Week 11 Notes - Adverse Drug Reactions.pdf

Therapeutic Agents and ADVERSE DRUG REACTIONS / EFFECTS (ADRs / ADEs) ADR = Any response to a drug that is noxious (harmful) and unintended, and that occurs at doses used in humans for prophylaxis, diagnosis or therapy, excluding failures to achieve the desired result. Side effects: include all...

Therapeutic Agents and ADVERSE DRUG REACTIONS / EFFECTS (ADRs / ADEs) ADR = Any response to a drug that is noxious (harmful) and unintended, and that occurs at doses used in humans for prophylaxis, diagnosis or therapy, excluding failures to achieve the desired result. Side effects: include all non-intended responses to a drug, both beneficial & detrimental. Incidence- occurs in 7-8% of all hospitalized patients and 3-4% of those affected die. MedWatch, the FDA Medical Products Reporting Program, was established in 1993: www.fda.gov/medwatch, & The Agency for Healthcare Research and Quality's (AHRQ) o Reports 2004, 2008, 201, 2014 (https://hcup-us.ahrq.gov/reports/statbriefs/statbriefs.jsp o ADRs are increasingly common, in part because of the substantial increase in prescription drug use. Between 2011 and 2014, 91 percent of U.S. adults aged 65 years and older reported use of a prescription drug in the past 30 days, compared with 74 percent reporting prescription drug use between 1988 and 1994. o The percentage of Americans aged 65 years and older who reported taking five or more drugs increased from 14 to 41 percent over the same time period. ADRs are produced  Drugs or metabolites are directly toxic to the cells  Drugs or metabolites reduce the hormonal or immunologic defense of the host  Drugs or metabolites evoke immunological or idiosyncratic reactions Types of ADRs o Based on severity: minor to life threatening or death o Predictable - looking at the patient and the action of the drug it can be determined whether or not an ADR could be expected in this patient. o Unpredictable - there is nothing that can be seen in a particular patient to determine that an ADR can be expected in this patient with a particular drug. Relevant factors in production of a predictable ADR  Age - young and old are susceptible  Dosage- larger doses are more harmful than smaller ones and they are dose related  Route of administration - usually an IV administration is more likely to produce this type of ADR than an oral dose  Ability of patient to metabolize or excrete the drug- liver disease and kidney disease cause increased blood levels and so a patient with these problems should be given lower doses of therapeutic agents. The very young and the very old also should be given lower doses than a normal adult.  Genetic factors- some genetic factors make people more susceptible to problems with particular agents  Concurrent therapy- many agents work together to produce an increased effect. This not only includes prescribed agents, but also over the counter medications e.g. someone who is on anticoagulant therapy should not take aspirin, which is also an anticoagulant. Dr M Hossu Notes 184  Relevant factors for an unpredictable ADR  Dosage is irrelevant in its production  Route of administration is not necessarily important  Pattern is unpredictable  A few drugs produce particular patterns- e.g. it is well known that a percentage of patients who receive I.V. chloramphenicol will experience bone marrow depression, but until a patient has this reaction it is not clear if a patient is one of that percentage  Immunoreactions often occur on second or subsequent exposure. Common Adverse Drug Reactions  Blood dyscrasias (half of all deaths) o Granulocytopenia, aplastic anemia, pancytopenia – antineoplastic agents, immunosuppressives, chloramphenicol o Hemolytic anemia, thrombocytopenia- Penicillin, methyldopa, quinidine  Cutaneous o Urticaria, macules, papules, vesicles, petechiae, exfolliative dermatitis, fixed drug eruptions- antineoplastic agents, sulfonamides, hydantoins and others  Cardiac o Arrhythmias- theophylline, hydantoins o Cardiomyopathy- doxorubicin, daunorobicin  Renal o Glomerulonephritis- penicillamine o Acute tubular necrosis- aminoglycoside antibiotics, cyclosporin, amphotericin B o Tubulointerstitial disease- phenacetin, salicylates  Pulmonary o Asthma- salicylates o Acute pneumonitis- nitrofurantoin o Interstitial fibrosis- busulfan, nitrofurantoin, bleomycin  Hepatic o Fatty change- tetracycline o Diffuse hepatocellular damage- halothane, isoniazid, acetominophen o Cholestasis- chlorpromazine, estrogens, contraceptive agents  Systemic o Anaphylaxis- penicillin o Drug induced lupus- Hydralazine  Central nervous system o Tinnitus and dizziness- salicylates o Parkinsonian symptoms- Phenothiazine antipsychotics o Respiratory depression- sedatives Dr M Hossu Notes 185  Specific therapeutic agents Halothane- is a general anesthetic.  It produces liver necrosis and is greater in those who have had prior exposures. Estrogen supplements  Endometrial carcinoma- postmenopausal estrogens increase the risk. Progestins counteract this effect  Breast cancer- may induce a small increased risk  Ovarian carcinoma - may increase postmenopausal risk two to three fold  Increased incidence of venous thrombosis and pulmonary embolism as well as stroke Oral contraceptives  Increased death rate due to thrombosis, and is particularly high in women who are over 35 and who smoke.  Endometrial carcinoma shows no increased risk  May protect against ovarian carcinoma  Increased incidence of liver adenoma and hepatocellular carcinoma  Increased incidence of hypertension Anticancer drugs  All these have as their primary function the destruction of cancer cells by interfering with division or metabolism of the cells. Unfortunately these agents also destroy some normal cells that are dividing.  Can produce hair loss, destruction of GI tract mucosa and so GI symptoms and destruction of bone marrow producing leukopenia, thrombocytopenia and anemia.  Doxirubicin is also cardiotoxic and bleomycin affects the lungs.  Long term effect of anticancer drugs is the possibility of development of things like leukemia 10 or more years following treatment. Anti-infectives  Hypersensitivity reactions  Emergence of drug resistant organisms  Alteration of normal microflora giving opportunistic organisms a chance to proliferate such as the production of diarrhea and the growth of candida Immunosuppressants  Predisposition to infections such as CMV, pnemocystis carinii pneumonia and fungi.  Increased risk of development of lymphomas  Azathioprine is toxic to lungs and cyclosporine causes renal injury. Over the counter medications  Aspirin o Acute toxicity  Usually in children this is accidental, in adults it is usually suicidal.  Ingestion of 2-4gms by children may be fatal, as may 10-30gms in adults Dr M Hossu Notes 186   Respiratory alkalosis occurs first because the aspirin stimulates the respiratory center to produce hyperventilation, later there is a metabolic acidosis as the effects of the aspirin itself is seen.  There is also usually severe bleeding into the stomach o Chronic toxicity  Persons who take 3g or more daily  Headaches, dizziness, ringing in the ears, difficulty hearing, confusion, nausea and vomiting  Exacerbation of peptic ulcer disease  Bleeding tendency  Analgesic nephropathy o Interaction with anticoagulants  Acetaminophen o Problem is particularly in over-dose o Usually therapeutic dose is 0.5gms; toxic dose is 15-25 gms o Nausea, vomiting, diarrhea and shock followed in a few days by jaundice o Serious toxicity produces liver failure and may have associated renal and cardiac damage o Problems occur at lower doses if there is concomitant alcohol intake. Dr M Hossu Notes 187