安徽医科大学：《临床药理学 Clinical Pharmacology》课程教学资源（授课教案，英文版）Chapter One

安徽医科大学国际教育学院教案与讲稿 Teaching Plan for International Students,AHMU Title of the course:Clinical Pharmacokinetics Chapter:One Teacher's name: Wu-Yi Sun Grade:2013 Department:School of International Education Time:14:30-16:50 Date(D/M/Y):3/9/2016 1.Review fundamental pharmacokinetic principles. 2.Understand the pharmacokinetic processes of absorption, distribution Teaching metabolism,and excretion of drug substances,and how they may play a role in Objectives; dosage regimen design. Teaching 3.Recognize which physiologic processes and disease states may alter the Requirements pharmacokinetics of a particular drug. 4.Recognize which patient characteristics,disease states,and drug interactions must be considered when recommending initial or subsequent dosage regimens. 1.ADME factors 2.Review of basic pharmacokinetic parameters Teaching 3.Mathematical basis of clinical pharmacokinetics Content 4.Effect of disease states on pharmacokinetics 5.Applications of clinical pharmacokinetics Teaching Focus:How ADME may play a role in dosage regimen design. Teaching Difficult Problems:The physiologic processes and disease states may alter the Focus; pharmacokinetics of a particular drug. Difficult Problems Solutions:Give examples of renal and liver diseases affect the drug and their pharmacokinetics.The lectures are conducted using a case-based format which Solutions promotes an active-learning environment.Other teaching styles such as didactic lectures,question-answer sessions and class discussions are used as appropriate. ADME factors 33min Review of basic pharmacokinetic parameters 15min Time Mathematical basis of clinical pharmacokinetics 15min Allotment Effect of disease states on pharmacokinetics 30min Applications of clinical pharmacokinetics 20min Discussion 7min 1.The concept of first-pass metabolism,bioavailability,half-life Assignment 2.A patient is overdosed with salicylic acid,which is a weak acid.How do you treat this patient in order to remove the drug faster from his blood? 1.Principle of Clinical Pharmacology(Second Edition);ArthurJ.Atkinson Reference 2.Drug Discovery and Evaluation:Methods in Clinical Pharmacology.Vogel, H.Gerhard;Maas,Jochen;Gebauer,Alexander.2011 Text 3.Oxford Textbook of Clinical Pharmacology and Drug Therapy;David Grahame-Smith,Jeffrey Aronson Memo

安徽医科大学国际教育学院教案与讲稿 1 Teaching Plan for International Students, AHMU Title of the course: Clinical Pharmacokinetics Chapter: One Teacher’s name: Wu-Yi Sun Grade: 2013 Department: School of International Education Time: 14:30—16:50 Date (D/M/Y): 3/9/2016 Teaching Objectives; Teaching Requirements 1. Review fundamental pharmacokinetic principles. 2. Understand the pharmacokinetic processes of absorption, distribution metabolism, and excretion of drug substances, and how they may play a role in dosage regimen design. 3. Recognize which physiologic processes and disease states may alter the pharmacokinetics of a particular drug. 4. Recognize which patient characteristics, disease states, and drug interactions must be considered when recommending initial or subsequent dosage regimens. Teaching Content 1. ADME factors 2. Review of basic pharmacokinetic parameters 3. Mathematical basis of clinical pharmacokinetics 4. Effect of disease states on pharmacokinetics 5. Applications of clinical pharmacokinetics Teaching Focus; Difficult Problems and their Solutions Teaching Focus: How ADME may play a role in dosage regimen design. Difficult Problems: The physiologic processes and disease states may alter the pharmacokinetics of a particular drug. Solutions: Give examples of renal and liver diseases affect the drug pharmacokinetics. The lectures are conducted using a case-based format which promotes an active-learning environment. Other teaching styles such as didactic lectures, question-answer sessions and class discussions are used as appropriate. Time Allotment ADME factors 33min Review of basic pharmacokinetic parameters 15min Mathematical basis of clinical pharmacokinetics 15min Effect of disease states on pharmacokinetics 30min Applications of clinical pharmacokinetics 20min Discussion 7min Assignment 1. The concept of first - pass metabolism, bioavailability, half-life. 2. A patient is overdosed with salicylic acid, which is a weak acid. How do you treat this patient in order to remove the drug faster from his blood? Reference Text 1. Principle of Clinical Pharmacology (Second Edition); ArthurJ. Atkinson 2. Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Vogel, H.Gerhard; Maas, Jochen; Gebauer, Alexander. 2011 3.Oxford Textbook of Clinical Pharmacology and Drug Therapy; David Grahame-Smith, Jeffrey Aronson Memo

安徽医科大学国际教育学院教案与讲稿 Teaching Plan for International Students,AHMU Title of the course:Clinical Pharmacokinetics Chapter:One Teacher's name:Wu-Yi Sun Grade:2013 Department:School of International Education Time:14:30-16:50 Date(D/M/Y):3/9/2016 Lecture Notes: [Outline] 2min ·ADME factors Review of basic pharmacokinetic parameters Mathematical basis of clinical pharmacokinetics Effect of disease states on pharmacokinetics .Applications of clinical pharmacokinetics ·Study questions [Four Basic Processes in Pharmacokinetics] 3min Drug Administration (e.g..parenteral,oral.etc.) (from s into plasma) PLASMA Storage in Tissue Depot (e.g,body fat》 Bound Fre Drug Site of Action Excretion (e.g.kidney,expired air. sweat.feces) [Absorption of Drugs] 6min 1.Routes of Drug Administration Oral absorption:First-pass metabolism Sublingual absorption Parenteral:iv.,im.,sc. 2.Factors influencing absorption Related to Drugs:Water/lipid solubility,Molecular size,Degree of Ionization,Route of administration. Related to Body:pH,Blood flow to the absorption site,Total surface area available for absorption,Contact time at the absorption surface. 2

安徽医科大学国际教育学院教案与讲稿 2 Teaching Plan for International Students, AHMU Title of the course: Clinical Pharmacokinetics Chapter: One Teacher’s name: Wu-Yi Sun Grade: 2013 Department: School of International Education Time: 14:30—16:50 Date (D/M/Y): 3/9/2016 Lecture Notes: [Outline] 2min
ADME factors
Review of basic pharmacokinetic parameters
Mathematical basis of clinical pharmacokinetics
Effect of disease states on pharmacokinetics
Applications of clinical pharmacokinetics
Study questions [Four Basic Processes in Pharmacokinetics] 3min [Absorption of Drugs] 6min 1. Routes of Drug Administration
Oral absorption: First - pass metabolism
Sublingual absorption
Parenteral: iv., im., sc. 2. Factors influencing absorption
Related to Drugs: Water/lipid solubility, Molecular size, Degree of Ionization, Route of administration.
Related to Body: pH, Blood flow to the absorption site, Total surface area available for absorption, Contact time at the absorption surface

安徽医科大学国际教育学院教案与讲稿 [Drug Distribution] 6min Factors influencing distribution: 1.Binding of drugs to plasma proteins: ·Reversible A bound drug has no effect ·Nonspecific Competitive displacement Renal failure,fasting,malnutrition can have effect on plasma protein binding 2.Physiological barriers to drug distribution:Blood-Brain Barrier,Placental Barrier 3.Blood flow 4.Selective accumulation of drugs [Drug Metabolism(Biotransformation)] 8min 1.Consequences of drug metabolism:inactive,active drug form,Toxic metabolite 2.General Metabolic Pathways:Phase I Reactions,Phase II Reactions 3.Enzymes Involved in Drug Metabolism:Cytochrome P450 Enzymes(CYP450) Characteristics of CYPs:Low Specificity Genetic variability Enzyme induction or inhibition 4.Factors Influencing Drug Metabolism ·Genetic variability ·Age Clinical or physiological condition Other drug administration (induction or inhibition) ·Food [Drug Excretion] 8min 1.Types of Excretion:Renal excretion,Non-renal excretion 2.Renal excretion of drugs: Glomerular filtration Active tubular secretion Active or passive tubular reabsorption 3.Factors Affecting Renal Excretion/Clearance Physicochemical properties of drug ·Urine pH Blood flow to the kidney Biological factors(Age,sex,species etc.) ·Disease state Review of Basic Pharmacokinetic Parameters 15min 1.Drug concentration-time profiles and AUC AUC can be used to assess the person's overall exposure to a drug. 2.Half-life 3

安徽医科大学国际教育学院教案与讲稿 3 [Drug Distribution] 6min Factors influencing distribution: 1. Binding of drugs to plasma proteins:
Reversible
A bound drug has no effect
Nonspecific
Competitive displacement
Renal failure, fasting, malnutrition can have effect on plasma protein binding 2. Physiological barriers to drug distribution: Blood-Brain Barrier, Placental Barrier 3. Blood flow 4. Selective accumulation of drugs [Drug Metabolism (Biotransformation) ] 8min 1. Consequences of drug metabolism: inactive, active drug form, Toxic metabolite 2. General Metabolic Pathways: Phase I Reactions, Phase II Reactions 3. Enzymes Involved in Drug Metabolism: Cytochrome P450 Enzymes (CYP450) Characteristics of CYPs: Low Specificity Genetic variability Enzyme induction or inhibition 4. Factors Influencing Drug Metabolism
Genetic variability
Age
Clinical or physiological condition
Other drug administration (induction or inhibition)
Food [Drug Excretion] 8min 1. Types of Excretion: Renal excretion, Non-renal excretion 2. Renal excretion of drugs:
Glomerular filtration
Active tubular secretion
Active or passive tubular reabsorption 3. Factors Affecting Renal Excretion/Clearance
Physicochemical properties of drug
Urine pH
Blood flow to the kidney
Biological factors (Age, sex, species etc.)
Disease state [Review of Basic Pharmacokinetic Parameters] 15min 1. Drug concentration-time profiles and AUC AUC can be used to assess the person’s overall exposure to a drug. 2. Half-life

安微医科大学国际教育学院教案与讲稿 Half-life has considerable importance for determining dosing frequency or adjusting doses in a patient. It takes approximately five half-lives for 97%of the drug to be eliminated from the body (regardless of the duration of the half-life). .Clinical situations resulting in changes in drug half-life 3.Bioavailability (F) 4.Clearance(CI) 5.Volume of distribution (Vd) 6.Steady state and Css Just as it takes approximately five half-lives for a drug to be essentially (97%)eliminated,it also requires five half-lives for a drug to reach steady state. Loading dose calculation Maintenance Dose Calculation [Mathematical Basis of Clinical Pharmacokinetics 15min 1.Two types of kinetics,related to the plasma concentration of a drug,describe the rate at which a drug leaves the body. Zero-order kinetics(non linear kinetics) First-order kinetics (linear kinetics) 2.Compartment models One-compartment model Two-compartment model [Effects of renal disease on pharmacokinetics] 15min 1.Effects of renal disease on drug elimination Renal dysfunction:Greatly impairs elimination of drugs primarily excreted by kidney.Some of the causes of renal failure are B.P,Diabetes,Pyelonephritis. ·Uremia 2.Effects of renal disease on drug distribution Impaired renal function is associated with important changes in the binding of some drugs to plasma proteins.In some cases the tissue binding of drugs is also affected. 3.Effects of renal disease on drug absoprtion [Effects of liver disease on pharmacokinetics] 15min 1.Effects of liver disease on pharmacokinetics ·Acute hepatitis Chronic liver disease and cirrhosis Pharmacokinetic consequences of liver cirrhosis 2.Use of therapeutic drugs in patients with liver disease Effects of liver disease on the hepatic elimination of drugs Effects of liver disease on the renal elimination of drugs Effects of liver disease on patient response Modification of drug therapy in patients with liver disease 4

安徽医科大学国际教育学院教案与讲稿 4
Half-life has considerable importance for determining dosing frequency or adjusting doses in a patient.
It takes approximately five half-lives for 97% of the drug to be eliminated from the body (regardless of the duration of the half-life).
Clinical situations resulting in changes in drug half-life 3. Bioavailability (F) 4. Clearance (Cl) 5. Volume of distribution (Vd) 6. Steady state and Css
Just as it takes approximately five half-lives for a drug to be essentially (97%) eliminated, it also requires five half-lives for a drug to reach steady state.
Loading dose calculation
Maintenance Dose Calculation [Mathematical Basis of Clinical Pharmacokinetics] 15min 1. Two types of kinetics, related to the plasma concentration of a drug, describe the rate at which a drug leaves the body.
Zero-order kinetics ( non linear kinetics)
First-order kinetics (linear kinetics) 2. Compartment models
One-compartment model
Two-compartment model [Effects of renal disease on pharmacokinetics] 15min 1. Effects of renal disease on drug elimination
Renal dysfunction: Greatly impairs elimination of drugs primarily excreted by kidney. Some of the causes of renal failure are B.P, Diabetes, Pyelonephritis.
Uremia 2. Effects of renal disease on drug distribution Impaired renal function is associated with important changes in the binding of some drugs to plasma proteins. In some cases the tissue binding of drugs is also affected. 3. Effects of renal disease on drug absoprtion [Effects of liver disease on pharmacokinetics] 15min 1. Effects of liver disease on pharmacokinetics
Acute hepatitis
Chronic liver disease and cirrhosis
Pharmacokinetic consequences of liver cirrhosis 2. Use of therapeutic drugs in patients with liver disease
Effects of liver disease on the hepatic elimination of drugs
Effects of liver disease on the renal elimination of drugs
Effects of liver disease on patient response
Modification of drug therapy in patients with liver disease

安徽医科大学国际教育学院教案与讲稿 Applications of Clinical Pharmacokinetics 20min 1.Rational dose selection in therapeutics Target concentration strategy ESTIMATE INITIAL DOSE TARGET LEVEL LOADING DOSE MAINTENANCE DOSE BEGIN THERAPY 0 ASSESS THERAPY PATIENT RESPONSE DRUG LEVEL REFINE DOSE ESTIMATE ADJUST DOSE 2.Clinical Pharmacokinetics in Drug Development Initial PK studies in humans Late PK studies in humans Therapeutic drug monitoring Clinical (Human)Testing Preclinical testing Dose response Population PK/PD trials a品。 m PK-guided Post- Dose Efficacy PK/PD in marketing In vitro PKPD esc alation Special surveillance Animn al PK/PD Safety Dosage selection populations 具分Assessment Patient variables Toxicity Animal Phase I PhaseⅡ PhaseⅢ testing [Study Questions] 7min 1.For a drug such as piroxicam with a 40-hour half life and being dosed once daily (i.e.,every 24 hours),steady state will be reached shortly following which DOSE(not which half-life)? (A)1st dose (B)3rd dose (C)5th dose (D)8th dose (E)12th dose 2.The addition of glucuronic acid to a drug: A.Decreases its water solubility. B.Usually leads to inactivation of the drug. C.Is an example of a Phase I reaction. D.Occurs at the same rate in adults and newborns. E.Involves cytochrome P450. 3.A drug,given as a 100-mg single dose,results in a peak plasma concentration of 20ug/mL.The 5

安徽医科大学国际教育学院教案与讲稿 5 [Applications of Clinical Pharmacokinetics] 20min 1. Rational dose selection in therapeutics Target concentration strategy 2. Clinical Pharmacokinetics in Drug Development
Initial PK studies in humans
Late PK studies in humans
Therapeutic drug monitoring [Study Questions] 7min 1. For a drug such as piroxicam with a 40-hour half life and being dosed once daily (i.e., every 24 hours), steady state will be reached shortly following which DOSE (not which half-life)? (A) 1st dose (B) 3rd dose (C) 5th dose (D) 8th dose (E) 12th dose 2. The addition of glucuronic acid to a drug: A. Decreases its water solubility. B. Usually leads to inactivation of the drug. C. Is an example of a Phase I reaction. D. Occurs at the same rate in adults and newborns. E. Involves cytochrome P450. 3. A drug, given as a 100-mg single dose, results in a peak plasma concentration of 20µg/mL. The

安微医科大学国际教育学院教案与讲稿 apparent volume of distribution is(assume a rapid distribution and negligible elimination prior to measuring the peak plasma level): A.0.5L B.IL. C.2L. D.5L E.10L 4.What's the definition of First-pass metabolism ·Half-life ·Bioavailability(F) ·Clearance(C) Volume of distribution (Vd) 5.A patient is overdosed with salicylic acid,which is a weak acid.How do you treat this patient in order to remove the drug faster from his blood. 6

安徽医科大学国际教育学院教案与讲稿 6 apparent volume of distribution is (assume a rapid distribution and negligible elimination prior to measuring the peak plasma level): A. 0.5 L. B. 1 L. C. 2 L. D. 5 L. E. 10 L. 4. What’s the definition of
First - pass metabolism
Half-life
Bioavailability (F)
Clearance (Cl)
Volume of distribution (Vd) 5. A patient is overdosed with salicylic acid, which is a weak acid. How do you treat this patient in order to remove the drug faster from his blood