integrated applied therapeutics: fundamentals of rational...

Pharmacy Education International © (2013): Enhancing Patient Lives Through Training Excellence

INTEGRATED APPLIED THERAPEUTICS:

FUNDAMENTALS OF RATIONAL PRESCRIBING

By

Michael F Perkin

All material Copyright Reserved © M.F. Perkin, and Pharmacy Education International cc 2013

S. A. Pharmacy Council Approved Provider Reg. No R00025S. A. Pharmacy Council Approved Provider Reg. No R00025

VOLUME 1: CLINICAL COMPONENTS OF DISPENSING:

Basics of Applied Pharmacotherapy and Therapeutics

Does patient understand his conditions and how meds work?

Any Adverse Reactions, Contraindications or Drug Interactions?

Medications Appropriate?Missing

Medications?

Effectiveness of past therapy???

Therapeutic Targets achieved?

POLYPHARMACY?Half Life? Dosing Interval?

Is the patient compliant?

Patient’s previous Medical and Drug history?

Does patient understand his conditions and how meds work?

Any Adverse Reactions, Contraindications or Drug Interactions?

Medications Appropriate?Missing

Medications?

Effectiveness of past therapy???

Therapeutic Targets achieved?

POLYPHARMACY?Half Life? Dosing Interval?

Is the patient compliant?

Patient’s previous Medical and Drug history?

INTEGRATED APPLIED

THERAPEUTICS:

FUNDAMENTALS OF

RATIONAL PRESCRIBING

________________________________________

COURSE TRAINING MANUAL

________________________________________

By

Michael F Perkin

By Optimising Drug Therapy through Training that Reinforces Clinical Skills of Health Professionals, PEI strives to improve the quality of life in the Community of Chronically Ill Patients

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INTEGRATED APPLIED THERAPEUTICS:

FUNDAMENTALS OF RATIONAL PRESCRIBING

COPYRIGHT M.F.Perkin, and Pharmacy Education International cc 2010 1 Meyer Street, Plumstead, 7800, Cape Town, SOUTH AFRICA P O Box 51, Bergvliet 7864, Cape Town, SOUTH AFRICA

FIRST Edition, First Impression April 2010

ISBN 978-0-620-47095-7

All rights reserved. No part of this publication or any supplement thereto may be printed, transmitted, or reproduced by any means, electronic, mechanical, or photographic or portrayed, translated, or included in any information storage and retrieval system, or used to print or otherwise reproduce a computer-generated interpretation without the prior written permission of the copyright holder. The copyright in this document and any software associated therewith, including but not restricted to the manuals and programmes in hard copy and in machine-readable form, vests in M.F.Perkin, and Pharmacy Education International cc in terms of the Berne Convention and Copyright Act 98 of 1978.

DISCLAIMER

In compiling this manual, every effort has been taken to ensure that the medical application of the information and material contained herein is as scientifically and technically accurate as possible. However, in view of the constant changes in medical science and in view of the possibility of human error, the author of this work does not accept responsibility for any errors or omissions thereof from the use or application of the information contained herein. The author furthermore disclaims all responsibility for any liability, loss, injury or damage incurred as a consequence, either directly or indirectly, of the use and application of any of the information contained in this training manual. Readers are therefore urged to confirm the information contained herein with other relevant clinical sources. In particular, when drug products are prescribed and used in treatment of the patient, practitioners should review the information contained in the manufacturer’s package insert and follow the manufacturer’s guidelines and recommendations contained therein.

SUPPLEMENTARY COURSE IN RATIONAL PRESCRIBING AND DISPENSING

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Integrated Applied Therapeutics: Fundamentals of Rational Prescribing ISBN:978-0-620-57868-4 Jan 2014: 2nd Edition

PHARMACY EDUCATION INTERNATIONAL© 2014: Enhancing Patient Lives through Training Excellence

Table of Contents

CHAPTER 1: RATIONAL PRESCRIBING AND CHRONIC DRUG USE......................................... 1

1) Poor Clinical Outcomes, Polypharmacy - the ‘Prescribing Cascade’ ....................................................2

2) Pharmacy Council’s Criteria that Define the act of ‘DISPENSING’........................................................4

3) High Risk Patients and High Risk Medications......................................................................................5

4) Approach to Case Analysis Part 1: Preliminary Case Workup ..............................................................7

4.1) Example Case: Patient George Mitchell..................................................................................7

4.2) Compile a Chronological Patient History ................................................................................9

5) Approach to Case Analysis Part 2: Systematic Assessment Procedure ..............................................14

5.1) Clinical Approach to assessing the effectiveness of Therapy................................................14

5.2) Consider Patient Age, Physiological Status and Clearence Capacity..................................... 14

5.3) Apply a Structured Procedure in Pharmacotherapy Assessment (SPIPA).............................15

5.4) SPIPA Quick Reference Summary Cards................................................................................17

5.5) Quantifying Appropriateness with the Medication Appropriateness Index.........................18

5.6) Using a PIVOT TABLE to identify Drug Interactions ..............................................................20

6) Approach to Case Analysis Part 3: Compiling a Case Report..............................................................21

7) Making Effective Use of the SAMF .....................................................................................................24

7.1) ATC Classification used by Medicine Formularies.................................................................24

7.2) General Layout of a Medicine Formulary THERAPEUTIC MONOGRAPH...............................24

7.3) Example THERAPEUTIC MONOGRAPH: Medications used in Diabetes ................................25

7.4) General Layout of a Medicine Formulary MEDICATION MONOGRAPH................................27

7.5) Example MEDICATION MONOGRAPH: Glibenclamide..........................................................27

7.6) Practical Application: Assessing Medication APPROPRIATENESS with SAMF.......................32

8) Case Study: Xolile Mguni ....................................................................................................................35

9) Assessment of the Prescription: Abridged Method ...........................................................................36

10) Factors that give rise to Inappropriate Prescribing ............................................................................37

10.1) Polypharmacy and the Prescribing Cascade .........................................................................37

10.2) Inappropriate Prescribing and the Prescribing Cascade .......................................................40

10.3) Brown Bag Reviews – Identifying Inappropriate Medication Use ........................................40

10.4) The C.A.R.E approach to avoiding the Prescribing Cascade..................................................41

10.5) Criteria that Define Inappropriate Prescribing .....................................................................42

10.6) Clinical Risk Factors for Inappropriate Prescribing ...............................................................43

INTEGRATED APPLIED THERAPEUTICS: FUNDAMENTALS OF RATIONAL PRESCRIBING


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10.7) Prescriber and Dispenser factors that lead to Inappropriate Prescribing ............................44

11) Clinical Approach to Rational Drug Use..............................................................................................46

11.1) Defining Rational Drug Use ...................................................................................................46

11.2) Clinical Instruments used to Asses the ‘Appropriateness’ of Prescribing.............................47

11.3.1) Beers Criteria ...................................................................................................................47

11.3.2) Screening Tool of Older persons Prescriptions (STOPP)..................................................48

11.3.3) The Medication Appropriateness Index (MAI) ................................................................48

11.3.4) The A.R.M.O.U.R. Tool .....................................................................................................48

11.3.5) Pallitive Algorithm for Improving Medication Therapy ...................................................50

12) Medication Withdrawal or Down-titration ........................................................................................51

12.1) General Aspects of Stopping Medications ............................................................................51

12.2) Medication–specific Guidelines for Stopping Medications ..................................................54

13) Medication Dosing in Patients with Compromised Disposition .........................................................55

13.1) Dosing in Patients with Renal Impairment............................................................................55

13.2) Dosing in Patients with Impaired Hepatic Function..............................................................62

13.3) Dosing in Elderly Patients......................................................................................................62

13.4) Dosing in Children .................................................................................................................66

CHAPTER 2 – ASSESSMENT OF PATIENT ADHERENCE ....................................................... 71

1) Introduction: ‘Compliance’ vs ‘Adherence’ ........................................................................................72

2) Magnitude of the Non-Adherence Problem.......................................................................................72

3) Forms of Non-Adherence ...................................................................................................................73

4) Causes of Non-Adherence ..................................................................................................................73

4.1) Patient factors affecting adherence......................................................................................74

4.2) Medication factors affecting adherence...............................................................................74

5) Management of Non-Adherence........................................................................................................75

5.1) Detecting Non-Adherence ....................................................................................................76

5.2) Identifying causes of Non-Adherence...................................................................................76

5.3) Developing a plan to manage Non-Adherence .....................................................................76

5.4) Monitoring the Non-Adherence Plan....................................................................................76

6) Assessing and Improving Non-Adherence..........................................................................................77

6.1) Monitoring Medicine Useage................................................................................................78

6.2) Determine if treatment goals are achieved..........................................................................78

6.3) Perform Pill Counts ...............................................................................................................78


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6.4) Question the Patient.............................................................................................................78

6.5) Patient Self-Report................................................................................................................79

7) Summary of factors that impact on Adherence .................................................................................79

8) Practical Adherence Assessment Instruments ...................................................................................81

8.1) Tablet Identification Test ......................................................................................................81

8.2) Regimen Adherence Scale.....................................................................................................82

8.3) Identifying Reasons for Missed Doses ..................................................................................83

8.4) Suggested Interventions for Missed Doses...........................................................................84

CHAPTER 3 PATIENT EDUCATION AND COUNSELLING...................................................... 87

PART 1 – GENERAL ASPECTS OF PATIENT COUNSELLING .................................................. 87

1) Patient Information Seeking Type ......................................................................................................88

2) ‘CORE’ Counselling Skills.....................................................................................................................88

2.1) Basic interviewing skills.........................................................................................................88

2.2) Facilitator technique .............................................................................................................89

3) Patient Demographics that Influence Education................................................................................90

4) The Patient Counselling Interview......................................................................................................92

4.1) Initiating the interview..........................................................................................................92

4.2) Explaining the medical condition(s) ......................................................................................93

4.3) Explaining the Treatment......................................................................................................94

PART 2 – BEHAVIOUR CHANGE COUNSELLING ................................................................103

1) Process Orientated vs Patient-Orientated Healthcare.....................................................................104

2) Behaviour Change Counselling Models ............................................................................................105

2.1) The Trans–Theoretical Model of Lifestyle behaviour Change ....................................................105

2.2) Motivational Interviewing Model of Behaviour Change.............................................................107

2.3) Practical Realities of the Behavior Change Cycle ........................................................................108

3) Behaviour Change Counselling - Background...................................................................................109

3.1) Underlying Philosophy of Behaviour–Change Counselling .........................................................109

3.2) Dynamics of Behaviour–Change Counselling..............................................................................111

3.3) Evidence for the Effectiveness of Behaviour–Change Counselling.............................................114

4) Practical Aspects of Behaviour-Change Counselling ........................................................................115

4.1) False Assumptions about Behaviour–Change Counselling .........................................................115

4.2) REFLECTIVE LISTENING – VITAL for effective Behaviour Change................................................115

4.3) EMPATHY – the KEY COMPONENT of Behaviour–Change Counselling.......................................116



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4.4) Seven Pillars of Behaviour–Change Counselling .........................................................................118

4.5) Critical Components of Behaviour–Change Counselling.............................................................119

5) Implementing Behaviour Change Counselling..................................................................................121

5.1) Obstacles to Behaviour–Change Counselling......................................................................121

5.2) Setting S.M.A.R.T Lifestyle behaviour Change Goals ..........................................................121

5.3) Roles of Patient and Counsellor in Goal Setting .................................................................122

5.4) The Plan–Implement–Review–Improve (P I R I ) Cycle: ......................................................123

5.5) Lifestyle behaviour Change Management: The 5A Cycle....................................................125

5.6) The BRIEF NEGOTIATION INTERVIEW (BNI) ........................................................................126

5.7) Assessing Patient Readiness to Change: THE DECISION BALANCE .....................................128

5.8) Setting Priorities..................................................................................................................128

5.9) What to do and when to do it.............................................................................................129

5.10) SPECIFIC STEPS IN THE PRACTICAL COUNSELLING PROCESS ..............................................131

6) Rating the Counsellor – Patient Interview........................................................................................141

6.1) Counsellor Communication Rating .....................................................................................141

6.2) Patient Self-Exploration Rating ...........................................................................................146

6.3) Likert Scale Ratings .............................................................................................................148

CHAPTER 4: REVIEW OF THE LADME ASPECTS OF DISPOSITION.......................................149

1) Introduction – the LADME processes of Disposition ........................................................................150

2) Passage of medications across membranes.....................................................................................151

2.1) Lipid Diffusion .....................................................................................................................151

2.2) Carrier Transport.................................................................................................................151

3) LIBERATION of the medication from the dosage form.....................................................................156

4) ABSORPTION of medication from its Administration Site ................................................................157

4.1 Factors affecting gastrointestinal absorption of oral dose forms..........................................158

4.2 Importance of Gastric Emptying Rate on drug absorption ....................................................159

5) DISTRIBUTION of the medication in the body compartments .........................................................160

5.1) Clinical example of how a drug is distributed - Metformin ................................................161

5.2) Protein Binding: How it affects activity and distribution of drugs......................................162

5.3) ‘Ion Trapping’ – how drugs can accumulate in body fluids.................................................163

5.4) Distribution across the Blood-Brain Barrier ........................................................................163

6) METABOLISM of Drugs .....................................................................................................................164

6.1) Metabolism Pathways.........................................................................................................164


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6.1.1) Phase 1 Metabolism ......................................................................................................165

6.1.2) Phase 2 Metabolism ......................................................................................................166

6.1.3) Using Aspirin to illustrate the steps in drug Metabolism .............................................. 167

6.1.4) Formation of Toxic Drug Metabolitse: Paracetamol .....................................................168

6.2) Introduction to the Cytochrome P450 Enzyme System......................................................168

7) ELIMINATION (Excretion) of Drugs ...................................................................................................170

7.1) Renal Excretion ...................................................................................................................171

7.2) Hepatic and Biliary Excretion ..............................................................................................172

7.3) Salivary Excretion ................................................................................................................172

7.4) Lung excretion.....................................................................................................................172

CHAPTER 5 – CLINICAL ASPECTS OF DRUG INTERACTIONS...............................................173

CHAPTER 5 - CLINICAL ASPECTS OF DRUG INTERACTIONS: PART 1 ..................................174

1) Introduction......................................................................................................................................174

2) Important Aspects in Managing Drug Interactions ..........................................................................175

2.1) High Risk Drugs and High Risk Patients ...............................................................................175

2.2) How to predict the number of possible Interactions in Polypharmacy ..............................176

2.3) Onset time of a drug interaction.........................................................................................177

3) Assessment of Drug Interaction Risk................................................................................................178

4) Practical Management of Drug Interactions ....................................................................................179

5) Classification and examples of Drug Interactions ............................................................................180

5.1) Pharmaceutical Interactions ...............................................................................................181

5.2) Pharmacodynamic Interactions ..........................................................................................181

5.2.1) Interaction at Receptors .....................................................................................................181

5.2.2) Interaction on a Physiological System ................................................................................182

5.2.3) Interactions on Intracellular Transport mechanisms..........................................................182

5.2.4) Interactions involving fluid and electrolyte balance...........................................................185

5.3) Pharmacokinetic Interactions ....................................................................................185

5.3.1) ABSORPTION INTERACTIONS ..............................................................................................185

5.3.2) DISTRIBUTION INTERACTIONS ............................................................................................191

5.3.3) METABOLISM INTERACTIONS .............................................................................................193

5.3.3) CYP 450 Summary Interaction Chart: Substrates-Inhibitors-Inducers................................203

5.3.4) ELIMINATION INTERACTIONS..............................................................................................205



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CHAPTER 5 - CLINICAL ASPECTS OF DRUG INTERACTIONS: PART 2 ..................................207

1) Top 10 Drug Interactions..................................................................................................................207

2) Important Clinical Points on CYP 450 Interactions...........................................................................209

3) Cinical Points to note on CYP 450 Interactions when Prescribing....................................................209

3.1) Important Prescribing Points on Metabolic Inhibition........................................................210

3.2) Important Prescribing Points on Metabolic Induction........................................................211

3.3) Combining Medications to Produce ‘Beneficial’ Interactions.............................................211

4) POLYMORPHIC CYP450 Variant Alleles: Clinical Implications...........................................................212

4.1) Cytochrome P450 Variant Allele Nomeclature ...................................................................212

4.2) Genetic Variation: Existence of different Forms of an Enzyme .......................................... 212

4.3) Polymorphism: The 4 Metabolic Phenotypes .....................................................................213

5) Polymorphic CYP450 Variants: How they are Inherited...................................................................218

6) Distribution and Clinical Consequences of Mutant CYP450 Alleles .................................................220

7) Important Clinical Points on CYP1A2................................................................................................222

8) Important Clinical Points on CYP2 Isoenzymes ................................................................................223

8.1) Important Clinical Points on CYP2C9...................................................................................223

8.2) Pharmacogenetics of WARFARIN DOSING: CYP2C9, CYP4F2 and VKOR.............................225

8.2.1) Warfarin: Factors that give rise to Variability in Patient Response ....................................225

8.2.2) Pharmacogenetics of Warfarin Dosing: PHARMACODYNAMIC ASPECTS ...........................227

8.2.3) Pharmacogenetics of Warfarin Dosing: PHARMACOKINETIC ASPECTS ..............................229

8.2.4) Predicting Warfarin Dose: Pharmacogenetic Modelling.....................................................232

8.2.5) Pharmacogenetics of Warfarin Dosing: Effect of Obesity...................................................232

8.2.6) Warfarin Dosing Algorithm: Variable Times to Steady State ..............................................232

8.2.7) Factors that increase Sensitivity to Warfarin......................................................................235

8.2.8) Warfarin Interactions by Drug Class ...................................................................................235

9) Important Clinical Points on CYP2C19..............................................................................................236

10) Important Clinical Points on CYP2D6................................................................................................237

11) Important Clinical Points on CYP3A..................................................................................................239

CHAPTER 6 – ADVERSE REACTIONS ................................................................................243

1) Terminology relating to ‘Unwanted’ Drug Actions...........................................................................244

2) The Economic Burden of Adverse Reactions....................................................................................246

3) Predisposing Factors for an Adverse Drug Reaction ........................................................................246

4) Incidence (rate of Occurrence) of ADR’s ..........................................................................................247


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5) ‘SERIOUSNESS’ versus ‘SEVERITY’ of an Adverse Reaction...............................................................251

5.1) Seriousness of an Adverse Reaction ...................................................................................252

5.2) Severity of an Adverse Reaction .........................................................................................252

6) Factors that RAISE SUSPICION about the PRESENCE of an ADR.......................................................254

7) Factors to consider when investigating Causality of an ADR ...........................................................254

8) Criteria that Define Causality of an ADR...........................................................................................256

9) Clinical Instruments used Assess Causality of an ADR......................................................................258

9.1) The Naranjo Scale ...............................................................................................................258

9.2) The 5 – Point Probability Scale............................................................................................260

10) Reporting Adverse Drug Reactions...................................................................................................261

10.1) Misconceptions about reporting Adverse Drug Reactions ................................................. 261

10.2) Official Adverse Reaction Reporting and Report Form.......................................................262

11) Classification and Mechanisms of Adverse Reactions......................................................................263

11.1) PREDICTABLE ADVERSE REACTIONS....................................................................................264

11.1.1) TYPE A (Augmented) Adverse Reactions.....................................................................264

11.1.2) TYPE C (Chronic) Adverse Reactions............................................................................266

11.1.3) TYPE D (Delayed) Adverse Reactions...........................................................................267

11.1.4) TYPE E (End of Dose) Adverse Reactions.....................................................................268

11.1.5) TYPE F (Failure to produce a Clinical Response) Adverse Reactions ...........................269

11.1.6) TYPE G (Genetic) Adverse Reactions ...........................................................................270

11.2) UNPREDICTABLE ADVERSE REACTIONS ..............................................................................271

11.2.1) Pharmacogenetic Adverse Reactions ..........................................................................272

11.2.2) Hypersensitivity (‘Allergic’) Adverse Reactions ...........................................................272

11.2.2.1) Components of the Immune System involved in Hypersensitivity ADR’s ................272

11.2.2.2) Hypersensitivity Reactions: Classification by Gell and Coombs Criteria ..................275

11.2.2.3) General Aspects of Hypersensitivity Reactions........................................................276

11.2.2.4) Type I Hypersensitivity: Anaphylactic or Immediate ADR’s .....................................278

11.2.2.5) Type II Hypersensitivity: Cytotoxic ADR’s.................................................................282

11.2.2.6) Type III Hypersensitivity: Immune Complex Mediated ADR’s..................................283

11.2.2.7) Type IV Hypersensitivity: Cell Mediated (Delayed Type) ADR’s ............................... 285

11.2.2.8) Type V Hypersensitivity ADR’s..................................................................................287

11.2.3) Pseudo-Allergic Reactions ........................................................................................288

12) Summary Table: - Examples of Adverse Reactions...........................................................................289



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13) Official Adverse Reaction Reporting and Report Form ....................................................................291

14) Clinical Guide to Selected Adverse Drug Reactions (requires download) .......................................292

CHAPTER 7: – APPLIED CLINICAL PHARMACOKINETICS ...................................................293

1) Importance of Applied Pharmacokinetics to Clinicians....................................................................294

2) Overview: Basic Principles of Clinical Pharmacokinetics ..................................................................294

3) Bioavailability, Bioequivalence and BioInequivalence .....................................................................296

3.1) Bioavailability ......................................................................................................................296

3.2) Bioequivalence....................................................................................................................296

3.3) Bio-Inequivalence................................................................................................................297

4) Variation in Plasma Drug Concentration with Time .........................................................................298

4.1) MEC and MTC: Define Onset, Duration and Intensity of Clinical Effect..............................298

4.2) Therapeutic Index and Dose Response Curves ...................................................................299

5) Body Compartments.........................................................................................................................301

5.1) The Body as One Compartment – Majority (>90%) of Drugs..............................................302

5.2) The Body as Two or More Compartments ..........................................................................303

6) Volume of Distribution (Vd) .............................................................................................................304

6.1) Understanding what is meant by ‘Apparent’ Volume of Distribution ................................304

6.2) Clinical significance of Volume of distribution....................................................................307

7) Quantifying the Rate ( Kinetics) of Drug Elimination........................................................................311

7.1) First Order (Linear) Elimination: Results in a CONSTANT Drug ‘Half Life’...........................311

7.2) Zero Order (Non Linear) Elimination: Drug ‘Half Life’ is NOT CONSTANT...........................313

7.3) Comparing First Order and Zero Order Elimination............................................................315

7.4) Mixed Order Elimination: Results in UNPREDICTABLE Drug Plasma Levels........................315

8) Factors that determine Dose and Dose–Interval .............................................................................319

8.1) Time for drug plasma level to reach a plateau or Steady State ..........................................319

8.2) Time for drug plasma level to drop from Steady State.......................................................320

8.3) Time taken for Plasma Steady State to change when dose is changed..............................320

8.4) Differences in Css with DIFFERENT doses given at the SAME dose interval .......................321

8.5) Differences in Css with the SAME doses given at DIFFERENT dose intervals .....................321

8.6) Loading Dose – Used to achieve Steady State Concentration rapidly ................................322

8.7) Effect of half-life on dose interval to achieve a sustained 24 hour response.....................322

8.8) The Shape of the Dose-Response Curve .............................................................................323

8.9) Factors to be aware of when titrating doses ......................................................................324


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8.10) Time Interval before a ‘Steady State’ clinical response is achieved ................................... 324

9) Working with Multiple Oral Dosing Regimens .................................................................................325

9.1) Drug Accumulation..............................................................................................................325

9.2) Estimating Plasma Concentrations and Doses with Multiple Oral Dosing..........................327

9.3) Estimating Trough and Peak Fluctuations with Multiple Oral Dosing ................................329

CHAPTER 8 – PHARMACOMEDICAL CALCULATIONS ........................................................331

1) Background.......................................................................................................................................332

1.1) Paracetamol Overdose: Why Competency in Calculations is Important ............................333

1.2) Paracetamol Overdose: Calculation Errors are a Universal Problem..................................334

2) Review of the Metric System............................................................................................................335

2.1) The Metric System and Commonly Used Prefixes ..............................................................335

2.2) Metric Units: Length (Km) (m) (cm) (mm) (mcm) ...............................................................336

2.3) Metric Units: Volume (L) (mL) (mcL) ...................................................................................336

2.4) Metric Units: Mass (Kg), Gram (g), Milligram (mg), Microgram (mcg) ...............................337

2.5) Performing Calculations: Convert quantities to the SAME UNITS ......................................337

3) Metric Conversions: Converting into Larger or Smaller Units .........................................................338

4) Manipulating Equations: Changing the Subject of a Formula ..........................................................339

5) Medicine Mixtures: Different ways to express Concentrations .......................................................341

5.1) Types of Medicine ‘Mixtures’..............................................................................................341

5.2) Different ways of expressing concentration in a ‘Mixture’.................................................341

6) Ratios and Proportions: Basis of most Dose Calculations.................................................................344

6.1) Ratios...................................................................................................................................344

6.2) Proportions .........................................................................................................................344

6.3) Percentage Calculations: Same as Proportions but Quantity is out of 100 ........................346

6.4) Percentage Calculations: ALWAYS convert Units to Grams................................................ 348

7) Calculating Concentration of a Liquid after Dilution ........................................................................349

8) Calculating Administration Rates of Intravenous Solutions .............................................................349

FLOW RATE of an IV Solution administered by a Perfusion Pump ................................................349

FLOW RATE of an IV Solution administered by an Administration Set..........................................350

APPENDIX: SOLMUCOL - ACETYLCYSTEINE PRODUCT INFORMATION ................................351


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CHAPTER 1: RATIONAL PRESCRIBING AND CHRONIC DRUG USE

Prescribing Cascade; Approach to Case Analysis; Compiling a Medical

History; Assessing Effectiveness of Therapy; Medicine Formularies; Criteria

for Rational Medication Use; Practical Guide to Medication Withdrawal or

Down Titration; Dosing in Patients with Compromised Elimination

OBJECTIVES ___________________________________________ After completing this chapter you should, 1) Be aware of the factors that give rise to what is

described as the ‘Prescribing Cascade’.

2) Be able to ‘Tease Out’ a problematic patient case

by compiling a systematic case history

3) Understand the architecture and layout of a

Medicines Formulary and how to use it to to achieve

Rational Medicine Use (RMU)

4) Be able to conduct a a Structured Procedure in

Pharmacotherapy Assessment (SPIPA) to review the

appropriateness of medications in a regimen

5) Be aware of the Medication Appropriateness Index

(MAI) as a quantitative measure of appropriate

prescribing and to consider ways to adapt the MAI so

that it is practical to implement in daily practice

6) Be aware of the factors that give rise to

Inappropriate Prescribing as well as the criteria that

define inappropriate prescribing

7) Be aware of the negative consequences of

polypharmacy on patient quality of life and of the

C.A.R.E. approach to minimize Polypharmacy

8) Know the criteria that define RMU as well as the explicit and implicit clinical instruments used to

assess appropriateness of prescribing

9) Be familiar with the practical aspects of medication withdrawal or down-titration

10) Be aware of the need to modify doses in patients with compromised disposition

CHAPTER OVERVIEW

___________________

The objective of this chapter is to equip practitioners with the foundation that underpins the basic

fundamentals of Appropriate Prescribing and Rational Medication Use.

Two example patient cases are used as practical learning exercises to reinforce the clinical

applications covered in this Chapter

� Poor clinical outcomes and the

‘Prescribing Cascade’,

� Criteria that define ‘DISPENSING’

� High Risk Patients and Medication

� Approach to Clinical Case Analysis

� Structured Procedure In

Pharmacotherapy Assessment

(SPIPA)

� Making Effective Use of the SAMF:

� Factors that give rise to

Inappropriate Prescribing

� Clinical Approach to Rational

Medication Use

� Medication Withdrawal or Down-

titration

� Dosing in Patients with Compromised

Disposition



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1) Poor Clinical Outcomes, Polypharmacy - the ‘Prescribing Cascade’

Poor Clinical Outcomes

Despite modern medications and technology the reality is that modern medicine is loosing the battle

against chronic illness. The following figures are the percentages of the South African population that

suffer from chronic diseases of lifestyle;

From this it is clear that however much we would like to convince ourselves otherwise - the reality is

that the healthcare we provide is failing our patients and costing an enormous amount of money.

Polypharmacy and the ‘Prescribing Cascade”

An idea of the magnitude of the magnitude of the polypharmacy problem is reflected in a study

(Spinewine A. et al; J Am Geriatr Soc. 2007; 55: 658-65) on patients admitted to an acute geriatric

ward. In this study;

� 60% of prescriptions had at least 1 inappropriate rating

� 30% of the patients were taking one or more medications that should be avoided

� In 50% of the patients there was one or more than 1 event of under-prescribing

Morbidity % of the South African population affected

Hypertension 21% - 1998

± 40% - 2013 (age group dependent)

CHD 5 – 7% population 65+yrs – 2001

Diabetes

5% - 2001

Projected 20% by 2020

10% - Women 65+ years - 2001

5% - Men 65+ years - 2001

High Cholesterol 5 767 205 sufferers - 2001

AIDS

1% - 1990

25% - 2001

30% - 2006

Asthma 12-16%(2001)

Projected 20% by 2010

Arthritis 40% - Women 65+ years - 2001

25% - Men 65+ years - 2001

TB 5% - 2001


Page 3



Polypharmacy is often the consequence of inappropriate prescribing that leads to the ’Prescribing

Cascade’. This results when medications are prescribed on an add-on basis when patients present with

symptoms which are medication-induced.

The prescribing cascade should be a flag for

medication review, because it is, very often,

associated with problems of medication management

and suboptimal prescribing.

Polypharmacy is not a clinically useful independent

marker of the quality use of medicines. The type and

dose of medications rather than the number of

medications determine meaningful clinical outcomes

THE PRESCRIBING CASCADE

“As older patients move through time,

often from physician to physician, they

are at increasing risk of accumulating

layer upon layer of drug therapy, as a

reef accumulates layer upon layer of

coral.”

Jerry Avorn, MD

MODULE 2 – ASSESSMENT OF PATIENT ADHERENCE

Page 71



CHAPTER 2 – ASSESSMENT OF PATIENT ADHERENCE

Compliance versus Adherence; Incidence of Non-adherence; Causes of Non-adherence; Detecting Non-adherence; Management of Non-

adherence; Compliance Assessment Tools

OBJECTIVES ___________________________________________ After completing this chapter you should,

1) Know how to detect non-adherence in a patient

2) Be aware of the factors that give rise to non-

adherence

3) Be able to use clinical tools that aid in the

detection and assessment of non-adherence

4) Be able to suggest interventions that improve

patient compliance

CHAPTER OVERVIEW

___________________

This chapter provides practical information on the detection and management of non-

adherence. It deals with the incidence, causes and detection of non-adherence.

Factors that assist in the management of non-adherence are discussed. Three clinical tools

that aid in the detection of non-adherence and the underlying reasons therefore are

presented.

A method of identifying practical interventions that enables the clinician to manage non-

compliant patients is also provided.

1) Compliance vs. adherence

2) Incidence of non-adherence

3) Forms of non-adherence

4) Causes of non-adherence

• Patient factors

• Medication factors

5) Detecting non-adherence

6) Management of non-adherence

• Positive factors

• Negative factors

7) Compliance assessment and

management tools

• Pills Identification Test (PIT)

• Regimen adherence scale

• Identifying reasons for non-adherence

MODULE 3: PATIENT EDUCATION AND COUNSELLING

Page 87



CHAPTER 3 PATIENT EDUCATION AND COUNSELLING

PART 1 – GENERAL ASPECTS OF PATIENT COUNSELLING

OBJECTIVES ___________________________________________ After completing this section you should,

1) Understand patterns information seeking

behavior

2) Be aware of basic interviewing skills

necessary to communicate effectively with

patients

3) Be aware of the factors that influence

patient education

4) Be aware of how a patient counselling

interview should be structured

5) Be aware of aspects that enhance patient

education

6) Be aware of the didactic criteria for

preparing a patient information leaflet

SECTION OVERVIEW

___________________

This section deals with all the factors that the South African Pharmacy Council consider

essential in achieving effective patient education.

Techniques for the counsellor as well as factors that influence patient attitude to

education are presented in a concise and practical manner.

1) Patient information-seeking behavior

2) Basic interviewing skills

3) Optimizing patient education

4) Factors Influencing patient education

• Age

• Ethnicity

• Family circumstances

• Socioeconomic status

5) Structure of the patient education

interview

• Initiating the interview

• Explaining the medical conditions

• Explaining the treatment

• Lifestyle education

• Medication education

• Summarising the interview

6) Aspects that enhance patient education

7) Patient information checklist

8) Patient Information leaflets

MODULE 4: REVIEW OF THE LADME ASPECTS OF DISPOSITION

Page 149



CHAPTER 4: REVIEW OF THE LADME ASPECTS OF DISPOSITION

Mechanisms of drug passage across biological membranes;

Liberation of drugs from dosage forms;

Distribution, Metabolism and Excretion of Drugs


1) Understand the processes by which drugs cross

body membranes

2) Understand how cells become ‘immune’

(develop resistance) to the biological action of

drugs

3) Understand how drugs are absorbed and factors

that affect the rate of absorption

4) Understand the factors that affect the

distribution of drugs to different parts of the

body

5) Understand the process of metabolism and how

it affects drug action.

6) Understand how drugs are eliminated from the

body by the processes of metabolism and

excretion

SECTION OVERVIEW

___________________

This section reviews the fundamental factors that control the duration and the magnitude

of action of drugs in the body because they govern the rate and extent of drug input

(absorption) and output (elimination) from the body. These factors are referred to as the

disposition of drugs – how they are absorbed, distributed, metabolised and eliminated from

the body.

This section has been included in the Manual for those who feel the need for a refresher on

this topic. The purpose of including this brief overview of Disposition at this point is to enable

counsellors to better understand the following chapter which deals with the practical clinical

aspects of identifying and managing drug interactions.

Liberation of drug from dosage form

Passage of drugs across membranes

• Passive lipid diffusion

• Carrier transport

• Active transport

Effect of pH on drug distribution

Absorption of drugs

Distribution of drugs

Metabolism of Drugs

• Phase 1 metabolism

• Phase 2 metabolism

• Formation of toxic metabolites

• Enzyme induction

• Enzyme inhibition

Excretion of drugs

• Renal excretion

• Hepatic and Biliary excretion

MODULE 5: CLINICAL ASPECTS OF DRUG INTERACTIONS

Page 173



CHAPTER 5 – CLINICAL ASPECTS OF DRUG INTERACTIONS

This module is divided into 2 parts

Part 1: Principles of Management of Drug Interactions; Main Categories

and Classification of Interactions; Clinically Important Interactions;

Genetic factors that influence Interactions

Part 2: Selected Clinical Topics on Metabolism and Drug Interactions;

Summary Drug Metabolism Charts: Substrates Inhibitors Inducers

OBJECTIVES ___________________________________________ After completing this Part 1 of this Module you should, 1) Understand the mechanisms of the different types

of drug interactions

2) Be able to predict the possibility of a drug

interaction occurring

3) Be aware of how the onset time and severity of a

drug interaction is influenced by the

pharmacokinetic properties of the drugs involved

4) Be aware of the clinical approach used to manage

drug interactions

5) Understand the systematic Classification of Drug

Interactions

6) Understand the genetic basis by which patients

may manifest markedly different clinical

responses to certain drugs.

CHAPTER OVERVIEW

___________________

This chapter deals provides an understanding of

the underlying mechanisms of the different types of

drug interactions. This enables the clinician to be able to predict the possibility of a drug

interaction occurring.

The variation in onset time and severity of drug interactions that arise from the

pharmacokinetic properties of drugs is explained. A guide is provided to the clinical approach

used to manage drug interactions. The genetic basis for interpatient differences in clinical

response to many medications is also explained.

PART 1

Introduction

Important Clinical Aspects

� High risk drugs and patients

� Predicting the number of possible

interactions in a regimen

� Interaction onset time

Assessing Drug Interaction Risk

Practical Management of interactions

Classification of drug interactions

1) Pharmaceutical interactions

2) Pharmacodynamic interactions

3) Pharmacokinetic interactions

• Absorption

• Distribution interactions

• Metabolic interactions

� Genetic Polymorphism

� Enzyme induction

� Enzyme inhibition

• Elimination interactions

MODULE 6: ADVERSE DRUG REACTIONS

Page 243



CHAPTER 6 – ADVERSE REACTIONS

Definition; Predisposing Factors; Onset and Severity; Incidence;

Identification and Causality; Management; Classification and Mechanisms


1) Be aware of the predisposing factors that

increase susceptibility to an ADR

2) Be able to correctly define and classify an

adverse event

3) Be able to classify the severity of an ADR –

i.e. be able to differentiate between

serious and severe adverse events

4) Know the criteria that establish the

probability of an ADR – i.e. be able to

evaluate the causal relationship between

an adverse event and a drug

5) Be able to identify, assess and manage an ADR

6) Be aware of the underlying mechanisms

that give rise to ADR’s and the different

TYPES of ADR’s.

CHAPTER OVERVIEW

___________________

This chapter provides a basis for an understanding of Adverse Drug Reactions (ADR’s).

Their underlying mechanisms are explained, as well as their classification, incidence,

potential severity, and time course.

Instruments for their assessment and identification include the CTCAE 5 Point Severity

Scale as well as the Naranjo and 5 Point Probability Ratings to establish Causality.

1) What is an Adverse Drug Reaction?

2) Predisposing Factors for an ADR

3) Onset and Severity of Adverse Reactions

4) Common Diseases in patients suffering an

ADR

5) Incidence of ADR’s by Drug Class, Organ

System and Categories of Occurrence

6) Identification of an Adverse Reaction

7) Clinical Instruments used Assess Causality

8) Management of Adverse Reactions

9) Classification and Mechanisms of ADR’s

(i) Predictable Adverse Reactions

� Type A (Augmented) Reactions

� Type B, C, D, E, and F reactions

(ii) Unpredictable Type B (Bizarre) ADR’s

� Pharmacogenetic reactions

� Allergic (Hypersensitivity)

reactions

� Pseudo-Allergic Reactions

10) Summary Table: - Examples of ADR’s 11) Adverse Reaction Reporting

MODULE 7: APPLIED CLINICAL PHARMACOKINETICSS

Page 293



CHAPTER 7: – APPLIED CLINICAL PHARMACOKINETICS

Bioequivalence and Bioinequivalence; Variation in Plasma Concentration

with Time; Compartment Models and Volume of Distribution; Elimination

Kinetics and Half-life; Dose and Dose-interval; Multiple Dosing Regimens

OBJECTIVES ______________________________________

After completing this chapter you should,

1) Understand how concentration of drug in the

circulation varies over time.

2) Understand how the body can be regarded as

different ‘compartments’ that drugs move

into and out of.

3) Understand how the concentration of drug

and the duration of drug action in the body

can be quantified by the RATE (‘kinetics’) of

drug elimination from the body

4) Understand the concept of drug ‘HALF-LIFE’

(t½) and how this relates to the

CONCENTRATION of drug in the body.

5) Understand how knowledge of the half-life of

a drug is applied in clinical practice to

decide on dose and dose interval for patient

drug regimens.

6) Be able to APPLY the fundamental principles

of Pharmacokinetics when working with

MULTIPLE DOSING REGIMENS

CHAPTER OVERVIEW

___________________

This chapter quantifies the disposition of drugs in the body by considering the rate of

elimination of drugs from the body.

This enables clinicians to make informed decisions on drug doses and dosing intervals

when initiating or changing drug therapy - rather than use a haphazard approach.

Most importantly, it enables one to predict and prevent potentially serious problems

when changes are made to patient drug therapy.

APPLIED PHARMACOKINETICS

1) The importance of Pharmacokinetics

2) Basics of Applied Pharmacokinetics

3) Bioequivalence & Bioinequivalence;

4) Variation In Plasma Concentration with Time

• Minimum Effective Concentrations

• Minimum Toxic Concentration

5) Body ‘Compartments’ into which drugs

distribute

6) Volume of Distribution

7) Drug Elimination Rates (Kinetics)

7.1) First order elimination (most drugs):

Enables Half-life (T½) to be computed.

� T½ controls dose & dosing interval for

most drugs

� T½ governs time taken for drug

concentration to stabilize with an

increase or decrease in dose

� T½ is the time it takes for the plasma

concentration of a drug drop by 50%

7.2) Zero and Mixed order elimination

(Alcohol, Phenytoin and Theophylline)

8) Factors determining Dose & Dose Interval

9) Working with Multiple Dosage Regimens

MODULE 8: PHARMACOMEDICAL CALCULATIONS

Page 331



CHAPTER 8 – PHARMACOMEDICAL CALCULATIONS

OBJECTIVES ___________________________________________ The objective of this chapter is that Health

Practitioners gain practical knowledge of Metric

Conversions and Medical Calculations that renders them

fully competent to administer medicine doses with

accuracy and confidence in a variety of clinical

situations.

After completing this chapter you should be familiar

with the following:-

1) Metric Conversions - Conversion of Amounts and

Units in the Metric System

2) Calculation of the quantities of medicine to

supply on a prescription when given a prescribed

dose, dose-interval and duration of treatment

3) Ratio Calculations – how to calculate

� the percentage concentration of a component

in a given medicinal preparation

� the dose of drug to be administered to

patient based on doses stated in dose/Kg

� the dose of drug to be administered to

patient based on doses stated in dose/m2

� the volume of injection required to

administer a prescribed dose

4) Calculation of the Concentrations of liquids or

Solids after Dilution

� Calculation of the amount or concentration of

a given solution that is required for the preparation of a dilute solution.

5) Calculation of Doses and Administration Rates of Injections and Intravenous Solutions

6) Calculation of Important Clinical Values including

� Body Mass Index (BMI)

� Waist to Hip Ratio (W/H)

� Glomerular Filtration Rate (GFR)

� Body Surface Area (BSA)

1) Background - a universal problem:

Overdose and Calculation errors

2) Review of the Metric System

� Common Metric Prefixes

� Units of Length, Volume and Mass

� In all Calculations – be sure to

convert quantities to the SAME

UNITS

� Converting into Larger or Smaller

Metric Units

3) Changing the Subject of a Formula

4) Different types of Medicine Mixtures

and ways to express Concentrations

5) Ratios and Proportions:

� Basis of most Dose Calculations

Percentage Calculations: Same as

Proportions but Quantity is out of

100

6) Calculating Concentration of a Liquid

after Dilution

7) Calculating Administration Rates of

Intravenous Solutions administered by

perfusion pump or admin set

integrated applied therapeutics: fundamentals of rational...

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