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Practice 1: Slide (9): Adverse drug reactions: Adverse event : Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment. (there is no cause effect relationship between the drug and the untoward medical condition). Ex. patient developed a dry cough after initiating treatment of Atenolol. We don’t know if the dry cough is caused by the drug or not. So, we can’t call this an adverse drug reaction nor a side effect. We call it an adverse event. Ex. patient developed a heart attack after initiating treatment of Atrovastatin. We don’t know if the heart attack is caused by the drug or not. It’s just a bad event started after the initiation of the drug. This is called an adverse event. (not necessarily that the drug is the cause but it may be the cause of this event). - Side effect: Any unintended effect of a pharmaceutical product occurring at doses normally used in humans, which is related to the pharmacological properties of the drug. (extension of the pharmacological effects of the medication that may be beneficial and not necessarily to be harmful ). -Adverse reaction: a response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of a disease, or for the modification of physiological functions. (necessarily to be harmful/noxious). -both side effects and adverse reactions occur at usual doses of the drug. -any undesired conditions that are caused at a high dose of the drug is called drug toxicity, poisoning or overdose. * side effects of a drug don’t usually lead to modifications of the therapy (they may lead to little modifications of the therapy) unlike adverse drug reactions that are harmful and lead to modifications of the therapy. EX. Patient is taking an antihistamine (first generation) and is suffering from drowsiness and a dry cough. Is this considered a side effect or a drug reaction? - this is a tolerable side effect that doesn’t lead to any changes of the therapy. Ex. Patient developed an acute kidney injury after initiating treatment of Lisinopril. This is called an adverse drug reaction and discontinuation of Lisinopril and addition of a new intervention is mandatory. The frequency of a side effect is usually predictable. Ex: metformin 10% can cause GI upset. Side effects are dose dependent. (when the dose increases, the intensity of the side effect increases). ** There are some conditions that are not considered side effects, adverse drug reactions or adverse drug events. EX. overdose of a medication, poisoning (intoxication), withdrawal symptoms and abuse (dependence) symptoms. - Adverse drug reactions and side effects are consequences due to medications. Adverse drug events are not necessarily due to medications. If an adverse event is proved to be due to medications we can call it an adverse drug reaction or a side effect depending on the magnitude of changes in the therapy. -consequences of adverse drug reactions: 1- Discontinuation of medications. 2- May prolong health care facility stay. 3- May require supportive treatment (additional cost). 4- May require Diagnostic procedures (if not sure if the adverse reaction is due to the medications or not). 5- May affect the prognosis of the disease. Ex. doxorubicin and daunorubicin are anti-neoplastic agents used mainly in the treatment of lymphoma and leukemia. Patients who use these medications usually develop heart failure. Ex. patient is taking aspirin and developed a hemorrhagic stroke (disability or mortality consequences). Types of Adverse effects: 1- Type A adverse effects (Drug actions): *extension of the drug’s pharmacological effects* and is predictable with low mortality rate and high incidence and is dose dependent. Is called drug actions because it depends on the drug not the patient. Ex. Patient with HTN is taking Carvedilol, the expected effect of carvedilol is to decrease BP. Hypotension is an extension of the intended pharmacological effect of Carvedilol. Ex. Hypoglycemia is an extension of the pharmacological effect of Sulfonylureas. * Type A is a predictable adverse reaction. (it can be predicted by the mechanism of action of the drug and the risk factors). * Type A is dose dependent (8 mg of glimepiride will cause more hypoglycemic effect than 1 mg). * low mortality rate and high morbidity rate with high incidence. Other examples: Sedation caused by hypnotic agents, bradycardia caused by beta blockers and constipation caused by opioids. *Treatment: dose adjustment. Sometimes we may discontinue the medication temporarily until the adverse effects are gone, then we initiate the drug again at a very low dose and we titrate it gradually. * there are some risk factors that may increase the incidence of type A adverse effects. Ex. Risk factors that increase the probability of hypotension due to the use of Carvedilol are: Age (Elderly patients), concomitant use of other antihypertensive agents, taking Carvedilol at empty stomach and in a hypovolemic state (excessive bleeding, vomiting or diarrhea). * what distinguishes type A adverse effects from type B is that the prediction depends on the presence of risk factors. Ex. Skipping meals, Acute or chronic renal impairment and age (elderly patients) are factors that increase the probability of hypoglycemia with Glimepiride. 2- Type B adverse effects (Patient reactions): - the drug is well tolerated by the majority of people, but small number of people elicit an allergic reaction due to this medication. It Is dose independent and is not predictable (not on the dose, mechanism of action or even risk factors). Ex. Penicillins, thiazide diuretics, fluoroquinolones. * Type B adverse effects is Acute (occurs after the first dose). * unexpected and usually severe. * low incidence and morbidity rate with high mortality rate. * Allergic reaction: is a hypersensitivity reaction that is caused when the body recognizes the drug as an antigen. It can be an immunological or non-immunological reaction. *Examples on Type B adverse reactions: Rashes, anaphylaxis, multi-organ failure, agranulocytosis (failure of all bone marrow elements: WBC’s, RBC’s and platelets are damaged “Aplastic anemia”) and polycystic hepatitis. * Treatment: Discontinuation of the medications. Types of adverse drug reaction depending on time/occurrence: 1- Rapid reactions: occurs only when a drug is administered rapidly when the drug must be administered gradually. Ex. Red man syndrome is a rapid reaction that is caused by the rapid administration of Vancomycin (Vancomycin should be given in an IV infusion over 0.5 to 2 hours). Ex: Hypotension is a rapid reaction that is caused by the rapid IV iron administration. 2- First dose reactions: occurs after the first dose of a course of treatment and not necessarily thereafter. Ex. Alpha blockers, hydralazine, ISDN, ACEIs, type 1 hypersensitivity reactions. These drugs with first dose reactions should be administered in hospitals or physician clinics. 3- Early reactions: occur early in treatment and then abate with continuing treatment. These are adverse reactions to which patients develop tolerance. Ex. Metformin (nausea and diarrhea), ISDN (Headache and flushing), ACEIs and ARBs (hyperkalemia), statins (muscle pain) 4- late reactions: occurs rarely or not at all at the beginning of treatment, but the risk increases with repeated exposure. it depends on the accumulation of medications (cumulative effect). Ex. Glucocorticoids (osteoporosis, needs several months), Metformin (B12 deficiency), Antipsychotics (Dopamine receptor antagonists) such as Haloperidol (extrapyramidal symptoms: tardive dyskinesia “involuntarily facial muscle movements” caused by the imbalance of dopamine in the CNS), withdrawal reactions (are late reactions but not adverse drug reactions). 5- delayed reactions: are observed after a certain time after exposure, even if the drug is withdrawn before the reaction appears. They are not very common. Ex. Thalidomide was prescribed during pregnancy to ease morning sickness before it was withdrawn because it caused defects and deformities of the delivered babies. Ex. Diethylstilbestrol (causes vaginal adenocarcinoma in women who where exposed to it in utero). Ex. Females who took antiepileptic agents during pregnancy, the cognitive development of their children will be lower than normal. *Severity of reactions: -Minor: no antidote, therapy or prolongation of hospitalization is required (no modifications) like GI upset caused by Metformin. -Moderate: requires changes in the drug therapy, specific treatment or an increase in hospitalization by at least one day (needs modifications like decreasing the dose of the drug or prophylaxis administration). -Severe: potentially life threatening, causing permanent damage, or requiring intensive medical care (needs ICU admission) like hemorrhagic stroke. -Lethal: directly or indirectly contributes to the death of the patient. ** What are the ways that help in deciding whether the adverse events are drug induced or not? - we can explain the side effects depending on the underlying diseases (Ex. Patient with HF and volume overload has been using enalapril for 10 years. The patient has developed a dry cough recently. The Dry cough is not drug induced and not caused by enalapril. It is disease induced (caused due to volume overload). - Discontinuation of the medication. If the adverse reactions disappear then they are drug induced. Naranjo Score: refer to slides 15,16,17 (should be memorized!) Score : Definite: more than 9 Possible: 1-4 Probable: 5-8 Doubtful: less than zero.