2535 patho week 3

Lilley (2020) Chs. 3, 4, 5, & 6

Chapter 3- Legal and Ethical Considerations

LEGAL CONSIDERATIONS

• Prescription drug use is crucial for treating and preventing illness.

• It's regulated by agencies like Health Canada, RCMP, and provincial laws.

• Traditionally, only medical doctors and doctors of osteopathy could prescribe medications.

• Dentists and podiatrists may prescribe within scope of practice.

• Some provinces allow physician’s assistants, pharmacists, and nurse practitioners to prescribe.

• In 2015, the Canadian Nurses Association (CNA) established a framework for RN prescribing.

• Colleges in Alberta and Ontario created educational standards for nurses prescribing medications/tests.

• As of May 1, 2019, RNs in Alberta working in specialty areas can prescribe specific medications and order tests.

• Increasing complexity of prescriptions and technological changes affect laws on drug use.

• Professional nurses have gained more autonomy in practice, leading to greater liability and accountability.

Canadian Food and Drugs Act

• Canadian Drug Legislation began in 1875 to prevent the sale of adulterated foods, drinks, and drugs.

• Legislation controls foods, drugs, cosmetics, and medical devices on a national basis.

• The Health Products and Food Branch Inspectorate (HPFB) regulates the Food and Drugs Act and Controlled Drugs and Substances Act.

• Acts aim to protect Canadian consumers from health hazards and fraud.

• The Personal Information Protection and Electronic Documents Act (PIPEDA) governs the collection, use, and disclosure of personal information.

• Provincial legislation like Ontario's Personal Health Information Protection Act (PHIPA) of 2004 mandates patient privacy.

• Protected health information includes health conditions, account numbers, prescription numbers, medications, and payment information.

• Proposal in 2013 aimed to revise PHIPA to Electronic Personal Health Information Protection Act (EPHIPA) for electronic health records.

• Goal of federal legislation: ensure the safety and efficacy of new drugs and protect patient confidentiality.

Canadian Food and Drugs Act (CDSA)

• Primary legislation governing foods, drugs, cosmetics, and medical devices in Canada.

• Inception: Established in 1953; has been amended multiple times.

• Schedule A: Lists diseases not permitted for public advertising; prohibits claims of treatment or cure for these diseases.

• Revisions (June 1, 2008): Includes life-threatening diseases like cancer; "liver disease" reclassified as hepatitis.

• Canadian Standard Drug (CSD): Must appear on drug packaging to confirm compliance with standards.

• Schedule B: Lists recognized pharmacopoeias and formularies governing drug standards.

  • Examples include: Pharmacopée française, British Pharmacopoeia, Canadian Formulary, U.S. Pharmacopoeia.

• Schedules C & D: C includes radiopharmaceuticals; D includes allergenic substances, vaccines, and others.

• Drug Samples: Regulated distribution, generally permitted to health care providers under certain conditions.

• Schedule F: Lists prescription drugs (excluding narcotics and controlled drugs), replaced by the Prescription Drug List.

• Prescription Identification: Marked with Pr symbol (black box with white letters) indicating it is a prescription drug.

• Label Information Regulation: Includes directions for use; refills may be authorized as indicated by prescriber.

• Current Regulations: Governed by Food and Drug Regulations; includes Parts G (controlled drugs) and J (restricted drugs). Controlled drugs must have a C marked on the label and must include the proper name of the drug.

Controlled Drugs and Substances Act

• Controlled Drugs and Substances Act (CDSA)

  • Passed in 1997; replaced Narcotic Control Act and parts of the Food and Drugs Act.

  • Regulates control and sale of narcotics and controlled drugs.

  • Prescription required from licensed medical practitioner for legal acquisition.

  • All controlled drugs are marked with the letter N and a symbol on labels.

  • Based on eight schedules categorizing by misuse potential or manufacturing ease:

    • Schedule I: Most dangerous drugs (e.g., opium, heroin, morphine, cocaine, fentanyls, methamphetamine).

    • Schedule II: Synthetic cannabinoid receptor type 1 agonists.

    • Schedule III: Dangerous drugs (e.g., amphetamines, LSD).

    • Schedule IV: Drugs like barbiturates, anabolic steroids (requiring prescription for possession).

    • Schedules V and VI: Precursors for controlled substances.

    • Schedules VII and VIII: Cannabis amounts for legal purposes.

  • Schedule determination factors: international requirements, dependency potential, abuse likelihood, public safety risks, therapeutic usefulness.

  • Enforced by RCMP; police exemptions for duties.

  • Related regulations for Benzodiazepines and other substances from Schedules I and II.

  • Precursor Control Regulations (2003) regulate essential chemicals used in drug production.

  • Marihuana Medical Access Program ended March 2014; replaced by Marihuana for Medical Purposes Regulations in 2015; repealed after legalization on October 17, 2018.

  • Cannabis Act and Cannabis Regulations govern medical cannabis access.

  • Medical cannabis access methods:

    • Buy from licensed federal sellers.

    • Register with Health Canada to produce prescribed amount.

    • Assign designate for production.

NEW DRUG DEVELOPMENT

• Drug Research & Development: An ongoing process in the pharmaceutical industry (multi-billion dollar industry).

• Continuous Development: Companies must develop new and better drugs to maintain a competitive edge.

• Research Duration: May take several years; many substances are isolated but never make it to market.

• Regulated Process: Systematic process monitored by Health Canada, ensuring patient safety and drug effectiveness.

• Stringent Standards: One of the most stringent drug approval systems in the world.

• Resources Required: Much time, funding, and documentation needed to ensure safety and efficacy.

• International Market: Many drugs are marketed overseas before Canadian approval.

• Drug-Related Calamities: Stringent approval helps avoid significant issues (e.g., thalidomide tragedy, March 1962, linked to severe malformations).

• Regulatory Framework: In 2003, National Health Products Regulations introduced, covering products like vitamins and herbal remedies.

• False Claims: Manufacturers cannot make false or misleading claims about product efficacy (e.g., cannot say “Known to cure depression”).

• Growing Information: Reliable information on natural health products is increasing with more research.

• Bill C-51 (2008): Drafted to support policies for foods and health products.

• Consumer Demand: Rising demand for alternative medicine drives this landscape.

• Patient Guidance: Patients must use caution and communicate with healthcare providers.

HEALTH CANADA DRUG APPROVAL PROCESS

• TPD of Health Canada: Approves drugs for clinical safety and efficacy before market.

• Stringent steps may take years to complete.

• Priority review process ("fast-track approval") allows life-saving medications to be available sooner.

• Eligible submissions: Shorter review target of 180 days vs. 300 days for non-priority.

• AIDS crisis: First major public health crisis for expedited drug approval.

• Enabled manufacturers to fast-track drugs showing promise in Phase I and Phase II trials for qualified patients.

• Controversy: Expedited approval process criticized after Vioxx recall (2004) due to severe cardiovascular events and withheld risk information.

• Drug approval process begins with preclinical testing (in vitro and animal studies) followed by clinical studies.

• Four phases of clinical trials: Leads to market after Phase III completion if approved by TPD.

• Phase IV consists of postmarketing studies.

• Goal: Provide information on safety, toxicity, efficacy, potency, bioavailability, and purity of new drugs.

• A Notice of Compliance indicates drug safety and effectiveness, allowing sales to the public under prescription.

• Approved drugs receive a Drug Identification Number (DIN) from Health Canada, which appears on labels of prescription and OTC products.

Preclinical Investigational Drug Studies

• Medical ethics require all new drugs to undergo laboratory testing first.

• Testing includes in vitro (cell/tissue) and animal studies before any human testing.

• In vitro studies test various types of mammalian cells (including human) to different drug concentrations.

• Cells/tissues collected from living or dead subjects (e.g., surgical/autopsy specimens).

• Purpose of in vitro studies: Determine if a substance is too toxic for human use.

• Many drugs are ruled out during the preclinical phase.

• A small percentage proceed to further clinical testing on humans.

Four Clinical Phases of Investigational Drug Studies

• Informed consent is required before testing on humans.

• Must be documented and signed by the patient and a witness.

• Involves a careful explanation of:

  • The purpose of the study.

  • The procedures to be used.

  • The possible benefits and risks involved.

• Consent form must be understandable and dated.

• Always voluntary; participants can decline or withdraw at any time.

• Must be obtained when the patient is mentally competent.

• Can be conducted by nurses or healthcare providers, based on study design.

• Medical ethics require informed volunteers; coercion is not allowed.

• Patients may have unrealistic expectations about the investigational drug's usefulness.

• Potential hazards and benefits must be fully disclosed to participants.

Phase I

• Phase I studies typically involve small numbers (fewer than 100) of healthy subjects.

• Exception: Studies may include subjects with life-threatening illnesses for toxic drugs with no viable alternatives.

• Purpose:

  • Determine potential adverse effects

  • Establish optimal dosage range

  • Assess pharmacokinetics: absorption, distribution, metabolism, excretion

• Additional tests: blood tests, urinalyses, vital sign assessments, specific monitoring tests.

• Duration: Usually lasts a few days to weeks.

Phase II

• Phase II studies involve 100 to 300 volunteers with the disease or ailment the drug targets.

• Participants are closely monitored for effectiveness and to identify any adverse effects.

• Therapeutic dosage ranges are refined during this phase.

• If no serious adverse effects occur, the study can progress to Phase III.

Phase III

• Phase III Studies: Involve 1000 to 3000 patients monitored by medical research centers.

• Purpose: Identify infrequent or rare adverse effects not observed in smaller studies.

• Placebo-Controlled: Use of a placebo (inert substance) to differentiate real benefits from bias.

• Blinded Studies:

  • Blinded Investigational Drug Study: Investigator knows the treatments, subjects do not.

  • Double-Blind Study: Neither researchers nor subjects know the treatment allocation.

• Dosage Forms: Drug and placebo often look identical except for a secret code.

• Objectives of Phase III: Establish clinical effectiveness, safety, and dosage range.

• Post-Phase III: Manufacturer submits a New Drug Submission to Health Canada.

• Marketing Exclusivity: Approval allows exclusive marketing until patent expiry (normally 20 years post-discovery).

• Recouping Costs: New manufacturers typically have 8 to 10 years post-marketing for cost recovery, with expenses in hundreds of millions.

Phase IV

• Phase IV studies: Postmarketing studies by pharmaceutical companies to prove therapeutic and adverse effects of new drugs.

• May be mandated by Health Canada.

• Data collected for at least 2 years post-release.

• Compare safety and efficacy with other drugs in the same category (e.g., new nonsteroidal anti-inflammatory drug vs. ibuprofen).

• Severe adverse effects may appear when used in the general population.

• If severe reactions are noted, Health Canada may request a voluntary recall from the manufacturer.

• If manufacturer refuses and severity reaches a certain level, Health Canada may pursue court action for an involuntary recall.

• Recall classes according to Health Canada:

  • Class I: Serious risk of health effects or death.

  • Class II: Temporary or reversible health effects, low lasting effects.

  • Class III: Not likely to cause significant health problems.

• Notification methods: Press releases, website announcements, or letters to healthcare providers.

• MedEffect Canada: Program for professionals and consumers to report adverse events with newly approved drugs.

• Recalls and Safety Alerts Database: Comprehensive list of advisories, warnings, and recalls: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/index-eng.php

• Drug information evolves as new events are reported; use current info with sound clinical judgment.

Special Access Programme

• Health Canada Special Access Programme: Provides compassionate access to drugs not available for sale in Canada.

• Limited to individuals with serious or life-threatening conditions:

  • Examples: intrac table depression, epilepsy, transplant rejection, hemophilia, terminal cancer, AIDS.

• Aims to provide experimental drugs for compassionate reasons or emergency situations when conventional therapies fail.

• New regulations (October 2013) prevent access to certain unauthorized controlled substances:

  • Includes heroin, unauthorized forms of cocaine, and restricted drugs like LSD, ecstasy, magic mushrooms, and bath salts.

Patient Access to and Costs of Prescription Drugs

• Rapid growth in prescription drug use and costs in 21st-century Canada.

• High drug expenses pose significant barriers to accessing drugs outside hospitals.

• 1 in 10 Canadians face out-of-pocket expenses, influencing adherence to prescriptions.

• Affected individuals: low-income, without drug benefits, and poor health.

• Prescription drugs not covered under the Canada Health Act.

• Patients must pay unless covered by a private drug plan or F/P/T drug plan.

• Provincial plans cover costs for poor, older adults, those with catastrophic costs, and some conditions (e.g., cancer, HIV/AIDS).

• Federal government provides coverage for indigenous peoples.

• Each province/territory has a formulary committee deciding on drug listings and reimbursements.

• Varied access to prescription drugs across Canada; eligibility and coverage vary by province/territory.

• Often, patients 65+ have most drugs paid but must cover dispensing fees.

• Coverage issues arise with trade name vs. generic drugs.

• Listing decisions consider effectiveness, cost, government priorities, and patient advocacy.

• Some drugs may face restrictions if they need special monitoring or are costly.

Drug Advertising

• Drug Advertising in Canada: Regulated by Health Canada.

• Direct-to-consumer advertising:

  • Restricted to names of prescription drugs.

  • Cannot make claims for product effectiveness.

  • Different from United States regulations.

• Professional health care journals:

  • Allow ads with claims and prescribing information.

• Advertising Standards Canada (ASC) and Pharmaceutical Advertising Advisory Board (PAAB):

  • Review ads based on Food and Drugs Act standards.

  • Clearance procedure is voluntary, but most companies comply.

LEGAL NURSING CONSIDERATIONS AND DRUG THERAPY

• Legislation: Provincial and territorial laws determine boundaries for nursing practice.

• Nurse Practice Acts: Define scope of practice, expanded roles, educational requirements, standards of care, and safety practices.

• Legal Boundaries: Set by regulatory bodies, policies, and procedures from institutions and professional nursing organizations (e.g., CNA).

• Accreditation: Hospitals must fulfill standards and maintain written policies accessible both internally and externally.

• Legal Accountability: Nurses must be familiar with policies to avoid liability in lawsuits involving negligence or malpractice.

• Specialty Standards: Defined for areas like oncology and surgical care to ensure appropriate practice.

• Professional Guidelines: Continuous updates in standards from nursing literature and provincial/territorial associations.

• Privacy Regulations: Governed by the Privacy Act and PIPEDA, ensuring confidentiality and handling of patient information.

• Confidentiality: Patient identities must not be linked to shared information unless consent is given.

• Safeguarding Information: Facilities must comply with PIPEDA, implementing access controls for electronic patient data.

• Nursing Ethics: Legal and ethical dimensions addressed in practice standards, ensuring safe medication administration and patient rights.

ETHICAL CONSIDERATIONS

• Decisions in health care are often collaborative, involving the patient, family, nurses, and the health care team.

• Team members must recognize and respect their own values, as well as those of others.

• Drug therapy has evolved to focus on responsibility and improving quality of life through the nursing process.

• Ethical principles serve as strategies for making ethical decisions:

  • Autonomy: respecting patient's rights.

  • Beneficence: promoting patient well-being.

  • Nonmaleficence: avoiding harm.

  • Justice: ensuring fairness.

  • Fidelity: maintaining trust.

  • Veracity: being truthful.

• Nursing practice presents many potential ethical conflicts.

• Each situation requires compassionate and humane solutions.

• When ethical dilemmas arise, actions should align with ethical principles.

Ethical Nursing Considerations and Drug Therapy

• Ethical Nursing Practice is based on fundamental ethical principles:

  • Beneficence: promoting patient well-being.

  • Autonomy: respecting patient's rights.

  • Justice: ensuring fairness.

  • Fidelity: maintaining trust.

  • Veracity: being truthful.

  • Confidentiality: safeguarding patient information.

• Frameworks of Practice include:

  • CNA Code of Ethics for Registered Nurses (2017)

  • CCPNR Code of Ethics (2013)

  • ICN Code of Ethics for Nurses (2012)

• These codes serve as ethical guidelines for nursing care.

Chapter 4- Patient-Focused Considerations

OVERVIEW

• Human Body Changes: From beginning to end of life, the body undergoes changes affecting drug therapy.

• Pharmacokinetics Phases: Affects absorption, distribution, metabolism, and excretion of drugs.

• Special Needs: Newborns, children, and older adults require tailored drug therapy.

• Adverse Effects: Higher likelihood of toxicity and adverse reactions at the extremes of the age spectrum.

• Predictable Changes: Understanding age-related pharmacokinetics helps anticipate drug responses.

• Study Demographics: Most research focuses on population aged 13 to 65 years; 75% of drugs lack pediatric guidelines.

• Drug Effectiveness: Many drugs are effective across ages but can behave differently in extremes.

• Safe Administration: Essential to recognize and adjust for age-related differences in drug therapy.

Drug Therapy During Pregnancy

• Fetal Exposure: A fetus is exposed to drugs taken by the mother (prescription, nonprescription, illicit).

• Greatest Danger: First trimester is period of greatest danger for drug-induced developmental defects.

• Transfer Mechanism: Drugs and nutrients transfer via diffusion across the placenta; not all drugs cross.

• Active Transport: Involves energy expenditure and cell-surface protein pumps.

• Safety Factors:

  • Drug properties: Chemistry, dosage, concurrent drugs (e.g., molecular weight, protein binding).

  • Fetal Gestational Age: Greatest risk of drug-induced defects in the first trimester; development of skeleton, muscles, limbs, organs.

  • Maternal Factors: Maternal physiology, kidney and liver function affect drug metabolism and fetal exposure.

• Judicious Use: Drugs should be used cautiously; necessary for maternal conditions (e.g., hypertension, epilepsy, diabetes).

• Regulatory Changes: FDA implemented labeling requirements in 1979 and updated in 2014 to provide clear risk-benefit categories for pregnant women.

• Health Canada Guidelines: Labels must include risk information during pregnancy and breastfeeding.

Drug Therapy During Breastfeeding

• Breastfed infants are at potential risk of drug exposure from the mother.

• A variety of drugs can cross from the mother’s circulation into breast milk and then to the infant.

• Drug properties affecting infant exposure include:

  • Fat solubility

  • Low molecular weight

  • Nonionization

  • High concentration

• Some weak basic drugs may accumulate in breast milk.

• Breast milk is not the primary route for drug excretion; levels in milk are usually lower than in maternal circulation.

• Exposure amount depends on the volume of milk consumed.

• Decision on drug use during breastfeeding should consider the risk–benefit ratio, weighing risks to the infant against benefits for the mother.

Considerations for Children: Neonatal and Pediatric Patients

• Pediatric Patients: Defined by age categories.

  • Neonate: Birth to 1 month of age.

  • Infant: 1 to 12 months of age.

  • Child: 1 to 12 years of age.

  • Adolescent: 13 to 19 years of age.

• Age ranges are detailed in Table 4.2

Physiology and Pharmacokinetics

• Pediatric Pharmacotherapy: Tailored to the unique needs of neonates, infants, children, and adolescents.

• Distinct Challenges: Pediatric patients differ significantly from adults in drug behavior.

• Drug Dynamics: Medications may not be absorbed, distributed, metabolized, or eliminated like in adults, impacting efficacy and safety.

• Organ Immaturity: Pediatric patients handle drugs differently due to the immaturity of vital organs.

• Developing Physiology: Anatomical and physiological systems in neonates and older pediatric patients are still developing.

Pharmacodynamics

• Pharmacodynamics: Drug actions vary in young patients based on organ maturity.

• Toxicity: Some drugs may be more toxic, others less toxic.

• Receptor Sensitivity: Varies with age, affecting dosage requirements.

• Tissue Sensitivity: Rapidly developing tissues may need smaller doses.

• Contraindications: Some drugs are generally contraindicated during growth years.

  • Example: Tetracycline can permanently discolour teeth.

  • Corticosteroids may suppress growth if given systemically.

  • Quinolone antibiotics can damage cartilage.

Dosage Calculations for Pediatric Patients

• Insufficient Research: Most drugs not well-studied for safety and effectiveness in children.

• Pediatric Dosage References: Many excellent resources available despite limited research.

• Susceptibility Factors: Premature infants and neonates at higher risk for drug interactions, toxicity, and unusual responses.

• Different Dosage Calculations: Pediatric patients need unique calculations compared to adults due to:

  • Thinner, more permeable skin

  • Lack of stomach acid to kill bacteria

  • Weaker mucous barriers in lungs

  • Less regulated body temperature; dehydration risk

  • Immature liver and kidneys, affecting metabolism and excretion.

• Common Formulas: Dosage calculations often based on Age, Weight, and Body Surface Area (BSA).

• BSA Method: Most accurate for chemotherapy; requires:

  • Drug order (name, dose, route, time, frequency)

  • Available dosage forms

  • Height (cm) and Weight (kg) of patient

  • BSA nomogram (e.g. West nomogram)

• Weight Method: Commonly used; based on mg/kg of body weight.

• Information Needed for Dosage Calculation:

  • Drug order

  • Patient's weight (kg)

  • Dosage from manufacturer/guidelines

  • Information on dosage forms

• Safety Checks:

  • Confirm weight in kilograms, not pounds.

  • Compare prescribed dosing to calculated safe range.

  • Report any concerns to healthcare provider immediately.

• Factors to Consider: Organ maturity, BSA, age, weight, and emotional development impact drug therapy decisions.

Considerations for Older Adult Patients

• Older Adult Definition: Defined as individuals 65 years or older.

• Physiological Differences: Aging leads to decline in organ function, affecting drug handling and therapy.

• Higher Risk: Increased chance of adverse effects and toxicity from drug therapy in older adults.

• Terminology Variation: Definitions of elderly and older adult differ among societies.

• Age Subgroups: Identified as "younger old" (65-75), "older old" (75-85), "oldest old" (85+).

• Population Growth: The older adult population is growing rapidly; 5% in early 20th century Canada.

• Life Expectancy: Currently about 81 years, trends expected to continue.

• Anticipated Rise: By 2030, over 65s expected to reach 23.6% of the population; could rise to 27.8% by 2063.

• Fastest Growing Group: Older adults 85+ are the fastest growing demographic in Canada.

• Technological Advances: Improved medical technology has contributed to increased longevity.

Issues in Clinical Drug Use in Older Adults

• Interindividual Variability: Older adults vary greatly in health, disability, age-related changes, and polymorbidity.

• Polypharmacy: Average older adult takes up to 10 prescription and OTC medications, increasing drug interactions risk.

• Statistics: 1.6 million seniors (1 in 4 Canadians >65) prescribed 10+ drug classes in 2016.

• Common Medications: Statins for high cholesterol, antihypertensives, beta blockers, diuretics, insulin, potassium supplements, analgesics, laxatives, and NSAIDs.

• Folk Remedies: Some older adults use folk remedies of unknown composition, complicating care.

• Chronic Diseases: >80% of patients on 8+ drugs have chronic illnesses, complicating medication regimens and increasing risk for self-medication errors.

• Pill Splitting: Common practice for financial reasons, raises the risk for medication errors.

• Multiple Prescribers: Encourages use of one pharmacy to track drug interactions and avoid duplicate therapy.

• Hospitalization: High rates due to adverse drug reactions; many use natural health products that can interact with medications.

• Interactions: Approximately 6% risk for drug interaction with 2 medications; rises to 100% with 10 or more.

• Prescribing Cascade: Sometimes medications are added to counteract adverse effects of others.

• Adverse Events: Increased adverse events such as falls, addiction risk, confusion, urinary retention, and fatigue due to multiple drugs.

• Reducing Polypharmacy: Important to monitor and minimize drug numbers and dosages.

• Dosing: Older adults may need half to two-thirds of standard adult dose; guidance is "Start low and go slow".

• Nonadherence: Drug nonadherence in ~40% of older adults, linked to hospitalization; factors include patient understanding, involvement in decisions, financial ability, prescribing practices, and healthcare system barriers.

Physiological Changes

• Physiological changes due to aging affect drug actions.

• Declining organ function impacts drug disposition.

• Sensitivity to drugs increases, requiring careful monitoring and dosage adjustments.

• Drug dosing criteria must consider body weight and organ functioning:

  • Emphasizes liver, kidney, cardiovascular, and CNS function.

• General decrease in body weight with aging.

• Changes in drug molecule receptors affect sensitivity.

• Increased sensitivity to CNS depressants (e.g., anxiolytics, antidepressants) due to blood-brain barrier integrity decrease.

• Liver and kidneys are vital for drug breakdown and elimination.

• Kidney function measurement essential for evaluating drug therapy effectiveness.

• Canadian guidelines for kidney assessment include eGFR and albuminuria.

• Albuminuria: urine albumin-to-creatinine ratio >2.0 mg/mmol (men), >2.8 mg/mmol (women).

• Routine assessments should include creatinine/albumin level screening.

• Lower serum creatinine may occur in older adults due to decreased muscle mass.

• Liver function testing evaluates liver enzymes (e.g., AST, ALT) for medication metabolism ability.

• Annual laboratory assessments needed for monitoring drug toxicity risks.

• More frequent assessments (1, 3, or 6 months) may be needed for higher-risk regimens.

Pharmacokinetics

• Pharmacokinetic Phases: Absorption, distribution, metabolism, and excretion vary in older adults compared to younger adults.

• Absorption:

  • Reduced absorption of dietary nutrients and drugs with advancing age.

  • Decreased gastric acid production affects drug absorption.

  • 50% reduction in blood flow to the gastrointestinal tract by age 65.

  • Decreased absorptive surface area leads to lower drug absorption.

  • Gastrointestinal motility is reduced, often causing constipation.

• Distribution:

  • Decrease in total body water content increases concentration of hydrophilic drugs.

  • Decreased lean muscle mass (20% reduction) and increased body fat (20% increase) alter drug distribution.

  • Higher levels of unbound (active) drugs in the blood due to reduced protein concentrations.

  • Example: Warfarin and phenytoin affected by low serum albumin levels.

• Metabolism:

  • Metabolism declines with age; liver mass and function reduce.

  • Less production of cytochrome P450 enzymes affects drug transformation.

  • Hepatic blood flow reduces by 1.5% per year after age 25.

  • Prolonged half-life of many drugs increases accumulation risk.

• Excretion:

  • Kidney function declines in two-thirds of older adults.

  • Glomerular filtration rate reduction of 40-50% can delay drug excretion.

  • Importance of monitoring kidney function and adjusting dosages accordingly to minimize toxicity and accumulation.

Problematic Medications for Older Adults

• Problematic Drug Classes: Certain classes of drugs can cause more issues in older adults due to physiological alterations and pharmacokinetic changes.

• Common Medications: A list of commonly problematic medications is provided in Table 4.4.

• Professional Recommendations: Organizations like the Institute for Safe Medication Practices Canada have identified drugs that should be avoided in older adults.

• Beers Criteria: An established tool since the 1990s to identify inappropriate prescriptions, inadequate medications, or those that might cause adverse drug reactions in older adults.

• Risk Assessment: The Beers Criteria assist in recognizing risk-associated situations and specific problematic drugs for older patients.

Ethnocultural Considerations

• Canada: Multiculturally diverse nation with changing demographics due to low fertility and strong immigration.

• Historical Immigration: Prior to 1970s, 78.3% of immigrants were from European countries (e.g., UK, Italy, Germany).

• Population Statistics: 2016 census: 21.9% of Canadians identified as landed immigrants or permanent residents.

  • Recent immigrants (2011-2016): 1,212,075 (3.5% of population).

  • Projected Increase: One in five Canadians born outside Canada, potentially 24.5%-30% by 2036.

• Sources of Immigration: Asia and the Middle East (61.8%), Africa (13.4%), remaining from Europe.

• Indigenous Population Growth: 2016: 1,673,785 Indigenous people, 42.5% increase since 2006.

  • First Nations: 39.3% increase to 977,230 members.

  • Métis: 51.2% increase to 587,545 members.

  • Inuit: 29.1% increase to 65,025 members.

• Future Growth: Indigenious population expected to exceed 2.5 million in 20 years.

• Impact of Colonization: Long-term effects on language, community relationships, and traditional practices.

• Truth and Reconciliation Commission (TRC) report (2015): Over 6,200 statements from 80,000 Indian Residential School survivors.

• Ethnocultural Considerations in Healthcare: Shifts impact health care delivery; understanding cultural factors in drug response is crucial.

• Terminology: Clarity needed on race, ethnicity, and culture; terms evolve (e.g., Indian to First Nations).

• Indigenous Groups:

  • First Nations: 65% of Indigenous population, over 50 cultural groups.

  • Métis: Distinct group, 30% of Indigenous population, mostly urban dwellers.

  • Inuit: Comprise about 5% of Indigenous population.

• Cultural Assessment in Nursing: Vital to recognize patient beliefs, values, and customs for optimal health.

• Intercultural Communication: Essential for proper assessment; avoid stereotypes.

• Religious Diversity: Significant impact on lifestyle choices and health care; requires responsive practice in health organizations.

Ethnocultural Influences and Genetics on Drug Response

• Polymorphism: Critical to understanding varied drug responses among individuals.

  • Example: Chinese patients may require lower dosages of antianxiety drugs than White patients.

  • Influences: Age, gender, size, body composition, and other characteristics on pharmacokinetics.

• Factors Categorized:

  • Environmental: Diet and nutritional status.

  • Cultural: Individual beliefs and practices.

  • Genetic: Inherited traits affecting drug metabolism.

• Adherence to therapy significantly affects medication response, which may vary due to:

  • Cultural beliefs

  • Personal and family expectations

  • Level of education

• Alternative remedies can impact drug metabolism:

  • Example: A high-fat diet increases absorption of griseofulvin.

  • Malnutrition can alter metabolic enzyme functioning.

• Historical Bias: Most clinical trials were conducted with White men, leading to gaps in drug response data for other ethnicities.

• Genetic Variability:

  • Some European and African descent individuals are slow acetylators, requiring lower dosages (e.g., isoniazid).

  • Japanese and Inuit individuals may be rapid acetylators, needing higher dosages.

• Cytochrome P450 Levels: Vary between ethnic groups, affecting drug metabolism.

  • Asian patients often need lower doses of psychotropic medications.

  • White patients may require higher doses due to faster metabolism.

• Adverse Effects: Differences exist among ethnic groups, e.g., African descent patients on lithium may require closer monitoring for toxicity.

• Ethnocultural Awareness: Critical for patient care, considering diverse health beliefs and practices:

  • Black patients may emphasize diet, herbal remedies, and spiritual practices.

  • Asian patients may focus on yin and yang concepts.

• Indigenous Practices: Include a blend of traditional and spiritual beliefs tied to the land and nature.

  • Use of the medicine wheel highlights holistic health aspects.

  • Common practices: smudging, traditional healing techniques.

• Traditional Healing Methods: Such as Ayurveda and Unani, focus on balance in lifestyle and health.

• Barriers in Healthcare: Include language, poverty, access, and differing beliefs about medicine.

  • Ethnocultural assessments necessary before medication administration:

    • Languages spoken

    • Health beliefs and past medicine use

    • Dietary habits

    • Responses to medical treatment.

Ethnocultural Nursing Considerations and Drug Therapy

• Cultural Knowledge: Important for understanding drug responses in culturally diverse patients.

• Varied Responses: Differences in therapeutic dosages and adverse effects based on ethnicity.

• Lower Dosages: Patients of Asian descent may respond to antipsychotics at lower dosages.

• Antidepressants: Patients of Chinese descent may require lower doses for effectiveness.

• Communication: Patterns may vary by race or ethnicity; includes language, tone, volume, spatial distancing, touch, eye contact, greetings, and naming format.

• Patient Care: Assess and apply cultural aspects in drug therapy and the nursing process.

• Patient Education: Provide clear instructions on medication use.

• Avoid Contractions: Use forms like cannot, will not, and do not to enhance understanding and prevent confusion.

NURSING PROCESS

ASSESSMENT

Pediatric Considerations

• Obtain thorough health history and medication history with assistance from parent, caregiver, or guardian.

• Include the following areas:

  • Age

  • Age-related concerns about organ functioning

  • Allergies to drugs and food

  • Baseline values for vital signs

  • Physical assessment findings

  • Height in centimeters and feet/inches

  • Weight in kilograms and pounds

  • Medical and medication history, including adverse drug reactions; current medication forms and routes, patient’s tolerance

  • Use of prescription and OTC medications in home setting

  • Level of growth and development and related tasks

  • Motor and cognitive responses and their age-appropriateness

  • Age-related fears

  • Anxiety state of patient or family members/caregiver

  • Usual method of medication administration (e.g., calibrated spoon, needleless syringe)

  • Usual response to medications

  • Resources available to patient and family

• Prescriber determines medication, nurse checks dosage and administration errors.

• Pediatric dosages often less than 1 mL, requiring accurate calculations checked multiple times.

• Follow the Ten Rights of medication administration, ensuring the correct dose is one right.

• Assess drug-related information: drug purpose, dosage ranges, routes, cautions, contraindications.

• Children are more sensitive to medications than adults due to weight, height, physical condition, immature systems, and metabolism.

• Immature organ development influences pharmacokinetics and drug responses.

• Organ function can be assessed through laboratory testing:

  • Liver and kidney function studies

  • Red and white blood cell counts

  • Measurement of hemoglobin, hematocrit, and protein levels.

Older Adult Considerations

• Age: Record age of the patient

• Medical History: Past and present medical history, including allergies to drugs and food

• Dietary Habits: Assess dietary habits and nutritional intake

• Substance Use: History of smoking and alcohol use (amount, frequency, years)

• Sensory Deficits: Evaluate visual, hearing, cognitive, and motor-skill deficits

• Lab Results: Focus on kidney and liver function tests

• Healthcare Providers: List all health-related care providers (e.g., physicians, dentists, chiropractors)

• Medications: Document all past and present medications, including prescription, OTC, and natural health products

• Polypharmacy: Identify existence of polypharmacy (use of more than five medications)

• Self-Medication: Assess self-medication practices

• Risk Situations: Identify risk situations based on Beers Criteria

• Patient Insight: Consider the patient's understanding of their own medical problems

• Communication: Speak slowly, loudly, and clearly for patients with sensory deficits

• Drug Information Systems: Aimed at reducing adverse drug events

• Brown-Bag Technique: Collect data on medications by having patients bring all medications in a bag

• Medication Reconciliation: Compare medication lists with what is prescribed and used

• Support Systems: Assess the patient's support systems for medication safety

• Chronic Conditions: Gather data on chronic illnesses and health problems

• Common Lab Tests: Include hemoglobin, electrolytes, creatinine, etc.

Ethnocultural Considerations

• Ethnocultural Assessment: Essential for ethnoculturally competent nursing care.

• Utilize assessment tools and resources (see Box 4.1).

• Factors must be assessed and applied to nursing care, particularly in drug therapy.

• Key questions to consider about patient's:

  • Physical Health: Sources of special foods, health education, and health services.

  • Mental Health: Ethnoculturally specific activities, beliefs about stress relief.

  • Spiritual Health: Resources for spiritual needs and traditional practices.

Maintaining Health

• Physical Health:

  • Sources of special foods and clothing items?

  • Types of health education in the patient’s ethnoculture?

  • Where does the patient obtain information about health and illness? Folklore?

  • Sources for health services?

  • Who are the health care providers (e.g., physicians, nurse practitioners, community services, health departments, healers)?

• Mental Health:

  • Examples of ethnoculturally specific activities for mental health and beliefs related to rest, relaxation, and reducing stress?

• Spiritual Health:

  • What resources are used to meet spiritual needs?

Protecting Health

• Physical Health:

  • Sources for special clothing and everyday essentials?

  • Examples of symbolic clothing for the patient?

• Mental Health:

  • Who within family/community teaches roles in ethnoculture?

  • Are there rules about avoiding certain individuals/places?

  • Identification of special activities that must be performed?

• Spiritual Health:

  • Who teaches spiritual practices?

  • Where to purchase protective symbolic objects (e.g., crystals, amulets)?

  • Are these items expensive and how available are they when needed?

Restoring Health

• Physical Health:

  • Where are special remedies purchased?

  • Can individuals produce or grow their own remedies, herbs, etc.?

  • How often are traditional and nontraditional services obtained?

  • Is the process and medication ethnoculturally safe for this patient?

• Mental Health:

  • Who are the traditional and nontraditional resources for mental health?

  • Are there ethnoculture-specific activities for coping with stress and illness?

• Spiritual Health:

  • How often and where are traditional and nontraditional spiritual leaders or healers accessed?

NURSING DIAGNOSES: AGE-RELATED

• Imbalanced Nutrition: Less than body requirements due to age, drug therapy, and potential adverse effects.

• Inadequate Knowledge: Arises from lack of information regarding drugs, their adverse effects, or when to contact the prescriber.

• Potential for Injury: Risks from adverse effects of medications or their administration methods.

• Potential for Injury: Risks from idiosyncratic reactions to drugs linked to age-related drug sensitivity.

PLANNING

• Nutritional Enhancement: Patient (caregiver, parent, or legal guardian) will state measures to enhance nutritional status due to age- and drug-related factors, including adverse drug effects on everyday nutrition.

• Adherence: Patient (caregiver, parent, or legal guardian) will state the importance of adhering to the prescribed drug therapy (or will take medication as prescribed with assistance).

• Communication: Patient will contact the prescriber when appropriate, such as when unusual effects occur during drug therapy.

• Complication Minimization: Patient (caregiver, parent, or legal guardian) will identify ways to minimize complications, adverse effects, reactions, and injury associated with the therapeutic medication regimen.

Expected Patient Outcomes

• Patient (caregiver, parent, or legal guardian) lists recommended caloric and protein intake with nutritional consultation support.

• Identify when to contact prescriber for symptoms such as nausea, vomiting, loss of appetite, diarrhea, or constipation during medication therapy.

• State rationale for medication, emphasizing timing, dosage, and duration of therapy; able to identify specific medication appearance.

• Describe intended therapeutic effects of medications, aiming for condition improvement, symptom reduction, and limited adverse effects.

• Demonstrate safe self- or assisted medication administration methods, such as using a week-long pill mechanism (e.g., blister pack, dosette) with proper labeling.

• Follow instructions specific to route of administration; demonstrate techniques (e.g., application of ointment, measuring taking liquid medication).

• List common adverse effects and potential toxicity of medication regimen; know when to contact health care provider for issues like fever, pain, vomiting, rash, diarrhea, difficulty breathing, or worsening condition.

• Report safe medication administration during follow-up appointment after starting prescribed therapy.

• Minimize adverse effects and dangers by adhering to prescription guidelines: taking medications as prescribed, at the right time, with proper fluids (120-180 mL of water), and following food instructions appropriately.

IMPLEMENTATION

• Ten Rights of Medication Administration: Always emphasize and practice.

• Prescriber’s Orders: Follow instructions carefully.

• Drug Checks: Verify medications three times against the Ten Rights before administration.

• Pediatric Considerations:

  1. Mix Medications: Use non-essential food items for taste improvement (e.g., sherbet).

  2. Avoid Mixing in Cups: Do not mix drugs in large fluid containers.

  3. Documentation: Record any special administration techniques for others' benefit.

  4. Fluid Addition: If necessary, add small amounts of fluids to elixirs.

  5. Terminology: Use the term medicines; avoid referring to drugs as candy.

  6. Safety: Keep medications out of reach of children; use childproof locks.

  7. Preferences: Ask about preferred medication forms.

• Older Adults: Encourage proper adherence to prescriptions and education on medication-related instructions.

• Transdermal Patches: Ensure safety to prevent accidental exposure for children.

• Providing Instructions: Offer clear, written, and verbal drug information (name, purpose, dosage, etc.).

• Polypharmacy Awareness: Educate patients about the risks of multiple medications.

• Patient Education: Simplify drug instructions in bold print for clarity.

• Beers Criteria: Use to identify potentially harmful medications in older adults.

• Clinical Judgment: Maintain constant awareness and knowledge in drug therapy decisions.

• Holistic Approach: Address patient’s age, gender, ethnocultural background, and medical history for safer drug therapy.

EVALUATION

• Lifespan Issues: Observation and monitoring are critical for safe and effective therapy.

• Patient Knowledge: Nurses must know a patient’s profile and history as well as drug information.

• Essential Information: Document the drug’s purpose, specific use, actions, dose, frequency, adverse effects, cautions, and contraindications.

• Comprehensive Monitoring: This information enhances monitoring of drug therapy across all age groups.

NURSING DIAGNOSES: ETHNOCULTURAL

• Sleep deprivation due to lack of adherence to cultural practices for stress release and sleep induction

• Inadequate knowledge regarding drug therapy from lack of experience and information about prescribed drug therapy

• Potential for injury from adverse and unpredictable reactions to drug therapy linked to racial or ethnic cultural factors.

PLANNING

• Goals:

  • Patient will state the need for assistance with non-pharmacological management of sleep deficit.

  • Patient will request written and verbal education about medication therapy.

  • Patient will state the need for information about the influence of racial or ethnic cultural factors on specific drug therapy, with emphasis on safety measures.

Expected Patient Outcomes

• Sleep Enhancement Measures:

  • Regular sleep habits

  • Decrease in caffeine

  • Meditation and relaxation therapy

  • Journaling sleep patterns and noting measures affecting sleep

• Medication Details:

  • List of medications with therapeutic and adverse effects

  • Dosage routes and methods for self-administration

  • Awareness of drug interactions and special considerations

• Ethnic Influences:

  • Impact of racial/ethnic influences on medications

  • Metabolic enzyme differences affecting drug response

  • Potential for increased adverse effects, toxicity, or altered effectiveness.

IMPLEMENTATION

• Ethnoculturally Competent Nursing Care: Nurses must be knowledgeable about various ethnocultures and their daily living practices, health beliefs, and emotional/spiritual health practices.

• Medication Responses: Be aware that medications can elicit varied responses due to racial or ethnic variations.

• Ethnopharmacology: Apply the principles of culturally competent care and ethnopharmacology in each patient care situation.

• Cytochrome P450 Enzymes: Understand the impact of cytochrome P450 liver enzymes on drug metabolism phases. Examples of enzyme differences are important.

• Communication Patterns: Consider verbal and nonverbal communication patterns of patients; their health belief systems can significantly impact care.

• Healthcare Providers: Identify both traditional health care providers and alternative healers involved in patient care.

• Patient Interpretation: Recognize how patients interpret space, time, and touch; this can affect their care.

• Cost Considerations: Be aware that cost can influence adherence to treatment regimens.

• Lifestyle Decisions: Lifestyle choices (e.g., tobacco or alcohol use) can impact drug responses and should be factored into treatment.

• Ethnocultural Background: A patient’s socioeconomic status may lead to medication nonadherence (e.g., skipping pills, splitting doses, not obtaining refills).

• Individualized Nursing Actions: Requires careful attention to diverse needs and circumstances of each patient to improve adherence.

EVALUATION

• Ethnocultural Competence: Nursing care should be evaluated through adherence to medication regimens.

• Safe Administration: Effective self-administration of medications must have minimal adverse or toxic effects.

• Individual Treatment: Patients must be treated as individuals with unique needs.

• Thorough Understanding: Patients should have a good understanding of their medication regimen

Chapter 5- Gene Therapy and Pharmacogenomics

OVERVIEW

• Genetic processes are complex and not fully understood.

• Genetic research is an active branch of science involving various health care providers, including nurses.

• Expected outcomes include increased knowledge of genetic influences on disease and the development of gene-based therapies.

• Nursing practice requires understanding of genetic concepts and related health issues.

• The goal of this chapter: introduce major concepts in health science regarding genetics.

• NCHPEG was founded in 1996 to promote education in applied genetics; closed in 2013.

• Jackson Laboratory now maintains NCHPEG materials and competencies.

• The Genetics Nursing Network was formed in 1984, leading to ISONG.

• Canadian Nurses Association recognized genetics in nursing in 2005, but it's not an official specialty.

• Growing understanding of genetics creates demand for clinicians to educate patients and tailor care.

• Calls for increased genetics education in nursing curricula and continuing education.

• Study of genetics has become commonplace in secondary and primary education.

BASIC PRINCIPLES OF GENETIC INHERITANCE

• Nucleic Acids: Two types - DNA (deoxyribonucleic acid) and RNA (ribonucleic acid).

• DNA: Makes up the genetic material passed during reproduction. RNA is used by some viruses (e.g., HIV).

• Chromosomes: Long strands of DNA in cell nuclei; humans have 23 pairs in somatic cells (non-reproductive cells) and 23 single chromosomes in sex cells (sperm/egg).

• Sex Chromosomes: Designated as X or Y; XX (females) and XY (males).

• Alleles: Alternative forms of a gene; can be dominant or recessive; each person has two alleles (one from each parent).

• Genotype: Combination of alleles; determines phenotype (trait expression).

• Sex-linked Traits: Passed differently to male and female offspring (e.g., hemophilia).

• Inherited Disease: Genetic defect passed from parents (e.g., hemophilia); Genetic Disease: Any disease caused by genetic mechanisms.

• Chromosomal Abnormalities: Can arise spontaneously during development.

• Acquired Disease: Develops from external factors; genetics can indirectly influence acquired diseases (e.g., atherosclerotic heart disease).

• Genetic Predisposition: Increased likelihood of certain conditions due to genetics; can be offset by lifestyle choices (e.g., diet, exercise).

• Old Genetics: Focused on single-gene inherited diseases (e.g., hemophilia).

• New Genetics: Recognizes complex interactions between genetics and environmental factors (e.g., Alzheimer’s, cancer).

DISCOVERY, STRUCTURE, AND FUNCTION OF DNA

• Genetics: Study of structure, function, and inheritance of genes.

• Heredity: Qualities genetically transferred from one generation to the next.

• 1953: Major turning point; Watson and Crick report DNA structure.

• DNA: Primary molecule for gene transfer from parents to offspring; exists in nucleus as chromosomes (chromatin).

• Chemical Structure: DNA contains four bases: adenine (A), guanine (G), thymine (T), cytosine (C).

• Sugar Molecule: Deoxyribose linked to a phosphate backbone forms classic double-helix structure.

• RNA: Similar to DNA; has sugar ribose and base uracil (U) instead of thymine; often single-stranded but can be double-stranded.

• Nucleotide: Structural unit of DNA; consists of a base, sugar, and phosphate.

• Oligonucleotide: Small sequence of nucleotides.

• Targeted Drug Therapy: Modifies function of immune cells (T cells, B cells) and focuses on modifying specific genes.

• Genome: Entire DNA structure of an organism (all genes combined).

• Genomics: New science for mapping, sequencing, and determining gene functions in health and disease.

Protein Synthesis

• Protein molecules drive all biochemical reactions.

• Protein synthesis is the primary function of DNA in human cells.

• Direct relationship between DNA nucleotide sequences and amino acid sequences enables precise protein synthesis.

• Only 2-3% of the human genome is involved in protein synthesis.

• Amino acid sequences control protein shape, affecting their functionality.

• Mutations in DNA can impair or destroy protein functions.

• In cell nuclei, DNA strands uncoil, and mRNA forms via complementary base pairing (transcription).

• mRNA detaches and enters the cytoplasm to be read by ribosomes (translation).

• Ribosomes consist of ribosomal RNA (rRNA) and accessory proteins.

• tRNA transports the corresponding amino acids to ribosomes along the mRNA strand.

• This process forms polypeptide chains, resulting in various protein molecules.

• Proteins include hormones, enzymes, and immunoglobulins, regulating bodily processes.

• Understanding of proteins aids in disease treatment through gene therapy.

• The complete set of proteins in a genome is called the proteome.

• Proteomics studies protein expression, modification, localization, and function.

• Most clinically approved drugs interact with body proteins like receptors and enzymes.

Human Genome Project

• Human Genome Project (HGP) initiated in 1990

• Worldwide research coordinated by U.S. Department of Energy and National Institutes of Health (NIH)

• Completed in 2003, 2 years ahead of schedule

• Goal: Identify 30,000 genes within 3 billion base pairs of the human genome

• Developed tools for genetic data analysis and storage

• Transferred technologies to the private sector

• Addressed ethical, legal, and social issues in genetic research

• Ultimate goal: Improved prevention, treatment, and cures for diseases

• Start: 100 known disease-related genes; Completion: 1,400 genes identified.

GENE THERAPY

Background

• Gene therapy: Experimental technique using genes to treat/prevent disease.

• Allows for insertion of a gene into patient’s cells instead of drugs/surgery.

• Research approaches include:

  • Replacing a mutated gene with a healthy copy.

  • Introducing a new gene to help fight disease.

  • Inactivating a malfunctioning mutated gene.

• Research is guided by understanding cellular processes and allelic variation.

• Utilizes genotypic risk factors for preventive therapy.

• Many clinical trials approved by Health Canada; however, no routine approvals yet.

• Goal: Transfer exogenous genes to provide temporary substitutes or permanent genetic changes.

• Originally focused on inherited diseases; now also studied for acquired illnesses (e.g., cancer, diabetes).

• Future potential for in-utero gene therapy to prevent serious diseases in fetuses.

Description

• During gene therapy, segments of DNA are injected into the patient’s body in a process called gene transfer.

• These artificially produced segments are known as recombinant DNA (rDNA).

• Gene transfer requires insertion into a carrier or vector.

• Current vectors include:

  • Liposomal spherical lipid compounds.

  • Plasmids (free DNA splices).

  • DNA conjugates linked to proteins or gold particles.

  • Various types of viruses, most commonly studied include adenoviruses (includes human influenza viruses).

Limitations

• Viruses for gene transfer can induce viral disease and be immunogenic in human hosts.

• Artificial proteins produced through this method can also be immunogenic.

• Positive effects (e.g., supplemented protein synthesis) may be temporary, requiring further treatments.

• Careful selection and modification of viruses is essential to optimize therapeutic effects and minimize adverse effects.

• Challenge for researchers: determining an ideal gene transfer method.

Current Application

• rDNA Technology: Established form of indirect gene therapy.

• Utilizes rDNA vectors in laboratories.

• Produces recombinant drugs: hormones, vaccines, antitoxins, monoclonal antibodies.

• Common example: Escherichia coli used to create human insulin.

• Gene Insertion: Human insulin gene inserted into bacterial genome.

• Results in large-scale artificial generation of human insulin.

• Purification Required: Insulin must be isolated from bacterial culture.

• Dominant method for producing medical insulin globally for over a decade.

Regulatory and Ethical Issues of Gene Therapy

• Gene Therapy Research: Inherently complex and carries great risks for patients.

• Patient Safety: Significant, especially for subjects with life-threatening illnesses (e.g., cancer).

• Case Reports: Deaths in trials raise awareness of risks.

• Oversight: The Biologics and Genetic Therapies Directorate (BGTD) of Health Canada reviews and approves all clinical trials involving human gene transfer.

• Research Ethics Boards: Required for all research involving human subjects to protect against unnecessary risks.

• Biosafety Committee: Ensures compliance with MCC guidelines for recombinant DNA and viruses.

• Eugenics Issue: Ethical concerns related to the intentional selection of desirable genotypes.

• Manipulation of Germ Cells: Potential ethical hazard; gene therapy currently limited to somatic cells in Canada.

• Funding Limits: Gene therapy in germ line cells not approved for funding despite potential benefits for chronic illnesses.

PHARMACOGENETICS AND PHARMACOGENOMICS

• Pharmacogenetics: Study of genetic variations in drug response; focuses on single-gene variations.

• Pharmacogenomics: Combination of pharmacology and genomics; examines how genetics affect the body's response to drugs.

• Opportunity to individualize drug therapy based on a patient’s genetic makeup rather than standard doses.

• Goal: Predict patient drug response, custom tailor drug selection and dosages for optimal outcomes.

• Warfarin sodium: Anticoagulant; specific genetic variations (CYP2C92, CYP2C93) increase bleeding risk, necessitating lower doses.

• VKORC1 gene variations: Influence sensitivity; more prevalent in Asian populations.

• Genetic polymorphisms: Variations occurring in at least 1% of the population; too frequent to be random mutations.

• Polymorphisms can alter drug-metabolizing enzymes, affecting body reactions to medications.

• Known examples: Impact metabolism of antimalarial drugs, isoniazid, and various cytochrome enzyme drugs.

• Patients may be classified as “poor” or “rapid” metabolizers of CYP-metabolized drugs (e.g., warfarin, codeine).

• Cultural safety: Important for routine gene-based drug dosing considering variations in cytochrome enzymes among ethnic groups.

• Genome analysis: Can allow for customized drug selection and dosing, enhancing treatment effectiveness and reducing adverse effects.

DNA Microarray Technology

• Trial-and-Error Dosage Changes: Most drug dosage changes are based on monitoring patient response.

• High-Density Microarray: An analytical tool developed by researchers.

• Technology: Uses microchip plates with thousands of microscopic DNA samples.

• Screening Process: Patient’s blood is screened for DNA sequences that bind to chip sequences.

• Gene Determination: Helps identify genes related to drug metabolism.

• Cytochrome Enzymes: Essential for metabolizing 25-30% of available drugs; over 40 cytochrome genes identified.

• Clinical Use: AmpliChip Microarray is the first DNA microchip for clinical screening.

• Enzyme Profile Screening: Used to assess individual cytochrome enzyme profiles.

• Future Standard: Although not widely practical yet, it is expected to become standard in clinical practice.

APPLICATION OF GENETIC PRINCIPLES AS A RESULT OF DRUG THERAPY AND THE NURSING PROCESS

• Recognition of Genetic Factors: Increasing awareness of genetic contributions to most diseases.

• Genetic-Environmental Interaction: Both genetic and environmental factors impact nursing care delivery.

• Shift to Clinical Practice: Genetic research is moving from laboratories to clinical settings.

• Nurse's Role: Nurses in general practice are not expected to perform in-depth genetic testing or counseling.

• Specialty Certification: Only nurses with specialty certification will conduct genetic testing and counseling.

• Knowledge Requirement: All nurses must have a working knowledge of genetic principles.

• “New Genetics” Paradigm: Nearly all diseases are understood to have a genetic component.

• Conditions of Interest: Myocardial infarction, cancer, mental health disorders, diabetes, and Alzheimer's.

• Assessment: Initial assessments include patient and family history across at least three generations.

• Identifying Genetic Disorders: Look for higher incidence of diseases in family, early-onset diseases, or unusual cancer forms.

• Medication Reactions: Inquire about unusual drug reactions in patients and family, indicating metabolic differences.

• Medication Administration: Assess the patient's response to each administered medication.

• Adjusting Drug Therapy: Genetic variations can inform adjustments in drug therapy.

• DNA Chip Technology: Makes it possible for patients to assess their genetic disease risks.

• Genotype Testing: Helps predict patient responses to drug therapy based on metabolism.

• Patient Education: Nurses should educate about genetic testing and address concerns.

• Informed Consent: Ensure the informed consent process is correctly followed for genetic testing.

• Confidentiality: Protect patient privacy during genetic testing and counseling.

• Patient Autonomy: Patients decide on sharing results with family members.

• Protection Against Misuse: Nurses and healthcare providers must safeguard against the misuse of genetic information.

• Policy Development: Nurses may help develop policies on genetic non-discrimination and prenatal testing.

Chapter 6- Medication Errors: Preventing and Responding

GENERAL IMPACT OF ERRORS ON PATIENTS

• Medical errors and medication errors (MEs) have gained significant national attention.

• Landmark IOM study (1999) reported 44,000 to 98,000 patient deaths from medical errors annually in U.S. hospitals.

• 2006 IOM study: 1.5 million people harmed yearly, with 117,000 hospitalizations, costing over $4 billion.

• 2010 follow-up showed 25.1 harms per 100 hospital admissions, with no significant change in preventable errors.

• 2004 Canadian study: 9,000 to 24,000 annual deaths due to adverse events/errors.

• Adverse drug-related events cause 12% of emergency visits, with 68% deemed preventable.

• In 2007, 17% of Canadian adults believed they experienced a medical error in the last 2 years.

• Contributing factors: numerous prescriptions, chronic conditions, insufficient physician time.

• 2016 report: 1 in 18 hospital stays involved harm, totaling 138,000 hospitalizations in the span of 2014-2015.

• Common medication incidents: insulin (9%), hydromorphone (7%), heparin (4%).

• Distractions during medication administration contributed to 27% of incidents.

• Prevention of medical errors is a top priority in health institutions.

• Reporting errors should not be punitive; it can aid in preventing future incidents.

• Shift in focus from individual nurse errors to broader context; development of “just culture.”

• Just culture recognizes systemic issues when errors occur; professionals must be held accountable for repeated errors.

• Remediation factors like workplace culture and management behavior may hinder reporting.

• Medical errors can happen at any stage of health care delivery and involve all health care providers.

• Common error types: misdiagnosis, patient misidentification, lack of monitoring, and wrong-site surgery.

• Many serious medication errors occur in the home, often from mixing prescription drugs with alcohol.

• Intangible losses from adverse outcomes include patient dissatisfaction and loss of trust in the health care system, leading to adverse health outcomes.

MEDICATION ERRORS

• Adverse Drug Event (ADE): General term for all clinical problems from medication use; includes Medication Errors (MEs) and Adverse Drug Reactions (ADRs).

• Adverse Drug Reactions (ADRs): Reactions from specific drugs; types include:

  • Allergic Reactions: Usually predictable.

  • Idiosyncratic Reactions: Generally unpredictable.

• Medication Errors (MEs): Common cause of adverse outcomes; effects range from negligible to causing patient disability or death.

• Importance of examining the entire medication use process:

  • Involves prescribers, transcribers, nurses, pharmacists, and ancillary staff.

• Systems Approach: Expands on the Ten Rights of medication administration; considers all factors influencing errors.

• Common drugs involved in severe MEs: CNS drugs, anticoagulants, and chemotherapeutic agents.

• High-Alert Medications: Require special care due to potentially toxic nature; not necessarily more error-prone, but risk of harm is higher.

• MEs often stem from look-alike/sound-alike names (e.g., SALAD, LASA).

• TALLman Lettering: Technique to differentiate similar drug names and enhance medication safety.

• Most MEs arise from system weaknesses rather than individual mistakes; these include:

  • Lack of a just culture for reporting errors.

  • Excessive workload with little preventive education.

  • Interruptions during preparation and administration.

• Importance of reporting errors: Essential for trend analysis and modifying processes to prevent future errors.

ISSUES CONTRIBUTING TO ERRORS

Organizational Issues

• Medication Errors (MEs) can occur at any step in the medication process:

  • Procuring

  • Prescribing (major problem; caught by pharmacists or nurses)

  • Transcribing

  • Dispensing

  • Administering (next most common cause of MEs)

  • Monitoring

• Pharmacists are key resources, available 24/7; collaboration with nurses is essential for preventing MEs.

• In rural areas, continuous access to a pharmacist may be limiting; agencies should develop policies to handle potential MEs.

• Involving patients in their care improves outcomes; encourages them to ask questions and advocate for their safety.

• Organizations like Safer Healthcare Now! and Canadian Patient Safety Institute promote patient safety practices.

• Technological solutions such as computerized prescriber order entry (CPOE) and bar coding help reduce MEs:

  • Standardizes prescribing functions

  • Enables bedside medication verification

• Costs of implementing new technology can be prohibitive (up to millions of dollars).

• Despite advancements, challenges include:

  • Workload issues (staff shortages)

  • Inadequate education on technology

  • Use of complex technology

• Self-medication can reduce errors if patients are cognitively alert and informed.

• The WHO has developed resources on patient safety initiatives and solutions.

Educational System Issues and Their Potential Impact on Medication Errors

• Double-check medication information before administering.

• Verify medication orders; know the drug.

• Utilize drug information guides and electronic references at the point of care.

• Institutions often subscribe to databases like Lexicomp or UpTodate.

• Patient safety starts in nursing education with students and faculty.

• Nurses play a vital role in safe medication administration.

• Nurse educators should promote a just culture of safety.

• Common student nurse errors:

  • Unusual dosing times

  • Issues with medication administration records (e.g., unavailable records, failure to document, extra doses)

  • Administering discontinued or held medications

  • Failure to monitor vital signs or lab results

  • Misadministering oral liquids (e.g., as injections)

  • Preparing medications for multiple patients simultaneously

  • Dispensing medications in different doses from those ordered (e.g., splitting tablets).

Medication Errors and Related Sociological Factors

• Effective Communication: Essential for improved patient care among health care teams.

• Workplace Bullying: Increasing issue among nurses; distinct from horizontal violence due to power differential.

• Gender Influence: The gender of both perpetrator and target can exacerbate bullying dynamics.

• Disruptive Behaviors: Impact nurse job satisfaction and staff retention, harming personal health and professional wellbeing.

• Communication Breakdown: Disruption leads to lack of collaboration among healthcare professionals, causing medical errors and poor patient care.

• Recruitment and Retention Issues: Poor communication affects worker health, patient safety, and organizational outcomes.

• Improved Team Communication: Communication between prescribers and healthcare teams has advanced due to progressive medical education focusing on team orientation and zero tolerance for violence.

• CIHC Competencies: Inclusion in education recognizes complexities of healthcare; acknowledges no single member can maintain all care aspects.

PREVENTING, RESPONDING TO, REPORTING, AND DOCUMENTING MEDICATION ERRORS: A NURSING PERSPECTIVE

Preventing Medication Errors

• Medication Errors (MEs): Preventable events leading to inappropriate medication use or harm.

• Categories of MEs (Canadian Medication Incident Reporting and Prevention System, 2011):

  1. Near Miss: Event with potential for harm but no injury.

  2. No-Harm Event: Incident occurs without patient injury.

  3. Harmful ME: Event results in patient harm.

  4. Critical Incident: Serious harm occurs.

• Prevention Strategies:

  1. Implement multiple systems of checks and balances.

  2. Ensure legible orders or use electronic prescriptions.

  3. Consult authoritative resources (e.g., pharmacists, drug literature) during the medication process.

  4. Check medication orders three times before administration.

  5. Consistently apply the rights of medication administration to reduce MEs.

Responding to, Reporting, and Documenting Medication Errors

• Reporting MEs is a professional responsibility of nurses, applicable to both students and professionals.

• Follow facility policies and procedures for reporting and documenting errors carefully.

• After assessing the patient and addressing urgent safety issues, report the ME to the prescriber and nursing management immediately.

• If the patient needs close monitoring due to condition deterioration, ensure another qualified health care provider stays with them while contacting the prescriber.

• Follow-up procedures or tests may be needed, as indicated by the prescriber.

• The nurse’s highest priority is the patient's physiological status and safety during medication administration and MEs.

• Complete all forms, including an incident report, as per facility policies.

• Document the ME with factual information only, avoiding judgmental terms like 'error.'

• Include details such as medication administered, actual dose, and any observed changes in patient status.

• Note that the prescriber was notified and any follow-up actions or orders implemented.

• Ongoing patient monitoring is essential.

• Additional documentation may be required, such as an unusual occurrence report.

• Documentation should remain thorough, accurate, and contain only factual information about the error and corrective actions taken.

• Do not note the completion of incident reports in the patient’s chart or keep copies; they are for risk management purposes only.

• Reporting options should allow for anonymity to improve error reporting and medication safety practices.

• Internal tracking systems may aid in developing better policies and procedures.

• All institutional pharmacy departments should have an adverse drug event monitoring program.

• External reporting of MEs may also occur through nationwide confidential reporting programs.

• Resources like the Canadian Medication Incident Reporting and Prevention System and Health Canada’s Vigilance Program provide platforms for report collection and safety information dissemination.

Performing Medication Reconciliation

• Effective Communication: Critical for safe medication delivery.

• Medication Reconciliation (MedRec): Formal process to reconcile medications at all healthcare entry and exit points.

• Best Possible Medication History (BPMH): Systematic review of all current medications.

• Prescriber Assessment: Evaluates whether to continue medications upon hospitalization.

• Avoid Discrepancies: Ensure consistency between home and hospital medications.

• Process Steps:

  1. Verification: Collect current medication information (prescription, OTC, natural products).

  2. Clarification: Professional review for appropriateness of medications and dosages.

  3. Reconciliation: Investigate discrepancies and document any changes in medication orders.

• Application: Repeat at each healthcare stage (admission, status changes, transfers, discharge).

• Education Tips:

  1. Ask open-ended questions to gather specific medication info.

  2. Avoid medical jargon unless understood by the patient.

  3. Prompt recall of all medications used (patches, creams, injections).

  4. Clarify any unclear information by consulting caregivers or pharmacists.

  5. Record all medication information in the patient's chart.

  6. Stress the importance of maintaining an up-to-date medication list for every healthcare encounter.

OTHER ETHICAL ISSUES

Notification of Patients Regarding Errors

• 2001 Article in Journal of Clinical Outcomes Management highlighted the obligation of health providers to ensure full disclosure to patients regarding errors in care.

• Emphasized ethical basis and legal implications of notification about medication errors (MEs).

• Disclosure Working Group of the Canadian Patient Safety Institute (2011) recommended a just culture of disclosure.

• Apology legislation in eight Canadian provinces protects apologies from being used as evidence in court, ensuring statutory protection.

• Honesty and transparency are critical for effective disclosure.

• Accreditation Canada requires healthcare organizations to establish formal, transparent disclosure policies for patients and families.

• The term "error" should be avoided; instead, "patient safety incident" is preferred.

• Three types of patient safety incidents:

  1. Harmful incident (previously termed preventable adverse drug event) results in patient harm.

  2. Near miss: did not harm the patient.

  3. No-harm incident: reached the patient but resulted in no harm.

• Efforts by the World Health Organization (2016) aim to standardize concepts for safety improvement.

• Organizations provide financial support for reasonable costs related to the disclosure process.

Possible Consequences of Medication Errors for Nurses

• Effects of Medication Errors (MEs): Range from no significant effect to permanent disability or death.

• Emotional Toll: Errors causing significant harm can affect the mental well-being of nurses involved.

• Malpractice Litigation: Nurses can be named as defendants; this can lead to financial consequences.

• Negligence Definition: Conduct that fails to meet legal care standards; characterized by inattention.

• Examples of Negligence: Include MEs leading to injury, instrument count errors, and failure to monitor conditions.

• Malpractice: Involves unethical conduct or lack of skill resulting in harm; compensation may be sought.

• Rarity of Charges: Malpractice charges against health care workers are rare in Canada, but patients increasingly seek compensation.

• Professional Liability Insurance: Many nurses carry personal malpractice insurance; institutional coverage varies.

• Canadian Nurses Protective Society (CNPS): Provides legal advice, risk management, and professional liability protection.

• Institutional Responses: Administrative actions for MEs vary; may include continuing education or disciplinary action.

• Culture Shift: Hospitals are adopting a more proactive, open, and nonpunitive culture regarding MEs.

• Student Nurse Accountability: Responsible for the quality of clinical work; must consult instructors if uncertain.

• Reporting Errors: Students should quickly notify clinical instructors of any committed errors for proper management.

SUMMARY

• The complexity of nursing practice increases the potential for medication errors (MEs).

• Common causes of errors:

  • Misunderstanding of abbreviations.

  • Illegibility of prescriber handwriting.

  • Miscommunication during verbal or telephone orders.

  • Confusing drug nomenclature.

• Organizational, educational, and sociological systems can contribute to MEs.

• Understanding these influences helps nurses take proactive steps to improve systems:

  • Foster better communication among healthcare team members.

  • Advocate for safer conditions for patients and staff.

• Priority when errors occur: Protect the patient from further harm.

• Treat all errors as red flags for further reflection, analysis, and preventive actions.

Loeffler & Hart (2020) Ch. 4

Chapter 4- Adaptation, Injury, Inflammation, and Repair

Review of Structure and Function

• The body consists of cells and intercellular substances capable of dynamic change.

• Tissues are functional groupings of similar cells and intercellular substances.

• An organ is formed from one or more tissues, carrying out major body functions (e.g., liver).

• Parenchymal cells are main functional cells of an organ (e.g., hepatocytes in the liver, osteocytes in bone).

• The nucleus contains DNA, essential for regulating cell function, and undergoes changes that indicate abnormal processes.

• Cytoplasm contains organelles and cytosol, surrounded by a specialized cell membrane.

• The cell membrane regulates ion and nutrient movement, impacting an electrical and osmotic gradient.

• Major organelles:

  • Mitochondria: Energy production.

  • Endoplasmic Reticulum:

    • Rough ER: Protein synthesis with ribosomes.

    • Smooth ER: Production of other biochemical substances.

  • Golgi Apparatus: Modifies and sorts proteins for secretion.

  • Lysosomes: Digestive enzymes for engulfed substances and worn out parts (autophagocytosis).

• Epithelial Cells: Cohesive units for specialized functions (e.g., protections, secretion).

• Connective Tissue Cells: Provide support and facilitate fluid/nutrient movement.

• Epithelial cells originate from embryonic ectoderm and endoderm, forming skin and glands.

• Types of epithelial cells: Squamous, Transitional, Columnar (e.g., stratified squamous epithelium forms tough barriers).

• Keratinized squamous epithelium: Outer layer of skin.

• Nonkeratinized epithelium: Lines mouth, pharynx, larynx, esophagus, vagina, and anus.

• Transitional epithelium: Multilayered, lacks keratin; confined to the urinary tract (renal pelvis, ureter, bladder, urethra).

• Columnar epithelium: Tall, mucus-secreting cells lining nose, trachea, bronchi, stomach, small intestine, colon, cervix, uterus, bile ducts.

• Epithelial cells: Arranged as glands (acini) or in tubules/cords; glandular organs include breast, salivary glands, thyroid, pancreas.

• Kidney: Predominantly composed of tubules; liver, adrenal glands, pituitary arranged in cords with blood sinusoids in between.

• Labile cells: Continuously replace mature cells (e.g., lower epithelium).

• Leukocytes (white blood cells): Mobile cells attacking foreign substances.

  • Neutrophils: Include polymorphonuclear leukocytes; engulf and digest foreign materials.

  • Monocytes: Differentiate into macrophages after leaving the bloodstream.

  • Lymphocytes: Direct attack; release cytokines and chemokines to target invaders.

  • B cells: Transform into plasma cells to produce antibodies.

• Connective tissue: Provides support and transportation; includes bone, cartilage, ligaments, tendons, fascia.

  • Fibroblasts: Produce collagen; associated with various connective tissues.

  • Chondrocytes: Relate to cartilage; osteocytes with bone; endothelial cells with blood vessels.

• Muscle cells: Derived from mesoderm; elongated structure.

• Nervous tissue cells: Derived from ectoderm; include neurons and support cells (glial cells in CNS).

• Endothelial cells: Form a lining in blood vessels; regulate substance movement.

• Basement membranes: Surround epithelial clusters; allow nutrient exchange.

• Collagen: Most abundant in connective tissues; relates to strength.

• Tissue fluid regulation: Influenced by pressure in vessels, osmotic pressure, and size of endothelial cell pores.

• Physiological cell replacement: Labile cells continuously divide; stable cells divide in response to injury; permanent cells (cardiac muscle, neurons) do not regenerate.

• Labile cells: E.g., skin, GI tract, can regenerate; undergo hyperplasia or neoplasia.

• Stable cells: E.g., liver, kidney, respond to injury; permanent cells do not divide post-maturity.

Cells’ Responses to Injury

• Cells are typically in a steady state.

• They respond to minor fluctuations in their environment (e.g., changes in pH, oxygen, nutrients, or electrolyte concentrations).

• This response is governed by homeostasis mechanisms.

• When physiologic demands are exceeded, cells must cope with the increased demands.

• Failure to adapt can lead to cell injury or death.

Adaptation

• Adaptation: Ability of cells to adjust to new physiologic conditions.

• Hyperplasia: Increase in cell numbers due to increased demands.

• Hypertrophy: Increase in cell size due to increased demands.

• Both hyperplasia and hypertrophy lead to an increase in tissue volume.

• Atrophy: Decrease in tissue volume, resulting from reduction in cell size or number.

• Regenerative Capacity: Determines whether cells undergo hyperplasia or hypertrophy.

  • Labile Cells: Undergo hyperplasia (e.g., breast epithelial cells stimulated by hormones).

  • Stable Cells: Undergo hypertrophy (e.g., skeletal muscle increases size with athletic training).

• Tissue may increase in volume due to both hyperplasia and hypertrophy (e.g., uterus during pregnancy).

• Pathologic Hypertrophy: Abnormal size increase (e.g., prolactin-producing pituitary adenoma causing lobule enlargement).

• Cardiac Hypertrophy: Increased heart size due to hypertension.

• Prostatic Hypertrophy: Enlargement of prostate gland due to hyperplasia causing urinary issues.

• Hyperplastic and hypertrophic cells can often revert to normal if the stimulus is removed, barring permanent changes.

• Atrophy occurs due to decreased cell size or number and can be physiologic or pathologic, caused by various stimuli.

Atrophy

• Senile Atrophy: Caused by aging; tissues shrink and lose functional capacity.

  • Example: Brain size reduction leads to memory loss and slowed cognition.

• Disuse Atrophy: Occurs when cells can't perform normal functions, e.g., muscle cells decrease in size and contractility when an arm or leg is immobilized (e.g., in a cast).

  • Potentially reversible: Function returns post-cast with exercise.

  • Denervation Atrophy: Permanent nerve loss results in persistent atrophy.

• Pressure Atrophy: Results from constant pressure on tissue, often from tumors or contributing to the formation of bedsores in bedridden patients.

• Endocrine Atrophy: Caused by decreased hormonal stimulation; specific organs rely on hormone levels to maintain function.

  • Example: Decreased estrogen and progesterone at menopause leads to atrophy of breast and uterine tissue.

• Metaplasia: Adaptive process where one adult cell type is replaced by another, frequently in epithelial tissues.

  • Example: Squamous epithelium in the esophagus may change to columnar, mucus-producing mucosa due to chronic acid reflux, aiding in protection against acidity.

  • Can be physiologic (normal response) or pathologic (abnormal changes, such as in smokers).

Reversible and Irreversible Injury

• Adaptation: Allows cells/tissues to respond to increased/decreased demands and achieve homeostasis.

• Cell Injury: Occurs when adaptation is exceeded; can be reversible (returns to normal) or irreversible (leads to cell death).

• Reversible Injury: Cells can return to normal structure/function if injurious stimulus is removed.

• Irreversible Injury: Leads to cell death via necrosis or apoptosis.

• Oxygen Deprivation: Extremely harmful; lack of oxygen results in hypoxia (insufficient oxygen delivery) or ischemia (insufficient blood supply).

• Selective Vulnerability: Metabolically active cells (e.g., neurons, kidney cells) are most susceptible to oxygen deprivation.

• Ischemic Injury: Localized tissue death from reduced blood flow; leads to infarct (dead tissue).

  • Common causes include thrombi (blood clots) and emboli (particulate objects traveling in bloodstream).

• Acute Injury: Sudden injury leading to rapid cell death (e.g., from trauma, infections).

• Chronic Injury: Prolonged injury, usually mild, can result in significant tissue injury and gradual cell death.

• Types of Cell Death:

  • Necrosis: Irreversible cell death with tissue destruction; three types include:

    • Coagulation Necrosis: Caused by anoxia; preserves tissue outline initially.

    • Liquefaction Necrosis: Caused by pyogenic bacteria; results in pus.

    • Caseous Necrosis: Associated with Mycobacterium tuberculosis, forms a cheesy mass.

  • Apoptosis: Programmed cell death without inflammation, often occurs in response to specific stimuli.

• Apoptosis Mechanism: Cells shrink and package contents into vesicles rapidly cleared by macrophages, avoiding inflammatory response.

• Stimuli for Apoptosis: Irreparable DNA damage (e.g., from radiation, chemotherapy), oxidative damage, certain viral infections.

• Critical Difference: Recovery of cell structure/function depends on injurious stimulus removal.

• Reversible Injury:

  • Cell membrane can be restored.

  • Mitochondrial function regained.

• Irreversible Injury:

  • Membrane and mitochondria damaged beyond repair.

• Degree vs. Kind: Difference is one of degree, not kind.

• Morphologic Features: Observed first at the ultrastructural level (only visible under electron microscope).

  • Signs include mitochondrial swelling, breaks in cell membrane, and endoplasmic reticulum dilation.

• Cell Changes:

  • Swells due to plasma membrane losing ability to maintain fluid and electrolyte homeostasis.

  • Hydropic change: Large irregular vacuoles in cytoplasm due to swelling.

• Nuclear Changes:

  • Condenses, fades, and fragments; takes hours to develop.

• Example: Myocardial infarct within 12 hours may show no histologic changes yet dead cells.

• Changes form a continuum: mild injury leads to sublethal changes; persistent functional changes indicate possible cell death, with recovery reliant on regeneration.

Inflammation

• Inflammation: A defense mechanism protecting the body from injury and promoting repair.

• Patients unable to mount an acute inflammatory response are at risk of infections that others can easily ward off.

• An inflamed lesion is characterized as red, hot, and painful.

• During inflammation, fluid, chemicals, and cells are delivered to the injured area to:

  • Limit injury extent

  • Remove necrotic debris

  • Prepare for the healing process.

• Involves complex chemical and neural mechanisms to quickly activate and deactivate the response, preventing excess damage to normal tissue.

• The inflammatory response is stereotyped; degree and duration depend on the cause and time course of the injury.

• Inflammation can have both protective and damaging effects.

• Research ongoing into modifying the inflammatory response to better understand its biochemical control mechanisms.

Acute Inflammation

Overview

• Acute Inflammation: Coordinated vascular and cellular events.

• Vascular Phase:

  • Increased blood flow to injured area.

  • Increased vascular permeability: water, electrolytes, and serum proteins leak into tissue.

• Cellular Phase:

  • Leukocytes (predominantly neutrophils and monocytes) move from blood to injury site.

• Cardinal Signs of Inflammation: Redness, swelling, heat, pain, and loss of function.

  • Hyperemia: Increased blood in dilated vessels causing redness.

  • Edema: Fluid leakage causing swelling.

  • Increased blood causes heat.

  • Pain from pressure and inflammation-triggered molecules acting on nerves.

  • Loss of function protects the swollen lesion from further injury.

• Effects of Inflammation:

  • Destroy or limit spread of causative agent.

  • Clean up debris in preparation for repair.

• In simple injuries, reaction is proportional to tissue damage.

• Tissue damage incites a mild inflammatory reaction, drawing leukocytes to digest and remove debris.

• Phagocytosis: Neutrophils and macrophages engulf particulate matter.

• Microscopic features: Abundant neutrophils mixed with few macrophages.

• Vascular Phase:

  • Small vessels dilate and become leaky at tissue injury site.

  • Mast cells release histamine, relaxing smooth muscle in vessel walls, increasing blood flow.

  • Causes sluggish blood flow (stasis), leading to redness in injured tissue.

  • Leakage allows large proteins and water to escape, resulting in edema (swelling).

• Cellular Phase:

  • Leukocytes (white blood cells) migrate from the bloodstream to the injury site and become activated.

  • Primarily phagocytes: neutrophils and macrophages.

  • Margination: leukocytes stick to endothelial cells and crawl into tissue (emigration).

  • Movement towards injury via chemotaxis (response to chemical gradient).

  • Neutrophils arrive first, important for combating bacterial infections (e.g., Staphylococcus aureus).

• Phagocytosis:

  • Recognition and engulfment of foreign particles (e.g., bacteria).

  • Enhanced by opsonization (coating with antibodies).

  • Lysosomes digest foreign material using enzymes and produce oxygen-derived free radicals (e.g., H2O2).

  • Phagocytosis effectively clears foreign debris from the injury site, but some bacteria resist it using capsules.

  • Antibodies facilitate phagocytosis of previously encountered pathogens.

  • Increased metabolic activity of neutrophils at the injury site causes heat and contributes to pus formation.

  • After neutrophils die, they cause additional tissue damage; macrophages later clean up the debris, including dead neutrophils.

  • Movement of cells and chemicals is facilitated by increased fluidity of the lesion, aiding lymph flow to carry away debris.

Molecular Mediators of Inflammation

• During the vascular & cellular phases of inflammation, various cells respond to tissue injury and foreign substances.

• Smooth muscle cells in blood vessels and endothelial cells are involved in a coordinated sequence of reactions.

• Molecular mediators promote and control the inflammatory reaction, preventing excess tissue damage.

• Histamine is a key vasoactive amine, causing vascular dilation and vessel permeability.

• Mast cells contain large amounts of histamine and release it in response to tissue injury.

• Plasma proteins like albumin leak into tissues, and water follows, diluting histamine.

• Leukocytes migrate to the injury site via chemotaxis along a chemical gradient.

• Plasma-derived mediators include the kinin, complement, and coagulation systems, activated in a series of enzymatic steps.

• Bradykinin increases vascular permeability and contributes to pain.

• The coagulation system converts fibrinogen to fibrin, creating a protective barrier for injuries (e.g., scabs).

• The Hageman factor (Factor XII) initiates both the kinin and coagulation systems.

• The complement pathway produces a polymer that lyses bacterial cell walls.

• Cytokines and chemokines (e.g., TNF, IL-1, IL-6) enhance the inflammatory process and systemic effects like fever and appetite suppression.

• Chronic inflammation can be caused by persistent acute inflammation or low-grade injury, with fibrous tissue formation as a hallmark.

Chronic Inflammation

• Chronic Inflammation:

  • Results from unresolved acute inflammation or long-term low-level causes.

  • Histologic appearance typically associated with prolonged inflammation.

  • Edema and hyperemia less pronounced; few or no neutrophils present.

• Cellular Infiltration:

  • Predominantly lymphocytes, plasma cells, and fewer macrophages.

    • Plasma Cells: Derived from B-lymphocytes; main function is antibody production.

• Lymphocytes:

  • Recognize foreign substances, kill host cells, and direct inflammatory response.

• Macrophages:

  • Involved in phagocytosis and can be cytotoxic.

  • Produce cytokines and chemokines that recruit other immune cells.

• Fibrosis:

  • Formation of fibrous tissue surrounding injured areas providing strength.

  • Chronicity assessed by the extent and age of the fibrous tissue.

• Symptoms: Similar to acute inflammation—edema, redness, heat, pain, and loss of function.

• Pathogenesis:

  • Driven by persistence of causative agents and immunologic responses.

  • Often linked to pyogenic bacteria, foreign bodies, and necrotic tissue.

• Granulomatous Inflammation:

  • Characterized by collections of epithelioid cells (modified macrophages).

  • Seen in conditions like tuberculosis, sarcoidosis, and certain fungal infections.

  • Granulomas can calcify over time and require careful diagnostic evaluation.

Transudates and Exudates

• Transudate: Fluid collection due to increased hydrostatic pressure or decreased osmotic pressure in the vascular system

  • Characteristics: Watery with low protein content.

• Exudate: Result of increased osmotic pressure due to high protein content, caused by inflammation or lymphatic obstruction.

  • Characteristics: Cloudy or protein-rich fluid; tends to be more localized than transudates.

• Serous Exudate: Contains fluid with small amounts of protein; indicates a lesser degree of damage.

  • Example: Fluid in blisters following skin burns.

• Fibrinous Exudate: Composed of large amounts of fibrinogen that forms fibrin.

  • Example: In bacterial pneumonia, creates a mesh to trap bacteria; forms scabs on skin wounds.

  • Coagulation system plays a significant role in its formation.

• Purulent Exudate (pus): Contains live and dead leukocytes, predominantly neutrophils.

Clinical Appearance of Acute and Chronic Inflammation

• Inflammatory Lesions: Red, swollen, and painful; may cause loss of function.

• Symptoms Vary: Dependent on injury nature and body organ.

• Abdominal Organs: Poorly innervated; present with general abdominal pain regardless of specific injury.

• Chronic Inflammation: Redness, swelling, and pain present but lesser; may develop fibrosis.

• Bacterial Infections: Purulent infections show signs of tissue necrosis; termed suppurative inflammation.

• Types of Inflammatory Lesions:

  • Abscess: Localized pus collection, spherical lesion containing liquefied dead tissue (purulent exudate).

  • Empyema: Pus-filled body cavity.

  • Cellulitis: Spreading acute inflammation; often due to streptococcal infections.

  • Ulcer: Local excavation of epithelium, commonly in stomach/duodenum or as bedsores.

• Abscess Causes: Typically caused by pyogenic bacteria; may include staphylococci and streptococci.

• Abscess Characteristics: Red, hot, swollen, painful; can spread if punctured early. Requires surgical intervention for larger abscesses.

• Necrotizing Fasciitis: Related to cellulitis; may lead to toxic shock syndrome.

• Ulcer Formation: Caused by injurious agents; rapid ischemic damage possible in bed-bound individuals; preventive measures include frequent position changes and skin inspections.

Accumulations

• Pathologic Processes: Result in abnormal accumulation of substances within cells.

• Identification: Provides clues to underlying disease processes visible in tissue sections.

• Types of Accumulations:

  • Hemosiderin: Breakdown product of hemoglobin, accumulates in macrophages after breaking down red blood cells during inflammation.

  • Enzymatic Dysfunction: Improper enzyme function can lead to accumulation, causing cell death, atrophy, and loss of function.

  • Fatty Change: Accumulation of lipid droplets in parenchymal cells, especially in the liver.

    • Distinction from adiposity: Increased fat storage in fat cells vs. abnormal fat in parenchymal cells.

    • Occurs due to:

      • Decreased production of lipoprotein.

      • Increased uptake of lipid from blood.

    • Causes include:

      • Diabetes mellitus.

      • Obesity.

      • Alcoholism.

      • Chemical injury (e.g., carbon tetrachloride poisoning).

      • Acute starvation affecting protein levels for lipoprotein formation.

  • Glycogen Storage: Accumulation in genetic conditions from missing glycogen breakdown enzymes; leads to organ malfunction.

  • Excess Protein: Produces hyaline deposits, often from excess collagen in scar tissue and fibrin clots.

  • Amyloid: Crystalline deposits from small proteins leaking and crystallizing; examples include immunoglobulin light chains and serum amyloid-associated protein.

    • Develop slowly, affect organ function late, and are not reversible.

  • Mineral and Pigment Accumulations: Include calcification, hemosiderosis, and brown atrophy.

    • Calcification Types:

      • Metastatic Calcification: Excess blood calcium accumulates

    • Dystrophic Calcification: Occurs in areas of cell death; involves calcium deposits in necrotic regions.

• Generally harmless but radiopaque; helps radiologists identify disease areas.

• Example: Caseous necrosis from tuberculosis shows on X-rays, persisting after infection.

• Mammography detects calcifications linked to breast cancer.

• Hemosiderosis and Hemochromatosis: Terms for excessive iron accumulation in tissues.

  • Hemosiderosis: Iron accumulates in tissues.

  • Hemochromatosis: Genetic condition causing liver damage due to excessive iron.

• Iron Regulation: Absorption is controlled to maintain red blood cell production; excessive intake can arise from blood transfusions, diet, or hemolytic anemias.

• Iron accumulates as ferritin, creating a brown pigment (hemosiderin) in macrophages and hepatocytes.

• Cirrhosis and diabetes mellitus are serious results of hemochromatosis.

• Treatment: Periodic blood withdrawal reduces iron stores and slows progression.

• Brown Atrophy: Refers to brown discoloration in heart and liver due to lipofuscin pigment accumulation, a marker for aging and cellular damage.

Repair

• Events after injury involve necrosis, inflammation, and repair.

  • These processes vary in proportion and occur on a continuum.

  • Inflammation is the body's response to necrosis or cell injury, limiting injury spread and removing debris.

  • Repair aims to replace dead cells through regeneration or fibrous connective tissue repair (scarring).

• Intensities of these processes depend on:

  • Magnitude of the injury

  • Duration of injury

  • Nature of injury

  • Location in the body

• Inflammation begins immediately after cell injury; repair starts after necrosis stops.

• Body's two repair methods:

  • Regeneration: Replacement by similar cells, restoring function (e.g., epidermal surface, fractured bone).

  • Fibrous repair: Tissue replaced by fibrous tissue (scar); does not restore original function.

• Many injuries heal through a mix of regeneration and fibrosis.

• Regeneration is ideal as it restores normal function, especially in vital organs.

• Permanent cells (neurons, cardiac muscle) cannot regenerate once damaged.

• Labile cells (epidermis, gastrointestinal tract, bone) have high regenerative capacity.

• Hypoxia increases risk of necrosis in metabolically active cells (kidneys, liver, neurons).

• Epidermis and intestinal mucosa can repair defects several centimeters wide; bone marrow has significant regenerative capacity.

• Fibrosis results in scar formation; it provides a bridge but does not restore function.

• Fibrous repair (organization) involves granulation tissue and scar formation stages:

  • Capillaries and fibroblasts grow into the damaged area, forming granulation tissue.

  • Fibroblasts produce collagen, leading to scar formation; this tissue eventually condenses over time.

• Repair is categorized into:

  • Primary union: Wound edges closely approximated.

  • Secondary union: Wound edges left separated, more tissue damage and inflammation occurs before healing.

• Primary Union: Best repair example following a clean surgical incision with minimal tissue damage.

• Wound edges: Closely approximated by tape or sutures.

• Serum fills space between edges, dries, and forms a scab.

• 1-2 days after, acute inflammation decreases, and capillaries bridge the gap.

• Epithelium grows across the gap.

• Fibroblasts deposit collagen, contracting and strengthening the wound edges.

• Incision appears well healed in about 2 weeks, full strength may take a month or more.

• Obstacles to healing: presence of dead tissue and foreign material (dirt, bacteria).

• Necrotic tissue forms quickly if bacteria present.

• Care of wounds: requires cleaning and debridement of necrotic tissue.

• Inflammation and repair are dynamic processes influenced by factors such as:

  1. Virulence of organisms (e.g., staphylococcus vs alpha-streptococci).

  2. Age: Elderly heal more slowly.

  3. Nutrition: Protein and Vitamin C are essential for collagen production.

• Secondary Union: Involves greater injury and inflammation, fills voids through capillary and fibroblast proliferation.

• Collagen is deposited by fibroblasts, aiding in wound contraction.

• Large wounds may require skin grafts if epithelium cannot bridge the gap.

• Diabetes: Affects small blood vessels, reducing nutrient delivery to healing tissues.

• Steroid therapy: Inhibits inflammatory response, impacting healing process.