2  Efek2 Ox + R3  OR3  Efek 3 Efek utama: efek yang paling menonjol Efek samping pROF jAZANUL aNWAR

EFEK OBAT YANG TAK DIINGINKAN DAPAT DIPRAKIRAKAN Keracunan Teratogenik Karsinogenik TAK DAPAT DIPRAKIRAKAN Adverse drug reaction, Alergi pROF jAZANUL aNWAR

PENYEBAB KERACUNAN Overdosis pROF jAZANUL aNWAR

Efek farmakologi yang meningkat Alergi Efek khronik Efek tertunda Bentuk ADR Efek farmakologi yang meningkat Alergi Efek khronik Efek tertunda Kegagalan pengobatan Kehebatan dan keparahan ADR Kematian Ancaman kehidupan Dirawat rumah sakit ( pemulaan atnau perpanjagan) Gangguan fungsi (permanan, sementara, Kelainana bawa lahir pROF jAZANUL aNWAR

TAK DAPAT DIPRAKIRAKAN Rekasi alergi: hipersentivitas Hapten: Obat + protein  alergen Antibodi Antigen pROF jAZANUL aNWAR

+ + Antibodi Antibodi Kompleks antigen-antibodi Hapten + Protein + Antibodi An -tigen An -tigen Antibodi Kompleks antigen-antibodi Merangsang sel dan jaringan Membebaskan mediator: histamin Manifestasi alergik pROF jAZANUL aNWAR

Mediator: Autakoid: Histamin Bradikinin Serotonin Prostaglandine pROF jAZANUL aNWAR

Bentuk alergi Idiosyncrasy Akut Subakut Khronis Serum sickness pROF jAZANUL aNWAR

GEJALA –GEJALA REAKSI ALERGI Pruritus, urtikaria Dermatitis exfoliativa Kulit : Selaput mukosa : Terut. Mata & hidung Keradangan hiperekskresi Saluran nafas : Susah bernafas Sistem vaskuler : Tekanan darah Pengurangan jumlah sel darah Darah & RES : pROF jAZANUL aNWAR

TERATOGENIK KARSINOGENIK Pertumbuhan alat tubuh janin abnormal Mekanisme kerja ??? KARSINOGENIK Periode laten Karsinogen: radiasi, viruses, senyawa kimia pROF jAZANUL aNWAR

What is an Adverse Drug Reaction (ADR)? “an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug” Ref. MCA/CSM Suspected adverse drug reaction (ADR) reporting and the Yellow Card Scheme, Guidance notes Things to say -This definition is taken from the CSM/MCAs ‘Guidance notes’ document (October 2002) which has been written for new reporters. Details of where to find this document on the MCA/CSM website is given later on. -Be aware that whenever a patient takes a drug, there is a potential risk of an adverse reaction to that drug. -The terms "adverse reaction" and "adverse effect" are interchangeable, however an adverse effect is seen from the point of view of the drug, whereas an adverse reaction is seen from the point of view of the patient. The term ‘side effect’ is also used. Useful information MCA/CSM Suspected adverse drug reaction (ADR) reporting and the Yellow Card Scheme, Guidance notes http://www.mca.gov.uk/ourwork/monitorsafequalmed/yellowcard/ycguidancenotes.pdf Alternative definition for an ADR:- WHO definition "a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function” pROF jAZANUL aNWAR

Definition WHO response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function excludes therapeutic failures, overdose, drug abuse, noncompliance, and medication errors pROF jAZANUL aNWAR

Examples of ADRs Common ADRs Constipation with opioids Sedation with antihistamines Nausea when starting fluoxetine Gastrointestinal upset with non steroidal anti-inflammatory drugs Information Use these examples or examples of your own pROF jAZANUL aNWAR

Who is most at risk from ADRs? Patients who; are young, or old or female are taking multiple therapies 50% of patients on 5 drugs or more have more than one medical problem have a history of allergy or a previous reaction to drugs Things to say Age – The very old and the very young are more susceptible to ADRs. In children, systems for handling drugs are not developed and in the elderly these systems may be slowing with age. The elderly are also likely to have multiple and often chronic diseases. E.g. Elderly patients much more susceptible to the effects of benzodiazepines leading to drowsiness the next day. Gender – Women appear to be at a higher risk of suffering ADRs. The reason is not clear. Multiple therapies – The incidence of ADRs increases sharply with the number of drugs taken, 50% patients on 5 drugs are likely to experience an ADR. Intercurrent diseases – Drug handling may be altered in patients with renal, hepatic, and cardiac disease. Allergy – patients with a history of allergic disorders are at the greatest risk of experiencing an allergic reaction. Useful information Specific diseases predispose to ADRs eg in HIV positive patients there is an increased frequency of idiosyncratic toxicity with anti-infective drugs such as co-trimoxazole (50% vs 3% in HIV negative patients). pROF jAZANUL aNWAR

Why are ADRs a problem? pROF jAZANUL aNWAR

Because…. they account for around 5% of hospital admissions they cause death in 1 in 1000 medical inpatients they complicate drug therapy they decrease compliance and delay cure Things to say Adverse drug reactions are a major clinical problem 1) Cause around 5% of all hospital admissions. A pilot study of 200 acute medical admissions undertaken at the Royal Liverpool University Hospital identified that 7.5% were due to ADRs. 2) Cause death in 1 in 1000 medical inpatients (and 1 in 10,000 surgical inpatients) 3) Drug therapy may affect the patients quality of life. In some cases medicines may have a greater impact on the patient than the symptoms of the disease itself. e.g. Drugs used to treat hypertension often produce adverse effects while hypertension itself often has no symptoms. 4) Non-compliance may lead to re-emergence of the original disease and can be particularly important if the treatment is prophylactic. E.g malaria prophylaxis, the oral contraceptive. Useful information Ref for 1) Green CF et al. Adverse drug reactions as a cause of admissions to an acute medical assessment unit: a pilot study. J Clin Pharm Ther 2000; 25: 355-361 Ref for 2) Pirmohamed et al. Adverse drug reactions. BMJ 1998; 316: 1295-1298 pROF jAZANUL aNWAR

Are ADRs avoidable? 30-50% are preventable Obvious interactions many drugs interact with warfarin Use of contra-indicated drugs use of a non-selective beta-blocker in an asthmatic  bronchospasm Drug use in an inappropriate clinical indication or medically unnecessary antibiotics for a viral infection antibiotics for viral infections Things to say You can use these examples or examples of your own Obvious interactions -many drugs interact with warfarin causing alteration of the INR which may lead to bleeding episodes Use of contra-indicated drugs - use of a non-selective beta-blocker in an asthmatic can lead to bronchospasm Drug use in an inappropriate clinical indication or medically unnecessary -antibiotics for a viral infection will not cure the infection but will expose patients to the adverse effects of the drug. pROF jAZANUL aNWAR

How do I recognise ADRs? Things to say We now know what an ADR is and why ADRs are a problem So How can you identify ADRs? pROF jAZANUL aNWAR

What should raise my suspicion of an ADR? A symptom that appears soon after a new drug is started appears after a dosage increase disappears when the drug is stopped reappears when a drug is restarted (do not deliberately rechallenge!) pROF jAZANUL aNWAR

Who might get an ADR? Anyone who takes a medicine Differential diagnosis should include the possibility of an ADR if the patient is taking any form of medication Things to say Not all ADRs will be apparent to the patient or the health care professional as ADRs can mimic any disease process. Always be alert to the possibility of ADRs as a cause of the patients symptoms. Useful information Quote taken from Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255-1259 pROF jAZANUL aNWAR

What you might see if an ADR has occurred Lab results liver function tests,  by statins and methotrexte full blood count, deranged by carbimazole biopsies, important for assessing liver dysfunction chest X-rays, pulmonary fibrosis with pergolide pROF jAZANUL aNWAR

What you might see if an ADR has occurred Clinical measurements BP,  by opiates weight,  by carbamzepine, increased appetite blood glucose,  by corticosteroids pROF jAZANUL aNWAR

How common are ADRs? Up to 40% patients in the community experience ADRs In the UK Non Steroidal Anti-Inflammatory Drug (NSAID) use alone accounts for1 65,000 emergency admissions/year 12,000 ulcer bleeding episodes/year 2,000 deaths/year 1Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291 Things to say 1) Up to 40% patients receiving drugs in the community are though to experience ADRs. It is difficult to study ADRs in the community and there are very few well designed studies 2) NSAID use is associated with significant morbidity and mortality in the UK each year. There is a strong association between NSAID use and likelihood for upper GI emergency admission. Useful information Ref for 1) In a 1979 study in general practice 41% of 817 patients surveyed were thought to have certainly or probably experienced an ADR. Martyrs C. Adverse reactions to drugs in general practice. BMJ 1979; 2: 1194-1197) Ref for 2) The data recorded in the trial was extrapolated to give the estimated UK figures. The study was a retrospective survey of case notes of all emergency upper GI admissions per annum attributable to NSAID use. The study was undertaken at 2 District General Hospitals in the North West of England (catchment population 550,000). Matched controls were emergency admissions not caused by upper GI diagnoses. (Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291) pROF jAZANUL aNWAR

Classification - Severity Severity of reaction: Mild bothersome but requires no change in therapy Moderate requires change in therapy, additional treatment, hospitalization Severe disabling or life-threatening pROF jAZANUL aNWAR

Classification Types of allergic reactions Type I - immediate, anaphylactic (IgE) e.g., anaphylaxis with penicillins Type II - cytotoxic antibody (IgG, IgM) e.g., methyldopa and hemolytic anemia Type III - serum sickness (IgG, IgM) antigen-antibody complex e.g., procainamide-induced lupus Type IV - delayed hypersensitivity (T cell) e.g., contact dermatitis pROF jAZANUL aNWAR

Classification - Type Reportable Hypersensitivity Life-threatening Cause disability Idiosyncratic Secondary to Drug interactions Unexpected detrimental effect Drug intolerance Any ADR with investigational drug The above list includes types of ADRs which are considered reportable. pROF jAZANUL aNWAR

Common Causes of ADRs Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics Diagnostic agents CNS drugs* *account for 69% of fatal ADRs pROF jAZANUL aNWAR

Body Systems Commonly Involved Hematologic CNS Dermatologic/Allergic Metabolic Cardiovascular Gastrointestinal Renal/Genitourinary Respiratory Sensory pROF jAZANUL aNWAR

Interactions Before Administration Phenytoin precipitates in dextrose solutions (e.g. D5W) Amphotericin precipitates in saline Gentamicin is physically/chemically incompatible with most beta-lactams, resulting in loss of antibiotic effect The next few slides will review some of the mechanisms for drug interactions in more detail. Several examples of drug interactions that occur prior to drug administration are listed here. When phenytoin is added to solutions of dextrose, a precipitate forms and the phenytoin falls to the bottom of the IV bag as an insoluble salt. When this happens, it is no longer available to control seizures. Amphotericin is still used widely as a urinary bladder perfusion to treat aggressive fungal infections. If it is administered in saline, the drug precipitates and can erode through the bladder wall if not removed. The clinical presentation of such cases is an acute abdomen due to perforation of the bladder.(Personal Communication, David Flockhart, MD, PhD., University of Indiana, July 2001) Lastly, aminoglycosides should not be co-mixed in IV fluids with beta-lactam antibiotics because covalent bonds are formed between the two drugs. This can markedly reduce antibiotic efficacy. pROF jAZANUL aNWAR

Interactions Before Administration Phenytoin precipitates in dextrose solutions (e.g. D5W) Amphotericin precipitates in saline Gentamicin is physically/chemically incompatible with most beta-lactams, resulting in loss of antibiotic effect The next few slides will review some of the mechanisms for drug interactions in more detail. Several examples of drug interactions that occur prior to drug administration are listed here. When phenytoin is added to solutions of dextrose, a precipitate forms and the phenytoin falls to the bottom of the IV bag as an insoluble salt. When this happens, it is no longer available to control seizures. Amphotericin is still used widely as a urinary bladder perfusion to treat aggressive fungal infections. If it is administered in saline, the drug precipitates and can erode through the bladder wall if not removed. The clinical presentation of such cases is an acute abdomen due to perforation of the bladder.(Personal Communication, David Flockhart, MD, PhD., University of Indiana, July 2001) Lastly, aminoglycosides should not be co-mixed in IV fluids with beta-lactam antibiotics because covalent bonds are formed between the two drugs. This can markedly reduce antibiotic efficacy. pROF jAZANUL aNWAR

In the GI Tract Pharmacodynamic interactions Sucralfate, some milk products, antacids, and oral iron preparations Omeprazole, lansoprazole, H2-antagonists Pharmacodynamic interactions Target organ Didanosine (given as a buffered tablet) Cholestyramine Block absorption of quinolones, tetracycline, and azithromycin Reduce absorption of ketoconazole, delavirdine Reduces ketoconazole absorption Binds raloxifene, thyroid hormone, and digoxin A number of interactions occur in the GI tract and reduce the entry of drugs into the systemic circulation. Particularly notable among these is the ability of aluminum-containing medicines such as sucralfate (Carafate®) and antacids to reduce the absorption of expensive and potentially life-saving antibiotics like ciprofloxacin (Cipro®) and azithromycin (Zithromax®). Women taking iron supplements often do not consider them as a medicine, and should be specifically questioned about whether they are taking iron if they are to be prescribed a quinolone or azithromycin. Drugs such as ketoconazole (Nizoral®) and delavirdine (Rescriptor®) require an acidic environment to be in the non-charged form that is preferentially absorbed. Solubility is drastically reduced in neutral or basic environments that occur when the patient takes medications such as omeprazole (Prilosec®), lansoprazole (Prevacid®), or H2-antagonists that raise the stomach’s pH. pROF jAZANUL aNWAR

Interactions in the Serum Protein “bumping” interactions in the serum are a test-tube phenomenon without clinical relevance Some drugs can “bump” other drugs off proteins in the plasma and result in an increased amount of free drug, but this is only transient because the usual elimination mechanisms respond by increasing the rate of elimination. There is no clinically relevant protein bumping interaction that has been reported. The cited examples have been subsequently shown to be due to inhibition of elimination, not plasma protein displacement. pROF jAZANUL aNWAR

Spectrum of Consequences of Drug Metabolism Inactive products Active metabolites Similar to parent drug More active than parent New action Toxic metabolites The next few slides will focus on drug metabolism. Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either inhibition of the enzyme or induction of the enzyme. There are many potential consequences of changes in drug metabolism for a given drug. It is made more complex by the fact that there are multiple pathways of metabolism for many drugs. The majority of drugs that are metabolized are converted to inactive metabolites. This is the most common fate for most drugs. Of the remaining drugs, some are converted to metabolites that retain the same activity as the parent. An example of this is fexofenadine (Allegra®), the active metabolite of terfenadine that has equal potency at the histamine receptor and now is on the market and used clinically for allergic rhinitis. However, fexofenadine is is more than 50 times less active in blocking potassium channels in the heart and therefore, unlike terfenadine, does not cause torsades de pointes.{Woosley} In some cases the metabolites are actually more potent than the parent. For example, a pro-drug such as enalapril must be hydrolyzed to enalaprilat to become active. In some cases, the metabolites have entirely new pharmacologic actions not seen with the parent drug. Metabolites can also be toxic, such as the metabolites of acetaminophen which can cause liver failure or the metabolite of meperidine which can cause seizures. Inhibition of metabolism could result in potentially toxic concentrations of the parent compound. On the other hand, if the parent drug needs to be metabolized to the active compound, therapeutic failure could result (as happens, for example, if codeine is not metabolized to morphine). Induction of drug metabolizing enzymes could similarly result in a subtherapeutic effect by reducing drug levels below that required for efficacy. Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993; 269(12):1532-1536. pROF jAZANUL aNWAR

Microsomal Enzymes Cytochrome P450 Flavin mono-oxygenase (FMO3) The major group of enzymes in the liver that metabolize drugs can be isolated in a subcellular fraction termed the microsomes. The largest and most important of these enzymes are the cytochrome P450 family of enzymes. The origin of the term “cytochrome P450” will be explained later. In addition to cytochrome P450, there are other enzymes in microsomes such as flavin monooxygenase (termed FMO3). These are also responsible for metabolism of some drugs, but not as generally important as the cytochrome P450 system. pROF jAZANUL aNWAR

Drug-Disease Interactions Liver disease Renal disease Cardiac disease ( hepatic blood flow) Acute myocardial infarction? Acute viral infection? Hypothyroidism or hyperthyroidism? In addition to the drug-drug interactions just reviewed, drug-disease interactions can occur. These include interactions between certain drugs and specific disease states. Severe liver disease can be associated with reduced metabolic clearance and higher plasma levels of drugs extensively metabolized by the liver.{Brouwer} Although liver disease reduces drug clearance on average, the change is relatively small and usually not clinically relevant except in patients with near terminal liver disease. The effects of renal disease on elimination of drugs that are primarily cleared renally are more predictable, and well-established guidelines exist for dosage of many drugs in renal disease.{Lam} Heart failure reduces liver blood flow and causes a reduction in clearance for drugs such as lidocaine or propranolol that are usually extensively cleared by the liver,{Shammas} and acute myocardial infarction reduces clearance of some drugs, such as lidocaine, as well.{Pieper} Acute viral infection and changes in thyroid function have been associated with altered clearance for some drugs, such as theophylline and warfarin.{Pokrajac}{Stephens}{Yamaguchi} However, the results are so variable between individuals that it is hard to predict who is at risk, and these changes are usually only clinical important in cases of extremely impaired organ function. Brouwer KLR, Dukes GE, Powell JR. Influence of liver function on drug disposition. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics, Inc., 1992: 6-1-6-59. Lam YW, Banerji S, Hatfield C, Talbert RL. Principles of drug administration in renal insufficiency. Clin Pharmacokinet 1997; 32(1):30-57. Shammas FV, Dickstein K. Clinical pharmacokinetics in heart failure. An updated review. Clin Pharmacokinet 1988; 15(2):94-113. Pieper JA, Johnson KE. Lidocaine. In: Evans WE, Schentag JJ, Jusko WJ, editors. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver,WA: Applied Therapeutics, Inc., 1992: 21-1-21-37. Pokrajac M, Simic D, Varagic VM. Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease. Eur J Clin Pharmacol 1987; 33(5):483-486. Stephens MA, Self TH, Lancaster D, Nash T. Hypothyroidism: effect on warfarin anticoagulation. South Med J 1989; 82(12):1585-1586. Yamaguchi A, Tateishi T, Okano Y, Matuda T, Akimoto Y, Miyoshi T et al. Higher incidence of elevated body temperature or increased C-reactive protein level in asthmatic children showing transient reduction of theophylline metabolism. J Clin Pharmacol 2000; 40(3):284-289. pROF jAZANUL aNWAR

Drug-Food Interactions Tetracycline and milk products Warfarin and vitamin K-containing foods Grapefruit juice Several drugs are known to interact with foods,{Williams} some of which are listed here. One of the early observations was the reduced absorption of tetracycline when taken with milk products. The chelation of tetracycline by calcium prevents it from being absorbed from the intestines. Dietary sources of vitamin K, such as spinach or broccoli, may increase the dosage requirement for warfarin by a pharmacodynamic antagonism of its effect. Patients should be counseled to maintain a consistent diet during warfarin therapy. Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolism of many drugs. This was first described for felodipine (Plendil®) {Bailey 1991} but has now been observed with several drugs.{Kane} This interaction can lead to reduced clearance and higher blood levels when the dugs are taken simultaneously with grapefruit juice. With regular consumption, grapefruit juice also reduces the expression of CYP3A in the GI tract.{Lown} Williams L, Davis JA, Lowenthal DT. The influence of food on the absorption and metabolism of drugs. Med Clin N Am 1993; 77(4):815-829. Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991; 337(8736):268-269. Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000; 75(9):933-942. Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99(10):2545-2553. pROF jAZANUL aNWAR

Some Serious Adverse Drug Reactions Adverse Drug Reaction Types of Drugs Examples Peptic ulcers or bleeding Corticosteroids taken by Hydrocortisone stomach mouth from the or by injection (not those applied to the skin or lotions in creams) Prednisone Nonsteroidal antiinflammatory Aspirin drugs Ibuprofen Ketoprofen Naproxen Anticoagulants Heparin Warfarin pROF jAZANUL aNWAR

Adverse Drug Reaction Types of Drugs Examples Anemia (resulting from Certain antibiotics Chlorampheni a decreased production or increased destruction of red blood cells) Some nonsteroidal anti- Phenylbutazone inflammatory drugs Antimalarial and Chloroquine antituberculous drugs Isoniazid in people with Primaquine enzyme deficiency pROF jAZANUL aNWAR

Adverse Drug Reaction Types of Drugs Examples Liver damage Some analgesics Acetaminophen (use of excessive doses) Kidney damage Nonsteroidal anti- Ibuprofen inflammatory drug Ketoprofen (repeated use of Naproxen excessive doses) Aminoglycoside Kanamycin antibiotics Gentamicin Cisplatin Confusion and Sedatives, Diphenhydramine drowsiness many antihistamines Antidepressants Amitriptyline (especially in older people) Imipramine pROF jAZANUL aNWAR