1. Introduction to Pharmacology and Pharmacokinetics Pharmacology 49.222 Bill Diehl-Jones RN, PhD Faculty of Nursing and Department of Zoology

2. Agenda The instructor The instructor The course The course organization organization expectations/grading expectations/grading Introduction Introduction Purpose of drug therapy Purpose of drug therapy Principles of Pharmacokinetics Principles of Pharmacokinetics

3. The Instructor Office: 333 Helen Glass Office: 333 Helen Glass Lab: 336 Helen Glass Lab: 336 Helen Glass Phone: 474-7136 Phone: 474-7136 Email: Email: Bill_Diehl- Jones@umanitoba.ca Bill_Diehl- Jones@umanitoba.ca Office Hours: Office Hours: by appointment by appointment

4. The Course Introductory level course designed for nursing students Introductory level course designed for nursing students Lecture notes are available on my website Lecture notes are available on my website Physiological and pharmacological principles will be integrated Physiological and pharmacological principles will be integrated

5. Optional Text It is currently in the U of M bookstore It is currently in the U of M bookstore Primary text: Primary text: Lilly and Aucker, 2001 Lilly and Aucker, 2001

6. Core Concepts Introduction to Pharmacology General Principles Pharmacotherapeutics The Role of the Nurse Drug Issues in Society

7. Evaluation Methods Mid Term Test - 25% Mid Term Test - 25% Final Exam - 35% Final Exam - 35% Patient Information Pamphlet - 20% Patient Information Pamphlet - 20% Pop Quizzes (x 4)- 10% Pop Quizzes (x 4)- 10% Test/exam will be multiple choice, true false and matching Test/exam will be multiple choice, true false and matching

8. Why Do We Study Pharmacology? A. It’s good for you A. It’s good for you B. You will be able to use fancy terms like ’bioavailabilty’ B. You will be able to use fancy terms like ’bioavailabilty’ C. My instructor likes torture C. My instructor likes torture D. A competent nurse must understand why his/her patient is getting a medication, and HOW IT WORKS D. A competent nurse must understand why his/her patient is getting a medication, and HOW IT WORKS

9. Purpose of Drug Therapy “… to prevent, control or cure various disease states.” “… to prevent, control or cure various disease states.” To achieve this, the right drug dose must be delivered to the tissues To achieve this, the right drug dose must be delivered to the tissues Every nurse must know… Every nurse must know… speed of onset of drug action speed of onset of drug action intensity of drug effect intensity of drug effect duration of drug action duration of drug action

10. A Graphical Example: Time in Hours Drug Concentration  Therapeutic Range Sub- Therapeutic Lethal Dose Peak Onset Duration

11. How Do We Study Pharmacology?

12. General Concepts Drug Dose Administration Drug Effect or Response Pharmaceutical Pharmacokinetics Pharmacodynamics Pharmacotherapeutics Disintegration of Drug Absorption/distribution metabolism/excretion Drug/Receptor Interaction

13. How are Drugs Administered?

14. Routes of Drug Delivery Parenteral (IV) Inhaled Oral Transdermal Rectal Topical Parenteral (SC, IM)

15. What Happens After Drug Administration? Drug at site of administration Drug in plasma Drug/metabolites in urine, feces, bile Drug/metabolites in tissues 1. Absorption 2. Distribution 4. Elimination 3. Metabolism Modified from Mycek et al. (1997)

16. We are now talking about … Pharmacokinetics

17. Factors Affecting Drug Absorption Transport Transport active vs. passive active vs. passive pH pH Physical factors Physical factors blood flow blood flow surface area surface area contact time contact time ATP ADP + Pi A - BH +

18. What Factors Affect Distribution? Blood flow Blood flow brain vs. fat brain vs. fat Capillary permeability Capillary permeability differences in capillary structure differences in capillary structure Binding to proteins Binding to proteins role of albumin role of albumin Endothelial cells in liver capillary Endothelial cells in brain capillary Glial cell

19. An Important Concept: BIOAVAILABIITY Def’n: Def’n: Fraction of a drug that reaches systemic circulation after a particular route of admin’n Fraction of a drug that reaches systemic circulation after a particular route of admin’n Affected by: Affected by: 1st pass metabolism (eg: Lidocaine, propranolol) 1st pass metabolism (eg: Lidocaine, propranolol) Solubility Solubility Instability (eg: Penicillin G, insulin) Instability (eg: Penicillin G, insulin) Serum Concentration Time Injected Dose Oral Dose

20. Volume of Drug Distribution Drugs may distribute into any or all of the following compartments: Drugs may distribute into any or all of the following compartments: Plasma Plasma Interstitial Fluid Interstitial Fluid Intracellular Fluid Intracellular Fluid Plasma (4 litres) Interstitial Fluid (10 litres) Intracellular Fluid (28 litres)

21. So What? Most drugs distribute into several compartments; however … Most drugs distribute into several compartments; however … Some drugs distribute into only one or two compartments Some drugs distribute into only one or two compartments Eg: Aminoglycoside antibiotics Eg: Aminoglycoside antibiotics Streptomycin Streptomycin Gentamycin Gentamycin Arggh! I can’t fit through these darn fenestrations!

22. More “So What?” It takes time for a drug to distribute in the body It takes time for a drug to distribute in the body Drug distribution is affected by elimination Drug distribution is affected by elimination Time Serum Concentration 0 0.5 1.0 1.5 0 Elimination Phase Distribution Phase Drug is eliminated Drug is not eliminated

23. Albumin Affects Distribution Drugs bind differentially to albumin Drugs bind differentially to albumin 2 drug classifications: 2 drug classifications: Class I: dose less than available binding sites (eg: most drugs) Class I: dose less than available binding sites (eg: most drugs) Class II: dose greater than binding sites (eg: sulfonamide) Class II: dose greater than binding sites (eg: sulfonamide) The problem: The problem: one drug may out- compete the other one drug may out- compete the other Sulfonamide Drug X Albumin

24. Drug Metabolism (we’re still talking about Pharmacokinetics)

25. Drug Metabolism First pass First pass metabolism of drugs may occur as they cross the intestine or transit the liver metabolism of drugs may occur as they cross the intestine or transit the liver eg: nitroglycerin eg: nitroglycerin Other drugs may be destroyed before absorption Other drugs may be destroyed before absorption eg: penicillin eg: penicillin Such reactions decrease delivery to the target tissues Such reactions decrease delivery to the target tissues

26. Drug Metabolism (cont’d) Two Phases: I and II Two Phases: I and II Phase I: conversion to lipophilic cpds Phase I: conversion to lipophilic cpds Phase II: conjugation Phase II: conjugation Phase I involves the cytochrome P-450 system Phase I involves the cytochrome P-450 system Ultimate effect is to facilitate elimination Ultimate effect is to facilitate elimination Drug Phase I Phase II Oxidation Reduction Hydrolysis Activation/Inactivation Conjugation Products Glucuronidation

27. An Example of Phase I and II Biotransformation: -OC 2 H 5 CH 3 CON- H -OH CH 3 CON- H -O- CH 3 CON- H -OH OH COOH HO O PHASE I PHASE II Phenacetin Paracetamol Glucuronic Acid Conjugate

28. An Example of Drug Metabolism

29. First Pass Metabolism Occurs Primarily in the Liver and Gut

30. Drug Elimination Most important route is the kidney Most important route is the kidney May also involve bile, intestine, lung, breast milk May also involve bile, intestine, lung, breast milk What clinical scenarios may affect drug elimination? What clinical scenarios may affect drug elimination?

31. Elimination of a drug is usually linked to renal filtration, secretion and reabsorption.

32. Food for Thought What conditions might affect renal function (and therefore drug elimination)? What conditions might affect renal function (and therefore drug elimination)? What other organ systems are involved in drug clearance? What other organ systems are involved in drug clearance?

33. Important Point The pharmacokinetic profile of a drug also depends on its mode of administration … The pharmacokinetic profile of a drug also depends on its mode of administration …

34. Example: Intravenous Infusions Plasma concentration rises until elimination = input Plasma concentration rises until elimination = input Faster infusions get more drugs on board, but does not change the time to achieve a steady state Faster infusions get more drugs on board, but does not change the time to achieve a steady state Plasma Concentration Time Slow Infusion Fast Infusion Time at which steady state is achieved

35. Example: Intravenous Injection Peak plasma concentration of the drug is achieved at time = 0 Peak plasma concentration of the drug is achieved at time = 0 There is no steady state concentration. Why? There is no steady state concentration. Why? Plasma Concentration Time 100 mg injected 50 mg injected

36. Example: Oral Dose A single oral dose will give you a single peak plasma concentration A single oral dose will give you a single peak plasma concentration The drug concentration then continuously declines The drug concentration then continuously declines Repeated doses result in oscillations in plasma concentration Repeated doses result in oscillations in plasma concentration Plasma Concentration Time

37. Are We Having Fun Yet?