Lecture 1 (HSS 3106) Winter 2024 PDF

Winter 2024 Pharmacology: Mechanisms and Compliance (HSS 3106) Class Notes Andrew D. Darnel, PhD The foxglove,1 Digitalis purpurea, contains digoxin, a cardiac glycoside. The plant was used on heart conditions long before the glycoside was identified. Digoxin is used to treat atrial fibrillation, at...

Winter 2024 Pharmacology: Mechanisms and Compliance (HSS 3106) Class Notes Andrew D. Darnel, PhD The foxglove,1 Digitalis purpurea, contains digoxin, a cardiac glycoside. The plant was used on heart conditions long before the glycoside was identified. Digoxin is used to treat atrial fibrillation, atrial flutter and sometimes heart failure. 1. Slater, A. (2009, June 10). Purple Foxglove. https://www.flickr.com/photos/pikerslanefarm/3614075359 Digitalis purpurea. Flickr. Lecture-1 Notes Page 2 of 9 University of Ottawa Pharmacology: Mechanisms & Compliance (HSS 3106) January 8 - 12, 2024 Lecture-1: Introduction to Pharmacology and Drug Regulations in Canada Figure 1. The foxglove,1 Digitalis purpurea, contains digoxin, a cardiac glycoside. The plant was used on heart conditions long before the glycoside was identified. Digoxin is used to treat atrial fibrillation, atrial flutter and sometimes heart failure.   1. LEARNING OUTCOMES After studying this module on the “introduction to pharmacology” you will master the following learning objectives:  LO1. Define pharmacology.  LO2. Discuss the interdisciplinary nature of pharmacology.  LO3. Compare and contrast therapeutics and pharmacology.  LO4. Compare and contrast conventional drugs, biologics, and natural health products.  LO5. Identify the advantages and disadvantages of prescription and over the counter (OTC) drugs.  LO6. Identify key Canadian drug regulations that help to ensure the safety and efficacy of medications.  LO7. Discuss the role of Health Canada and the Health Products and Food Branch (HPFB) of Health Canada and its Therapeutic Products and Directorate in the drug approval process.  LO8. Describe the stages of approval for therapeutic and biologic drugs in Canada. BACKGROUND READING AND ONLINE RESOURCES Readings o Adams, M., Holland, N., Bostwick, P. M., El-Hussein, M., & Osuji, J. (2020). Pharmacology for Nurses, Third Canadian Edition. Pearson.  Chapter 1: Introduction to Pharmacology and Drug Regulations in Canada o Flower, R. J. (2013). Pharmacology 2.0. British Journal of Clinical Pharmacology, 76(5), 625–629. https://doi.org/10.1111/bcp.12088 Online Resources o What is pharmacology? (NIH): https://biobeat.nigms.nih.gov/2023/08/what-is-pharmacology/ o What is pharmacology? (British Pharmacological Society): https://www.bps.ac.uk/careers-in-pharmacology/a-level-and-college-student/what-is-pharmacology o Pharmacogenomics (BioNinja): https://ib.bioninja.com.au/options/untitled/b4-medicine/pharmacogenomics.html o The Health Products and Food Branch's (HPFB) (Health Canada): https://www.canada.ca/en/healthcanada/corporate/about-health-canada/branches-agencies/health-products-food-branch.html Videos o YouTube Video #1: Introduction to Pharmacology  https://youtu.be/r95HUvHa4VM?si=22c6lebZjR_moABK o YouTube Video #2: Introduction to Pharmacology (Lecturio Nursing)  https://youtu.be/Yo2MDlWv_kc?si=LY5oGqkOLTthDtFG o YouTube Video #3: Children of Thalidomide  https://www.youtube.com/watch?v=y2lhmSCunrI o TEDEd 1: How does your body process medicine? Author: Céline Valéry.  https://www.ted.com/talks/celine_valery_how_does_your_body_process_medicine 1. Slater, A. (2009, June 10). Purple Foxglove. Digitalis purpurea. Flickr. https://www.flickr.com/photos/pikerslanefarm/3614075359 Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024 Lecture-1 Notes Page 3 of 9 2. PHARMACOLOGY o Pharmacology – study of medications o Drug – substance capable of producing a biologic response. o Medication – a drug given for the purpose of producing a therapeutic response.  Classifying a substance as a drug or a medication is not always simple. o Effective use of drugs and medications by a health care team depends on being able to apply knowledge related to:  Anatomy & Physiology  Pathophysiology  Chemistry  Microbiology Therapeutics Classification of drugs 1. Traditional medications 2. Biologics 3. Natural Health Products Traditional medications  Produced by pharmaceutical manufacturer (i.e., aspirin). Biologics  Agents produced by animal cells and microorganisms.  Hormones, antibodies, vaccines. Figure 2. Insulin therapy2 using insulin purified from porcine or bovine pancreas revolutionized diabetes therapy in the 1920s. A series of advances including cloning human insulin cDNA enabled the development of recombinant human insulin with improved features. Insulin treatment for diabetes may well be upended by β-cell replacement therapy in the coming decades. 2 Sakurai, T., Kubota, S., Kato, T., & Yabe, D. (2022). Advances in insulin therapy from discovery to β‐cell replacement. Journal of Diabetes Investigation, 14(1), 15–18. https://doi.org/10.1111/jdi.13902 Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024 Lecture-1 Notes Page 4 of 9 Natural Health Products  Natural plant extracts  Vitamins, minerals  Dietary supplements 3. PRESCRIPTION DRUGS AND OVER THE COUNTER (OTC) DRUGS Prescription Drugs o Require a dispensing order (prescription) from a qualified health care professional prior to patient receiving drug. Classification of Prescription Drugs  Drugs that may be too harmful for self-administration.  Treat complex conditions.  Require skill to administer.  Patient must receive authorization to receive the drug.  Drugs that may be addictive. Non-Medicinal (NM) Prescription Drugs of Abuse amongst Ontario Students (1977 – 2019)  In 2017, one-in-ten (11%) students in grades 7-12 (an estimated 98,300 in Ontario) report using a prescription opioid pain reliever (e.g., Percocet, Percodan, Tylenol #3, Demerol, Dilaudid).  In 2017, about 3% of students in grades 7-12 ( an estimated 23,000 in Ontario) report using a drug typically used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children (e.g., Adderall, Ritalin, Concerta, Dexedrine) without a prescription. Table 1. Past Year Drug Use (%) for the Total Sample, by Sex, and by Grade, 2019 OSDUHS 3 (N=14,142) 4 3 4 OSDUHS = The Ontario Student Drug Use and Health Survey Centre for Addiction and Mental Health (CAMH). (2020). Drug use among Ontario students : detailed OSDUHS findings. 1977-2019. https://www.camh.ca/-/media/files/pdf---osduhs/summary_drugusereport_2019osduhs-pdf.pdf Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024 Lecture-1 Notes Page 5 of 9 Benefits of Prescription drugs  Health care provider can examine and diagnose patient prior to ordering medication, ensuring that order is appropriate for patient and condition.  Dose and frequency of dispensed drug can be controlled.  Patient provided with education about drug including dosing, interactions, adverse effects.  Maximize therapy.  Patient follow-up. Over The Counter (OTC) Drugs o Drugs that can be obtained by patients without consultation with a health care provider. Benefits of OTC drugs:  Cost-effective  Convenience  Quick relief  Self-treatment: patients can treat themselves for common conditions by following directions on packaging.  Usually have a high margin of safety and few adverse effects.  Do not require authorization from health care provider.  Must carefully follow directions.  No monitoring from health care provider needed. Risks of OTC drugs  No drug is without risk.  Patient may not choose proper medications.  No assistance from health care provider.  May interact with food, herbals, prescription, or other OTC drugs.  May be ineffective or harmful. Figure 3. OTC drugs vs Prescription drugs. Reclassification o Prescription drugs can be changed to over-the-counter drugs. o Decision initiated by manufacturer or mandated by FDA. o High safety margin must exist. Supplements o Herbal and dietary supplements are not drugs. o Not subjected to same regulatory process. o Can cause side effects and interact with medications. o Not tested by FDA for safety. Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024 Lecture-1 Notes Page 6 of 9 4. CANADIAN DRUG REGULATIONS o Created to protect the public from drug misuse and to provide mechanism for quality assurance for safety and efficacy. o Health Products and Food Branch (HPF B) of Health Canada is res ponsible for ensuring the safety and quality of drugs, biologics, and natural health products. o Standard is set by Food and Drug Act and Regulations. Figure 4. The governance structure for therapeutic products in Canada. 5 Health Products & Food Branch at Health Canada Therapeutic Products Directorate (TPD)  Federal authority that regulates pharmaceutical drugs  Manufacturer must provide substantive evidence of a drug’s safety, efficacy, and quality, per Food and Drugs Act and Regulations, to TPD for approval.  TPD approval required for drug to be marketed in Canada. Biologics and Genetic Therapies Directorate  Parallel branch to TPD that regulates biologics and radiopharmaceuticals. Natural and Non-prescription health Products Directorate  Parallel branch to TPD that regulates natural health products. Figure 4. Summary of the drug review and approval process in Canada.6 Canadian Drug Approval Process o A seven-step process that includes preclinical and clinical trials, pre-market review and approval and post-market evaluation: Step 1: Preclinical trials  Preclinical trials using cultured cells, living tissues and small animal models 5 6 Adams, M., Holland, N., Bostwick, P. M., El-Hussein, M., & Osuji, J. (2020). Pharmacology for Nurses, Third Canadian Edition. Pearson SPharm. (2023, November 10). The drug review and Approval Process in Canada - an eGuide. Canada’s Regulatory Experts for Drug & Health Products. https://spharm-inc.com/the-drug-review-and-approval-process-in-canada-an-eguide/ Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024 Lecture-1 Notes Page 7 of 9 Figure 4. Summary of the drug review and approval process in Canada.7 Step 2: Clinical Trial Application and testing  Phase I – healthy subjects. o Evaluate safety of drug and possible adverse effects.  Phase II – small group of patients with target condition.  Phase III – large group of patients with target condition. Step 3: Manufacturer completes New Drug Submission (NDS) to Health Canada  Outlines test data obtained from clinical trials, indication, adverse effects, production, and packaging. Step 4: Review of NDS submission  Committee of drug experts reviews NDS to identify benefits and risks. Step 5: Health Canada shares information about drug with health care providers and consumers Step 6: Issuance of DIN and notice of compliance.  If approved, Health Canada issues a Drug Information Number (DIN) and a Notice of Compliance to manufacturer.  Both required for marketing drug. Step 7 – evaluation of drug safety and efficacy.  Health Canada continues to evaluate drug safety and efficacy through quality assurance (QA) processes. How the thalidomide scandal led to safer drugs. 8 o YouTube Video #3: Children of Thalidomide  https://www.youtube.com/watch?v=y2lhmSCunrI Background  The release of thalidomide in the 1950s and 1960s led to the world’s most publicized pharmaceutical disaster.  Thalidomide was invented in the early 1950s by scientists working for a German pharmaceutical company ChemieGrünenthal, who believed the drug could succeed as a sleeping pill and sedative and it was marketed in 1957, first in Germany and then throughout Europe. Figure 5. Skeletal formulae of both thalidomide enantiomers. 7 8 SPharm. (2023, November 10). The drug review and Approval Process in Canada - an eGuide. Canada’s Regulatory Experts for Drug & Health Products. https://spharm-inc.com/the-drug-review-and-approval-process-in-canada-an-eguide/ Kingsland, J. (2020, December 15). How the thalidomide scandal led to safer drugs. Medical News Today. https://www.medicalnewstoday.com/articles/how-the-thalidomide-scandal-led-to-safer-drugs#Complete-safety Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024 Lecture-1 Notes Page 8 of 9 Popularity  Thalidomide was marketed internationally to pregnant women in the late 1950s and early 1960s as a treatment for morning sickness.  Horrifically, it killed an estimated 80,000 children around the world before they were born, and 20,000 mor e who survived were born without limbs, with severe nerve damage and an array of other ailments.  By 1960, thalidomide was marketed in 46 countries, with sales nearly matching those of aspirin. Figure 6. Many children in the 1960’s, like the kindergartner pictured above, were born with phocomelia as a side effect of the drug thalidomide, resulting in the shortening or absence of limbs. 9 Thalidomide babies 10  Australian obstetrician Dr. William McBride discovered that the drug also alleviated morning sickness. He started recommending this off-label use of the drug to his pregnant patients, setting a worldwide trend.  McBride began to associate this so-called harmless compound with severe birth defects in the babies he delivered. The drug interfered with the babies normal development, more than 10,000 children in 46 countries were born with deformities such as phocomelia as a consequence of thalidomide use.  Other effects included deformed eyes and hearts, deformed alimentary and urinary tracts, blindness, and deafness. Removal from market  It took some time before the increasing number of babies being born with malformations was connected with thalidomide, despite the existence of reports of birth defects associated with the drug.  Initially he phenomenon was blamed on nuclear weapon testing and lack of healthy nutrition and behavior of the mothers.  When a German newspaper published that 161 babies were adversely affected by thalidomide, marked he beginning of the end, leading the makers of the drug to finally stop distribution within Germany. Other countries followed and, by March of 1962, the drug was banned in most countries where it was previously sold. FDA refusal  ChemieGrünenthal approached Smith, Kline & French (SKF), with a request to market and distribute the drug in the United States, however said marketing and distribution of the drug were denied by the FDA.  FDA inspector Frances Kelsey considered the application for thalidomide contained incomplete data on its safety and effectiveness. ChemieGrünenthal applied for its approval 6 more times, through different distributors and manufacturers, and 6 more times Frances Kelsey refused. Figure 7. Grünenthal research lab11 in Aachen around 1965. 9 10 11 McCombe, L. (2009, July 28). The Thalidomide tragedy: Lessons for Drug Safety and Regulation. Helix. https://www.helix.northwestern.edu/2009/07/28/the-thalidomide-tragedy-lessons-for-drug-safety-and-regulation/ Dr Frances Kelsey: thalidomide and the precautionary principle. (2017, November 17). The Ecologist. https://theecologist.org/2015/aug/25/dr-frances-kelsey-thalidomide-and-precautionary-principle Grünenthal GmbH. (2024). The Thalidomide tragedy in Germany. Grünenthal. https://www.thalidomide-tragedy.com/the-history-of-thethalidomide-tragedy Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024 Lecture-1 Notes Page 9 of 9 Thalidomide distribution in the US  Clinicaltrials were not under supervision nor needed approval by the FDA at the time, which resulted in about 2,5 million doses being distributed in the United States.  Smith, Kline, and French and other pharmaceutical companies conducted animal tests and ran clinical trials of the drug in the United States involving about 20,000 people, including pregnant women.  A total of 17 children in the United States were born with thalidomide-induced malformations. Time for a change  FDA inspector Frances Kelsey, who prevented the drug’s approval within the United States was praised as a hero and received the President's Award for Distinguished Federal Civilian Service by John F. Kennedy.  The tragedy surrounding thalidomide helped motivate profound changes in the FDA. By passing the Kefauver-Harris Drug Amendments Act in 1962, legislators tightened restrictions surrounding the surveillance and approval process for drugs to be sold in the United States, requiring that manufacturers prove they are both safe and effective before they are marketed. Figure 8. President John F. Kennedy gave Dr. Frances Oldham Kelsey the nation’s highest federal civilian service award in 1962,12 saying she had “prevented a major tragedy of birth deformities.” 12 McFadden, R. D. (2015, August 7). Frances Oldham Kelsey, Who Saved U.S. Babies From Thalidomide, Dies at 101. The New York Times. https://www.nytimes.com/2015/08/08/science/frances-oldham-kelsey-fda-doctor-who-exposed-danger-of-thalidomide-dies-at-101.html Pharmacology: Mechanisms & Compliance (HSS 3106) Darnel, A.D. © winter 2024