Pharm term paper outline Medication safety and adverse drug reactions Evaluation of (Western) drug interactions with nutraceutical products Development of drug tolerance and drug resistance Requirement: Write an essay on one of the topics above in English (> 2000 words; submit in MS Words format) 1. Background: statistic: no of people suffering from adverse reaction & fatal data (Preventable ADRs) : US statistics The Institute of Medicine reported in January of 2000 that from 44,000 to 98,000 deaths occur annually from medical errors.1 Of this total, an estimated 7,000 deaths occur due to ADRs. To put this in perspective, consider that 6,000 Americans die each year from workplace injuries. However, other studies conducted on hospitalized patient populations have placed much higher estimates on the overall incidence of serious ADRs. These studies estimate that 6.7% of hospitalized patients have a serious adverse drug reaction with a fatality rate of 0.32%.2 If these estimates are correct, then there are more than 2,216,000 serious ADRs in hospitalized patients, causing over 106,000 deaths annually. If true, then ADRs are the 4th leading cause of death—ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths. These statistics do not include the number of ADRs that occur in ambulatory settings. Also, it is estimated that over 350,000 ADRs occur in U.S. nursing homes each year.3 The exact number of ADRs is not certain and is limited by methodological considerations. However, whatever the true number is, ADRs represent a significant public health problem that is, for the most part, preventable. 2. Definition: adverse drug reaction & medication safety Adverse drug reaction - An adverse drug reaction (ADR) can be defined as ‘an appreciably harmful or unpleasant reaction resulting from an intervention related to the use of a medicinal product > include toxic effects & side effects Medical safety Medical safety refers to the safety regarding the medical devices, diseases, and health care of the diseased patients. Medical safety can also be termed as the safety and efficacy of medications that are carried out by people. (https://www.longdom.org/scholarly/medical-safety-journals-articlesppts-list2182.html#:~:text=Medical%20safety%20refers%20to%20the,are%20carried %20out%20by%20people.) 3. Types of adverse drug reactions - drug toxicity > different divisions 1. Dose Dose-related [quantitative] Drug property: therapeutic index (TD50, ED50) Disease state Multiple drug therapy (can mention western&Chinese med ) Age Non-dose related Biological variations （genetic） 2. Exposure [time] Acute: <24hrs Chronic: >3 months [location] Local (organ-based) Systemic > extent Mild Moderate Severe Lethal Classification (Ralph) 6 types 1. Type A: dose-related= 2. Type B: non-dose related=biological variations (hypersensitivity) 3. Type C: dose-related and time-related= reaction brought by prolonged exposure of accumulative dose of drugs 4. Type D: Time-related (delayed)=reactions that occur sometime after the use of drug 5. Withdrawal=reactions that occur after the withdrawal of drugs 6. Unexpected failure of therapy=reaction causing the failure of therapy 4. Guidelines managing the adverse reactions for medical safety Monitoring Diagnosis Management Surveillance: report system Epidemiology 1. Distribution 8, 5 [8] - ADR: most common iatrogenic illness > complicate 5-15%of therapeutic drug courses - In the US, > 100,000 deaths attributed annually to serious ADR ; 3-6% of hospital admission are because of ADR ; 6-15% of hospitalized patients (2.2. million people in the US in 1994) experience a ADR [5] - A recent review (2015) showed that 3.6% of patients were admitted to hospitals in Europe due to ADRs and 10% of patients developed side effects during their inpatient stay - The latest report issued by MiDatabank in cooperation with the Medicines and Healthcare Products Regulatory Agency, shows an increasing trend in the number of reported ADRs in the period between 2011 and 2016 across the UK [7] - The prevalence of ADR-related hospitalisations was relatively more consistent among studies in developed countries than developing countries 2. Determinants: Common risk factors 9, 7, 2(p. 2), (5?), pharm-L06 (Chinese med), 8(p.3) Pharmacological: dose, drug formulation, pharmacokinetic or pharmacodynamic abnormalities, and drug interactions > Increased levels of reactive drug metabolites, their impaired detoxification, or decreased cellular defense against reactive drug products Immunological & Genetic : body reactions > ethnic variation - patient-related age: both very young and old - elderly > take multiple drugs > liver dysfunction with age > loss of ability of drug metabolism > change of fat tissue to water proportion Decrease of water content > increase in concentration of water-soluble drugs Increase proportion of fat tissue > increased accumulation of lipid-soluble drugs > kidney dysfunction > failure of drug excretion > retention time of drug in human body increases with age > prolonged time of drug effects - smaller capacity of drug elimination - less likely to be studied in research - more variable and less predictable drug absorption and metabolism - infants and very young patients: low/ clearly evaluated capacity of drug metabolism because they are not full developed 1. Neonates have immature renal tubular function when they are below the age of 8 weeks, avoiding digoxin, aminogly- cosides, ACE inhibitors, NSAIDs is a must (De-gregori et al., 2009). 2. Physiologic hypoalbuminemia in neonates affects drug dosing. Caution is recommended when dealing with high pro- tein binding drugs such as NSAIDs (Anderson and Lynn, 2009). 3. Neonates, have low body fat; they might be affected by fat soluble drugs (Ibanez et al., 2009). 4. Increased anesthetic effects due to immature blood brain barrier at <8 weeks of age (Schoderboeck et al., 2009). 5. Predisposition to hypotension due to poor cardiac compliance and immature baroreceptors (Pellicer et al., 2009). Gender - Female: lower bodyweight and organ size, more body fat, different gastric motility and lower glomerular filtration rate > affect the way the body deals with drugs by altering the pharmacokinetics and pharmacodynamics of the drugs including drug absorption, distribution, metabolism and elimination. - Different frequency and severity of ADR to antiretroviral drugs - Female: more active hepatic enzyme (CYP3A4) > different effects on drug metabolism e.g. higher metabolism of midazolam vs men: more other enzymes - More likely to suffer from torsade de pointes ventricular tachycardia when prescribed with drugs that prolong cardiac repolarization - Different pharmacodynamic effects on cardiac and psychotropic drugs e.g. higher efficacy of Chlorpromazine and fluspirilene on women for same dosage and plasma concentration - Male: affected fertility when prescribed with colchicine that treats diseases including Familial Mediterranean fever vs female: no effect on fertility - Female: more common hepatic drug reactions > hepatotoxicity - Female: more drug effects due to specific issues like pregnancy, menstruation e.g. pregnancy > lower efficacy of anti-epileptics due to faster elimination Habit of contraception: female Race and ethnicity Determinants of susceptibility include kinetic factors, such as gene polymorphisms in cytochrome P450 enzymes, and dynamic factors, such as polymorphisms in drug targets - Hypersensitivity reaction to abacavir: Caucasian higher risk - angiotensin-converting enzyme (ACE) inhibitors: African Americans were found to be more susceptible to developing ACE-related angioedema - > National Institute for Health and Care Excellence guidance has suggested that patients of African or Caribbean descent should be prescribed an angiotensin-II receptor blocker in favour of an angiotensin converting enzyme (ACE) inhibitor for hypertension [S2] cardiovascular drugs: black patients- higher risk of angioedema, intracranial haemorrhage blood pressure lowering drug: black patients - higher risk of angioedema east-asian patients – higher risk of cough thrombolytic therapy when using streptokinase and tissue plasminogen activators: black patients have higher risk of bleeding Social factors Alcohol drinking Direct - Cause ADR with consuming alcohol with some drugs e.g. nausea, vomiting, headaches, drowsiness, fainting, loss of coordination, hypotension e.g. cause internal bleeding in patients suffering from peptic ulcer or ex-peptic ulcer or gastritis when they uptake alcohol with NSAIDS due to severe ulceration - Unexpectedly amplify the drug effect e.g. alcohol magnify inhibitory effect of sedatives and narcotics at their site of action in brain - indirect - cause damage to the organs responsible for drug metabolism > chronic consumption > activation of enzymes that converts drug into toxic substances that damage organs including liver > alcohol damages liver (liver cirrhosis & hepatitis) > impaired ability of metabolizing drugs > increase the toxicity of drugs e.g. increase beta blockers’ toxicity smoking - decreased pharmacological effects by affecting liver enzymes which induce hepatic cytochrome P-450 isoenzymes like 1A2 to which many drugs bind. - Tobacco stimulates sympathetic nervous system - Smoking affects therapeutic responses of certain drugs such as theophylline, oral contraceptives, insulin e.g. insulin-dependent diabetic smokers needed 15–20% more insulin than non-smokers, and up to 30% more if they smoked heavily > increase the rate of hepatic clearance by increased binding of heparin to antithrombin III due to activated thrombosis > decrease the rate of insulin absorption thanks to the cutaneous vasoconstriction after subcutaneous administration e.g. smoking > reduced effect of beta blockers on blood pressure and heart rate - Drug-related factors Polypharmacy: number and severity of ADR increases with increasing number of drugs taken ADRs may occur due to drug interaction, synergism, duplication, additive effect, discontinuation of therapy (inability of some patients especially the elderly to keep track of using their medications), changing the dose to save money, skipping some medications and physiological antagonism - - - - - [6] Skipping some of the drugs in treatment > shortage of treatment & development of adverse events Prescribing cascade caused by polypharmacy which includes drugs used to treat other drugs’ ADR give raise to other ADR > endless line of medication e.g. prochlorperazine to prevent drug- induced dizziness > Prochlorperazine for instance may cause postural hypotension which may exacerbate any hypotensive effect of antihypertensive drugs > cause accidents e.g. hip fracture due to serious dizziness >maybe caused by misdiagnosis by physicians: see ADR as the symptom of diseases > prescribe more drugs > worsening of the ADR or putting patients at risk of new ADRs e.g. 1. Thiazide diuretics may cause hyperuricemia which leads to prescribing colchicines which in turn may cause diarrhea Drug-drug interaction: effects of a drugs changed by another drug Frequency & prevalence of interactions depend on the number of concomitant drugs and complexity of regimen >two classification 1. pharmacodynamic: lead to additive or antagonistic pharmacological effects 2. pharmacokinetic: involve induction or inhibition of metabolizing enzymes in the liver or elsewhere, displacement of drug from plasma protein binding sites, alterations in gastrointestinal absorption, or competition for active renal secretion Addition of non-prescription medication: drug combination may sometimes cause synergistic toxicity (greater than the sum of the risks of toxicity of either agent used alone) e.g. Patients concurrently receiving corticosteroids and NSAIDs had a risk of peptic ulcer disease that was 15 times greater than that of nonusers of either drug e.g. Both vancomycin and narcotics induce dose-dependent skin reactions and synergize to cause adverse reaction Adverse effects occur when take certain herbal medicine with some orthodox drugs e.g. uptake of Dan Shen (Radix Salvia Miltiorrhiza) >With chronic warfarin, cause exaggerated prolongation of prothrombin time, leading to internal bleeding >Reduce the efficacy of anti-ulcer drugs by forming non-absorbable precipitates Chemical properties and molecular weight of the drugs (hypersensitivity reaction) Larger drugs with greater structural complexity: more likely to induce immune response (immunogenic) [S8] e.g. drugs heterologous antisera, insulin Route of drug administration [S8] Topical, intramuscular, intravenous administration: more likely to cause hypersensitivity reactions when compared with oral administration R: efficiency of antigen presentation in skin, adjuvant effect of repository drug preparation, high conc of circulating drug antigen rapidly achieved by I.V. Types of ADR 2, 6, 8 Pharmacovigilance Intro: Many ADR: preventable [S7: abstract, S2 p.2 [s2] - many are preventable with adequate foresight and monitoring: Epidemiological studies tend to find that between a third and a half of ADRs are (at least potentially) preventable prevention 1. identification of susceptibility: physicians should have adequate knowledge of risk factors of ADRs > stay vigilant when encountering patients with higher susceptibility & make cautious choice on the use of drugs in the treatment e.g. co-prescription of folic acid with methotrexate: reduce ADRS associated with folate deficiency 2. Monitoring [s2] - monitoring: keep track of body condition of patients e.g. monitoring electrolytes and renal function when treating with renally active drugs or diuretics e.g. monitor the change in liver function tests in a patient treated with antituberculous chemotherapy can prevent the development of acute liver failure 3. Diagnosis [s2] - Identify the types of ADRs and the drugs causing ADRs by investigation through observations on the sign and symptoms resulting from ADRs [esp. those of immediate generalized reactions which are the most life-threatening form of ADRs >signs such as wheezing, urticaria: manifest thew imminent cardiovascular collapse > death > stop the prescription of the drugs immediately], enquiry about the medication history of the patients, and features of ADRs like such as asking if ADRs stop when patients stop taking the drugs - Evaluation on the appearance signs and symptoms of immediate generalized reactions which are the most life-threatening form of ADRs >signs such as wheezing, urticaria: manifest thew imminent cardiovascular collapse > death > stop the prescription of the drugs - Investigation to confirm the diagnosis e.g. testing the intracellular tissue deposition of the drug or a metabolite (eg indinavir crystalluria and nephropathy). e.g. Skin testing for type I hypersensitivity reactions (8) > detect the presence of antigen-specific IgE 4. Reporting system for surveillance - Todays’ problem 1. Many cases of ADRs: underreported > system developed x give analysis of data with high accuracy [2] - Nowadays reporting system 1. Yellow Card Scheme in the UK, operated by the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) [2] Collect data of information from a report which can be submitted through the internet: an identifiable patient, a reaction, a suspected medicinal product and an identifiable reporter [2] 2. Reporting of ADRs detection to a national centre responsible for providing general information about drugs which is then sent to the WHO worldwide database for data analysis by WHO Collaborating Centre for International Drug Monitoring [6]
