Pharmacology_Primer_BMS_2024.pptx

Pharmacology: A Primer  Mustard Gas Source: NPR, June 2015 Source: The-Scientist Magazine, April 2019 World WAR...

Pharmacology: A Primer  Mustard Gas Source: NPR, June 2015 Source: The-Scientist Magazine, April 2019 World WAR I & II Chemical Louis Goodman & Alfred Gilman From: Military History Archives Source: britannica.com/technology/chemical-weapon Image: The Journal of Organic Chemistry 2012 77 (14), 5914-5921 Nitrogen Mustard: Mechanism of Action It’s an alkylating agent! (Goodman et al.,1946)  In 1942, a 47-year-old man named J.D. worked at a Connecticut ball-bearing factory, struggling with his native Polish language and living alone. After failed attempts to learn English, he sought medical help for neck and throat pain at Yale following previous treatments elsewhere. Diagnosed with a large tumor in his neck's lymph nodes, initial radiation therapy led to temporary improvement, but the tumor resisted further treatment. J.D.'s face swelled, and pain returned as he learned of a new treatment option from his doctor Gustaf E. Lindskog, involving intravenous chemotherapy. J.D.'s outlook was bleak, noted in medical records; he became the first to receive intravenous chemotherapy using nitrogen mustard. His case was overshadowed by chemotherapy pioneers Louis Goodman and Alfred Gilman's research, classified during WWII for its potential against mustard gas. Lindskog applied their research on mice and rabbits to J.D., initiating the first successful use of intravenous chemotherapy for cancer. Gustaf E. Lindskog, MD At a medical event, Robert Udelsman and John E. Fenn revealed J.D.'s identity and the collaborative administration of nitrogen mustard. J.D.'s story was briefly documented in a 1946 issue of JAMA, with inaccurate dates and limited details; Fenn and Udelsman aimed to rectify this. After a search for J.D.'s medical records, Fenn found crucial documents including treatment details and dosage of "substance X" (nitrogen mustard). J.D. began treatment on August 27, 1942, with a scaled dosage based on rabbit research, leading to tumor shrinkage and improved condition. However, his white blood cells were obliterated, and he passed away in December, marking the birth of modern medical oncology beyond surgery. Source: medicine.yale.edu/news/yale-medicine-magazine/article/surgeons-find-new- twists-to-an-old-story/ Pharmacodynamics (PD) is the study of how drugs affect the human body given their mechanism of action. Pharmacokinetics (PK) is the study of what the body does to the drug and describes information about ADME: absorption, distribution, metabolism, and excretion. (ADMETox) Lippincott® Illustrated Reviews: Pharmacology, 8e  Please provide examples for different routes of administration.  Choose three specific routes of administration. Then, compare their advantages and disadvantages. Create a chart illustrating the drug plasma concentration over time.  What do you think is the preferred route of administration? Why? UNIT I: Principles of Drug Therapy 1: Pharmacokinetics (Page 1-23) Lippincott® Illustrated Reviews: Pharmacology, 8e “Fit a Square peg in a round hole” – Apollo 13 Determine Bioavailability of Drug X using only two of the follow Scissors Drug X (Pill) Pipette Duct tape Drug X (Liquid) Mannequin Balance pH meter  ADME (Absorption, Distribution, Metabolism, and Excretion) hlight key concepts in the topic assigned to you (5-6 points would suffice; no calculations only overview) an example to explain your assigned topic Group 1 Absorption of Drugs Group 2 Drug Distribution Group 3 Drug Clearance (by metabolism, by Kidney & other routes Class Discussion on Dose Optimization UNIT I: Principles of Drug Therapy 1: Pharmacokinetics (Page 1-23) Lippincott® Illustrated Reviews: Pharmacology, 8e Drug: Warfarin Absorption: Warfarin is well-absorbed after oral administration. It's primarily absorbed in the small intestine. Its absorption can be affected by food, as certain foods rich in vitamin K can interfere with its anticoagulant effects. Distribution: Warfarin has a high degree of protein binding (approximately 99%) to plasma proteins like albumin. This binding limits the amount of free, active drug in the bloodstream. Because of this, drug interactions that affect protein binding can influence its distribution. Metabolism: Warfarin undergoes extensive metabolism in the liver, primarily by the enzyme CYP2C9. The metabolites formed are less active than the parent drug. Genetic variations in CYP2C9 can lead to individual differences in the drug's metabolism, affecting dosing requirements. Excretion: The metabolites of warfarin are excreted mainly in the urine. The elimination half-life of warfarin varies widely among individuals due to factors such as genetic polymorphisms, liver function, and drug interactions. This example highlights how ADME processes can have a significant impact on the pharmacokinetics and pharmacodynamics of a drug like Warfarin. It also underscores the importance of considering individual variability in drug responses when prescribing and dosing medications. Dosage: Warfarin dosing can vary widely depending on the patient's condition & response, which reflect the blood's ability to clot. Dosing is highly individualized. Initial Dose: Typically, an initial dose of 2.5 to 5 mg is commonly prescribed. The initial dose is often adjusted based on INR monitoring and can be increased or decreased as needed. Maintenance Dose: The maintenance dose of warfarin usually falls within a range of 2 to 10 mg per day. However, many patients require lower doses, around 2 to 5 mg per day, to achieve the desired INR range (usually between 2.0 and 3.0 for most indications).  Pharmacodynamics hlight key concepts in the topic assigned to you (5-6 points would suffice; no calculations only overview) an example to explain your assigned topic Group 1 Receptor-Drug Interactions & Signal Transduction Group 2 Dose-Response Relationships Group 3 Intrinsic Activity Class Discussion Quantal-Dose Response Relationships UNIT I: Principles of Drug Therapy 2. Drug–Receptor Interactions and Pharmacodynamics Page 24-38 Lippincott® Illustrated Reviews: Pharmacology, 8e Cumulative percentage of patients responding to plasma levels of warfarin (A) and penicillin (B). Therapeutic index The therapeutic index (TI) of a drug is the ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response (ED50) in half the population: The TI of a drug is determined using drug trials and accumulated clinical experience. These usually reveal a range of effective doses and a different (sometimes overlapping) range of toxic doses. Although high TI values are required for most drugs, some drugs with low therapeutic indices are routinely used to treat serious diseases.