Therapeutics and Medicines Use PDF

Therapeutics Medicines Use Dr Patricia Vella Bonanno 1 Pharmacokinetics and biopharmaceutics - pharmacokinetics and pharmacodynamics - different routes of administration - - plasma concentration time curves 2...

Therapeutics Medicines Use Dr Patricia Vella Bonanno 1 Pharmacokinetics and biopharmaceutics - pharmacokinetics and pharmacodynamics - different routes of administration - - plasma concentration time curves 2  Use of medicines Main factors which determine whether or not a drug will reach its intended site of action and have its intended effect: - Bioavailability of the drug - Pharmacokinetics - Pharmacodynamics - Route of administration 3  Biopharmaceutics Dosage forms and dosage form design LADME as applicable to different routes of administration Initiation of treatment and achievement/maintenance of steady state Therapeutic window Plasma concentration against time curves for different dosage forms administered by different routes of administration 4  Routes of administration of medicines Gastro-intestinal Skin tract Oral buccal Vascular Topical preparations mouth system s.c. injection i.m. injection Circulatory system stomach i.v. injection (drug or metabolites) Small Vascular Direct Lungs intestine system or Large Hepato- Vascular Aerosols intestine enteric system Gases Rectal rectum rectal preparations Drug or metabolite in tissues and extra cellular fluid Drug in Drug in faeces Kidneys saliva, exhaled air Drug in etc. urine Excretion and elimination Schematic diagram illustrating pathways a medicine may take following 5 administration of a dosage form by different routes 6 7 8  Administration of medicines Medicine – active ingredient plus excipients Dosage forms Routes of administration 9 Range of dosage forms for different routes of administration Route of Dosage forms administration Oral Solutions, syrups, elixirs, suspensions, emulsions, gel, powders, granules, capsules, tablets rectal Suppositories, ointments, creams, powders, solutions topical Ointments, creams, pastes, lotions, gels, solutions, topical aerosols parenteral Injections (solutions, suspensions, emulsion forms), implants, irrigation and dialysis solutions lungs Aerosols (solution, suspension, powder, emulsion forms), inhalations, sprays, gases nasal Solutions, inhalations eye Solutions, ointments ear Solutions, suspensions, ointments 10  Liberation and absorption of a medicine from a tablet Increase in effective surface area of medicine exposed to gastrointestinal fluids Intact tablet disintegration Granules deaggregation Primary drug particles Low rate of Moderate rate Relatively rapid rate of drug dissolution of drug drug dissolution dissolution Drug in solution in gastrointestinal fluid Absorption Drug in blood Factors influencing drug absorption from the GIT and bioavailability: physiological, pH, intestinal 11 motility, other medicines, food interaction, solubility of the drug, type of dosage form  Bioavailability Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action. Applicable to medicines which exhibit a systemic effect Considering that the substance in the general circulation is in exchange with the substance at the site of action 12  Absolute and relative bioavailability Bioavailability from different dosage forms Bioavailability from intravenous (i.v.) injections is 1 ‘Absolute bioavailability’ of a given dosage form as compared with that (100%) following intravenous administration (e.g. oral solution vs i.v. injection) ‘Relative bioavailability’ of a given dosage form as compared with another form administered by the same or another non intravenous route (e.g. tablets vs oral solution) 13  Pharmacokinetic and pharmacodynamic considerations for the design of a dosage regimen Pharmacokinetics Pharmacodynamics Dosage Plasma Site of Effects regimen concentration action Plasma drug concentration-time data is used as Effects produced are used as feedback to feedback to modify the dosage regimen for some achieve optimal therapy medicines as indicated 14 Pharmacokinetics and pharmacodynamics 15  Pharmacokinetics Pharmacokinetics - how the body handles the drug Liberation – of medicine from its dosage form Absorption – the process of drug movement from the site of application towards the systemic circulation. When a drug is administered intravenously it is placed directly in the blood stream. Absorption from the GI tract is affected by: - gastric acid secretion - bile salt formation - gastric emptying time - intestinal motility - bowel length and effective absorptive surface - microbial flora 16  Pharmacokinetics Distribution – after entering the general circulation, a drug distributes throughout the body and partitions in various tissues. Distribution in fluid compartments and tissues is generally unequal. The rate of entry of a drug into tissues depends on the rate of blood flow to the tissue mass and the partition characteristics of the drug between blood and tissue. 17  Pharmacokinetics Metabolism – the process of chemical alteration of drugs in the body. The liver is the principal site of drug metabolism. Some metabolites are pharmacologically active. Rate of metabolism is affected by individual variation, concurrent disease states and drug interactions. Excretion – the process by which a drug or metabolite is eliminated unchanged from the body. The kidney is the major organ of excretion and is responsible for eliminating water-soluble substances. The biliary system also excretes certain drugs and metabolites. Volatile anaesthesia is excreted via the lung in expired air. 18  Pharmacodynamics Pharmacodynamics – how the drug affects the body Pharmacodynamics - the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body - The mechanisms of drug action and the relationship between drug concentration and effect e.g. Drug- receptor interaction Receptor binding - The binding of ligands (drug) to receptors - Agonistic and antagonistic effects - Only unbound drug can bind the receptors - Drug interactions lead to competition for receptor sites 19 Concentration-time curves: for 3 different formulations of the same medicine Max safe conc Medicine concentration Therapeutic window Min effective conc Formulation 1 Formulation 2 Formulation 3 Time following administration of a single dose Concentration against time curves for single dose administration for 3 different formulations of the same medicine administered in equal single doses by the same extravascular route 20  Plasma concentration vs. time Plasma concentration of drug MSC – Risk of toxicity increases maximum safe conc. Therapeutic window Effect likely to be sub-therapeutic MEC – minimum effective conc. 21 Time Concentration-time curves: oral route, different dosage frequency/intervals Medicine Conc. Therapeutic window oral route daily oral route bd 8 16 24 Time oral route tds Concentration against time curves at steady state for oral route bd, tds, daily 22  Concentration-time curves: oral route Steady state Medicine Conc. Therapeutic window 8 16 24 32 Time -- no loading dose ------ with loading dose Concentration against time curve starting from zero and achieving steady state23  Concentration-time curves Absorption Elimination phase phase Medicine Conc. 0 Time Concentration against time curve for a single dose by the oral route 24 Concentration-time curves: iv administration, different method of administration Medicine Conc. Therapeutic window i.v. continuous i.v. bolus tds 8 16 24 Time i.v. intermittent infusion tds Concentration against time curves at steady state for i.v. continuous, i.v. 25 bolus tds and i.v. intermittent infusion tds 26 27 Development of new drugs 28 Research and development 29 A scheme for new drug development Years 1 2 3 4 5 6 7 8 9 1 11 12 13 14 0 Chemistry Synthesis Manufacturing Scale-up Pharmacology Pharmacology Drug Screening /side-effects interactions Toxicology Acute Sub-acute toxicology Chronic toxicology toxicology & teratology Carcinogenicity Pharmacokineti Animal Human cs metabolism metabolism Pharmacy/ Formulation Packing & Long term Pharmaceutical & stability dosage form stability tests Medical Efficacy & safety Effic & Pharmacology dose ranging – safety – Phase I Phase II Phase III Registration Compilation of Product license Consideration of regulatory needs regulatory documents granted 30 Clinical trials Regulated since 2005 Authorisation is based on: ▪ evaluation of scientific information (Medicines Authority) ▪ ethical approval (Health Ethics Committee) Regulation is primarily aimed at protecting clinical trial subjects Clinical trials produce information required for the evaluation of marketing authorisations and changes to authorisations List of clinical trials authorised is published on www.clinicaltrialsregister.eu 31 Pre-clinical and clinical phases 32 Phases of a clinical trial Marketing authorisation ↓ 33 Steps in a clinical trial 34 35 Medicines Use in Clinical Practice 36  Therapeutic regimens Activity – toxicity Pharmacokinetics Therapeutic window Liberation Side-effects Absorption Toxicity Distribution Concentration-response Metabolism relationship Excretion DOSAGE REGIMEN Clinical Factors Other factors State of patient: age, weight, Route of condition being treated, administration other disease states Dosage form Tolerance- Management of therapy: dependence multiple drug therapy, Pharmacogenetics – convenience of regimen, idiosyncrasy adherence to medicine Drug interactions Cost 37 38  Medicines optimisation vs medicines management Medicines optimisation focuses on patient outcomes, medicines management focuses more on processes and systems Improved outcomes help to ensure optimisation of value from the investment in medicines Medicines optimisation looks at how patients use medicines over time, including review of treatment and stopping of some medicines and starting others Consideration of opportunities for lifestyle changes and non-medicinal therapies to reduce the need for medicines Improving safety, adherence to treatment and reducing waste 39  Patient characteristics Factors relating to patient characteristics that should be considered during a clinical check: - Patient type Any cautions or contra-indications to treatment, specific patient groups, ethnic groups, gender - Co-morbidities Renal or hepatic impairment, heart failure - Patient intolerances and preferences Patient factors which affect the choice of treatment include known adverse events to medicines, dietary intolerances, patient preferences, religious beliefs, patient knowledge and understanding of medicines and why they are being taken 40  Monitoring of drug therapy Why monitor drug therapy: 1. To check therapeutic response 2. To assess drug toxicity 3. To assess adherence to therapy Monitoring of response to drug therapy - Monitoring incidence and intensity of therapeutic and undesirable effects - Use of alternative endpoints - Plasma drug concentration monitoring (for limited number of drugs) An ineffective response may indicate: - Less than the minimum required dose has been administered - Other factors such as lack of adherence 41  Concentration of drug in plasma People vary considerably in the extent to which they absorb, distribute and eliminate medicines Factors that modify drug plasma concentration for a given dose: - Formulation - Genetic variation - Environmental variation - Effects of disease - Drug interactions 42 Factors that modify the effect of the drug for a given drug plasma concentration - Drug interactions - Electrolyte balance - Acid-base balance - Age - Bacterial resistance - Plasma protein binding 43 Factors affecting the use of medicines Allergies to medicines (can be from the active ingredients and/or from the excipients) Simplification of dosage regimen Medicines should be prescribed with a pre-defined duration of treatment Difficulties with taking the medicine (e.g. difficulty with swallowing) or difficulties with opening the container (e.g. elderly have difficulty with opening child-resistant containers) Interactions with other medicines or interactions with food Importance of information about medicines being taken and about the efficacy and risks from medicines use 44  Medication regimen factors Indication Ascertain indication for treatment, medicine prescribed appropriate for the indication, compatibility with guidelines Changes in regular treatment Confirm that changes to regular therapy are intentional Dose, frequency and strength Check that the dose, frequency and strength of prescribed medicines are appropriate considering the patient’s age, renal and hepatic function, weight and surface area (where appropriate), co-morbidities, concomitant drug therapy and lifestyle patterns The dosing of the formulation Check that the formulation, the dose and the frequency are appropriate Drug compatibility Evaluate regular and new therapies for any clinically significant interactions, duplications and antagonistic activity Monitoring requirements Check results and ascertain whether any dose adjustments are required 45 Examples of abbreviations related to administration used during dispensing of medicinal products Term of phrase Abbreviation meaning Bis in die b.i.d b.d. Twice a day Ter in die t.i.d t.d.s Three times a day Quarter in die q.i.d q.d. Four times a day Sexies in die Sex. In d. Six times a day quotidie Quot. daily Primo mane Prim.m. Early in the morning mane m In the morning nocte n At night Omni nocte o.n. Every night Ante cibos a.c. Before meals Post cibos p.c. After meals Inter cibos i.c. Between meals 46 Calculation of doses of medicinal products Concentrations of solutions: Weight in volume solutions e.g. 1% w/v solution Volume in volume solutions e.g. 1% v/v solution Percentage means grams per 100ml – 5% dextrose means 5 grams per 100ml of solution Proportions e.g. adrenaline 1: 1,000 means 1 g in 1,000 ml (1mg/ml) Milliequivalents per unit volume e.g. milliequivalent (mEq) per litre. A milliequivalent is one thousandth part of the gram equivalent weight Mole is the unit of chemical quantity Proportional calculations and alligation- e.g. the mixing of two similar preparations but of different strengths to produce a preparation of intermediate strength 47  Medication history Medication history provides foundation for assessing the appropriateness of a patient’s current therapy and directing future treatment choices Identification of medication errors Identification of poor- or non-adherence, cross-check adherence Sources of information: patient or patient representative, medicines, repeat prescriptions, GP referral letters, hospital discharge summaries, community pharmacy patient medication records, home care records, medicines treatment chart, other healthcare professionals Obtaining a medication history: explain to patient why the history is being taken, use a balance of open-ended and closed questions, avoid jargon and keep it simple, clarify vague responses, keep the patient at ease Ask patient about non-daily and ‘when required’ medicines, medicines taken on certain days of the week Ask about historical medicines – recently stopped or changed medicines Self-medication – products which the patient is taking – whether prescribed or not, including OTC medicines, herbal products, vitamins, dietary supplements, recreational drugs Get accurate information about the length of therapy, administration devices or brand for injectables, medicines with variable dosing regimen such as warfarin Ask to see the patient monitoring booklet where applicable e.g. oral anticoagulant booklet Prompt the patient to get the required information 48  Administration and monitoring The route of administration - Suitability of prescribed route of administration for the patient - Whether a preparation is available for that route - Compatibility with other medicines and food The need for administration aids - Any adherence aids required by the patient e.g. spacer devices, eye drop devices, Braille or large type or pictogram labels, additional sheets or verbal information Record keeping - Important for continuity of care - Record of significant clinical checks and interventions made - Details of discussions and agreed decisions with other healthcare professionals - Types of records kept 49  Criteria for drug formulations Sufficient bioavailability Safe excipients Palatable and/or acceptable properties Acceptable dose uniformity Easy and safe administration Socio-cultural acceptability Precise and clear product information 50  Impact of adverse drug reactions ADR’s : expected/unexpected severity of ADRs Other impacts of ADRs: 0.12 – 0.22% of hospital admissions result in death due to ADR 3 – 10% of hospital admissions are caused by ADRs 2.1 – 6.5% of hospitalised patients suffer from an ADR ADR related costs (other than hospitalisation) €63.2 billion annually Total societal costs of ADRs in the EU €79 billion annually European Commission, Pharmacovigilance Assessment Report (SEC(2008) 2671) 51  Pharmacovigilance Limitation of pre-clinical and clinical data on safety at MA New risks identified with the use of a product in clinical practice: new side-effects, perceived efficacy not achieved, New legislation on Pharmacovigilance (July 2012) Adverse drug reaction (ADR): - a response to a medicinal product which is ‘noxious and unintended’: ADRs from the authorised use of products Medication errors that result in an ADR Uses outside the terms of the SmPC Centralised EU database for ADRs and MEs Black triangle for additional close monitoring HCPs are encouraged to report ADRs Patients can report ADRs 52  Classification of adverse drug reactions Edwards R. et al., 2000 Type of reaction Features Management Dose-related - common, Reduce dose (augmented) - related to a pharm action of the drug Consider effects of - predictable concomitant therapy Non-dose related - Uncommon Withhold and avoid in future (bizarre) - Not related to pharmacological action of drug - Immunological reactions and Idiosyncratic reactions - Unpredictable - High mortality Dose-related and - Uncommon Reduce dose or withhold time-related - Related to cumulative dose (chronic) Time-related - Uncommon - Often intractable (delayed) - Usually dose-related - Becomes apparent some time after the use of the drug Withdrawal (end of - Uncommon Reintroduce and withdraw use) - Occurs soon after withdrawal of the drug slowly Unexpected failure - Common Increase dosage of therapy (failure) - Dose-related Consider effects of - Often caused by drug interactions concomitant therapy  Drug allergies Drug allergy is any reaction caused by a drug with clinical features compatible with an immunological mechanism - allergies to penicillins - allergies to non-steroidal anti-inflammatory drugs (NSAIDs), especially people with asthma - allergies to NSAIDs in people with chronic urticaria involves angioedema and anaphylaxis - anaphylaxis-type reactions occur in approximately 1 in 1000 of the general population - Anaphylaxis during general anaesthesia occurs in 1 in 10,000 – 20,000 anaesthetics Reported incidents illustrate the serious harm, and in some cases fatalities that have occurred to patients who have been prescribed drugs to which they have had a pre-existing allergic response. The tragedy is that this harm is preventable It is important to invest time and effort into reducing the number of patients who receive medication which they are documented to be allergic to. NICE published guidance on drug allergies. NICE, Drug allergy: diagnosis and management Clinical Guideline (CG 183) https://www.nice.org.uk/guidance/cg183  Information on medicines SmPC with information on pharmacokinetics and pharmacodynamics of different medicinal products 56 57  SmPC information Refer to SmPC information for medicines of different dosage forms Sources: Medicines Authority, Malta http://www.medicinesauthority.gov.mt/ Electronic Medicines Compendium (Emc) European Medicines Agency, London http://ema.europa.eu/ema/ 58 Use of medicines in older persons 59 Europe is ageing Source: Priority Medicines for Europe and the World, Update 2013 Report, 60 cited from Data from the World Bank Use of medicines in older persons Medicines play an expanding role in health care as patients grow older Increased incidence of disease such as dementia, cancer and osteoporosis Need for clinical trials in the older persons - 39% of RCTs excluded older persons - 81% of RCTs also excluded people with co-morbidities Initiatives to increase studies in older persons 61 Factors affecting use of medicines in older persons Changed pharmacokinetics and pharmacodynamics Changed physiology Changed spectrum of diseases Older persons are prescribed more than one kind of medicine (many take three or more) – polypharmacy Increased risk of: - medicines interactions, - mix-ups - potential for side-effects Interaction with alcohol and food 62  Altered functions in older persons Altered function Implications Examples Change in body Differences in drug Liphophilic medicines composition partitioning leading to different accumulate in fat and serum levels depending on show longer half-life. Decreased the polarity of the drug. proportion of body Hydrophilic medicines water and increased Fat-soluble drugs are likely to show higher serum proportion of body accumulate in body fat which levels and need a lower fat could prolong their effect. loading dose. Decreased liver size Higher bioavailability of Decreased first-pass and blood flow hepatic metabolised drugs metabolism leads to higher serum level. Decreased renal Decreased clearance of If drugs with a small function water-soluble drugs and therapeutic window glucuronised metabolites accumulate there is leading to higher serum levels increased risk of serious adverse effect. 63  Accessibility of medicines in older persons Age-related changes like - memory loss - poor eyesight - arthritis - Parkinsons disease Difficulties with taking medicines: - opening of packaging and dividing tablets - calculation of doses - swallowing of oral medication - reading and understanding information Mobility may affect accessibility Older persons reside in different care 64 settings depending on the level of care needed Affordability of medicines Financial difficulties may affect access to medicines 65 Prescribing for older persons Prescribe in accordance with SPC Note special precautions for use Monitor treatment for indications and for adverse effects Keep updated list of all medicines including non- prescription and herbal medicines and supplements Review of medication, not just add-on Pre-define and review length of treatment Be aware whether patients have access to their medicines Ensure that patients/carers understand and follow regimen Address non-concordance 66 Minimise risk factors, find remedial action for problems Dispensing of medicines to older persons Review treatment and maintain list of all medicines being taken (prescription/ non-prescription, herbal) Explain any changes in medicines prescribed and in products dispensed to patient/carer Ensure that clear directions for taking medicines are given, labelling is clear and is understood by patients Include special warnings about interaction with alcohol, other medicines and food Ensure that patients can open packaging Ensure that dosage form is appropriate Advise on ways to ensure concordance Help patients to access and store medicines 67 Use of medicines in children 68  Use of medicines in children Children : - are not small adults, - are a vulnerable population with specific needs - changing physiology in children - a heterogenous patient group - a scope of diseases different from those of adults - scarcity of data on appropriate medicines delivery - suitable formulations and products for children - initiatives at EU to support the development and administration of paediatric medicines and improve information 69 available on their use  Differences in paediatrics Children are different from adults in: - body development - pharmacokinetics -pharmacodynamics Pharmacokinetics: - slower GI absorption - faster i.m. absorption - different distribution - higher % of water - water (EC >IC) - limited protein binding - immature enzymes - immature livers 70 - small and immature kidneys  Dosing and formulations in children Dosing - higher blood-brain barrier permeability - longer half-life for elimination than adults - often small children have no linear dose- per-kg correlation with adults - paediatric dosing regimen cannot simply be extrapolated from adult data Formulations - appropriateness of a formulation to achieve safe and accurate dose administration - taste preferences in children - novel formulations with dose adjustment - reduction of risk of medication errors - enhance adherence to medication 71  Selection of appropriate preparation Preparation should be chosen on a case- by-case basis considering the child’s: - age - size - condition (e.g. critical illness, ability to swallow, concomitant medication) - usage environment - sufficient bioavailability - dosage frequency - allergies to ingredients and excipients - minimum impact on lifestyle - taste acceptance - socio-cultural acceptability e.g. suppositories - clear product information 72 Suitability of paediatric medicines Diversity of children Accuracy of dosing with lower doses and volumes Inability to swallow solid dosage forms Taste masking in oral forms Stability and safety of excipients Needle phobia Ability for child to take medicine – cognitive and motor skills, dependence on caregivers Dosage form preference (depends on age group) Length of use of medicine – oral formulations are preferred for long-term use, parenteral administration is preferred in neonates and in emergencies 73 Medicines use process Rational use of medicines Medication errors 74  Medicines use process Prescribing - assessing the need for and selecting the correct drug - individualising the therapeutic regimen - designating the desired therapeutic response Dispensing - dispensing the medicine in a timely manner - Labelling of the product - Information for use of the product Administration - administering the right medication to the right patient - Administering at the right time - Informing the patient about the medicine and its use 75  Medicines use process Monitoring - Monitoring and documenting the patient’s response - Identifying and reporting adverse drug reactions - Identifying and reporting any medication errors - Re-evaluating drug selection, regimen, frequency and duration Systems and management control - Audit of systems - Collaborating amongst care givers - Reviewing and managing patient’s complete therapeutic drug regimen 76  Use of medicines under different legal status (National terms used) Use of a product in line with the Summary of Product Characteristics (SmPC) Compassionate use (Regulation (EC) No 726/2004) Article 81. Use of products not yet authorised through the centralised procedure. Off label use – product has a marketing authorisation in Malta but not used in line with SmPC Unlicensed product – product does not have a marketing authorisation in Malta. Brought for specific patients/clinical units Personal use – parson gets stock for his own personal use. Cannot be distributed to others. 77 Principles of Therapeutics The clinical use of medicines Medicines and disease management Objectives of treatment: prevention/ cure/ mitigation Treatment and care of a patient Administration of medicinal products Information about medicinal products Monitoring of therapeutic response and pharmacological action Minimisation of adverse effects Use of medicines in different clinical settings (primary care, secondary care) Medicines for different types of disease conditions (emergency treatment, chronic diseases, diagnostics) Decisions for optimal therapy is based on benefits/risks of medicines and considers aspects related to the patient characteristics, his environment, diagnosis, monitoring of treatment (efficacy and adverse effects) 78 Path from evidence generation to clinical application 1. generation 5. making 2. evidence 3. forming 4. applying of evidence clinical synthesis clinical policy policy from research decisions patient’s circumstances Factors to consider for clinical decisions patient’s evidence wishes 79  Information and support systems for clinical decision making Keeping abreast with new knowledge Advertising of medicines for patients and for HCPs Information/evidence: - SmPCs - Clinical guidelines and protocols - Decision support systems (e.g. decision trees) - Educational programmes 80 Information sources Priority Medicines for Europe and the World, Update 2013 Report, World Health Organisation, 2013. Government Formulary List http://ehealth.gov.mt/HealthPortal/chief_medical_officer /pharm_pol_mon/med_within_ghs/gov_form_list.aspx The British National Formulary Medicines Authority, Malta http://www.medicinesauthority.gov.mt/ European Medicines Agency, London http://ema.europa.eu/ema/ National Institute for Health and Care Excellence, 2014, Guideline and Full Guideline: Managing medicines in care homes, http://www.nice.org.uk/guidance/sc/SC1.jsp 81 Use of medicines by patients -Empowerment of patients to participate in decisions about their treatment -Sources of information for pateints - Use of the internet -Sourcing of medicines through internet - Adherence to medication the process by which patients take their medications as prescribed, composed of initiation, implementation and discontinuation. Initiation: occurs when the patient takes the first dose of a prescribed medicine. Implementation: is the extent to which a patient’s actual dosing corresponds to the prescribed dosage regimen, from initiation to the last dose. Discontinuation: occurs when the patient stops taking the medicine for whatever reason/s. 82  Considerations for medicines use Pharmacoepidemiology: incidence of disease, demographics of the population Changes in pharmacokinetics and pharmacodynamics in specific age groups Interactions of medicines with medicines, food, alcohol Rational use of medicines Adherence to treatment Access and affordability of medicines Recommendations for prescribing and dispensing Administration of medicines Advertising of medicinal products 83  Adherence to medicines Adherence is the process by which patients take their medicines as prescribed/dispensed. There are three phases: - initiation, which occurs when the patient takes the first dose of the medicine - Implementation, which is the extent to which a patient’s actual dosing corresponds to the set dosage regimen, from initiation to the last dose - Discontinuation, occurs when the patient stops taking the medicine for whatever reason/s. The management of adherence includes the process of monitoring and supporting patient’s adherence The concept of adherence (which involves the will of the patient) has replaced the previous concept of compliance (which has a connotation of enforcement/patronisation) 84 Factors which affect adherence to medicines regimen Polypharmacy Complication of the dosage regimen Dosage form and presentation of medicines Level of the patient’s understanding of the dosage regimen and of knowledge about the medicines taken and the disease Patient’s perception of the benefit and risks (side- effects) of taking the medicines The patient’s disease condition and complications of the disease The patient’s ability to administer the medicine. Certain impairments may affect the patient’s ability to take medicines or to access the medicines’ supply 85  Improving adherence to medicines - By supervision of the patient taking the medicine or administration through a HCP or a carer - Use of depot formulations - Use blisters or medicines containers for preparation of doses - Use of calendar packs to remember taking the daily dose - Removing barriers to adherence – e.g. improve palatability, use of liquid formulations for patients who cannot swallow, change formulation if needed, - Simplifying therapeutic regimen (reduction of the number of tablets or the frequency of administration, or use of combination products) - By educating the patient 86 Strategies to meet needs of specific patients Older adults Patients with disabilities Terminally ill patients Patients with mental health problems Cultural competence Patients with low health literacy Patients with HIV/AIDS Communicating with children and their parents 87 Medication safety incidents Medication safety incident Potential Adverse adverse drug event drug event Adverse Hazardous Medication Near miss drug conditions error reaction 88  Medication errors ‘a failure in the treatment process that leads to or has the potential to lead to, harm to the patient’ A medication error is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing, order communication, product labelling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use." 89  Medication errors Medication errors may involve different activities: - Prescribing - Ordering - Dispensing - Distribution - Preparation - Administration - Labelling - Packaging and nomenclature - Communication and education - Use and monitoring of treatment  Medication errors Medication errors may be related to: - Professional practice - Products - Procedures - Environment - Systems Causes of error: - individuals can be considered to be the cause of error - latent conditions within an organization - triggering factors in clinical practice Checks and error traps should therefore be built in all medication processes Errors in the medication cycle 92  Medication errors Type Definition Prescribing errors Incorrect drug, dose, concentration, etc. for a medicine prescribed Omission error Failure to administer an ordered dose Wrong time error Administration outside a redefined time interval Wrong dosage form Use of a dosage form other than that prescribed error Wrong drug- Product incorrectly formulated preparation error Wrong administration Improper technique for administration technique error Deteriorated drug Medicinal product expired or its integrity was error compromised Monitoring error Failure to review prescribed regimen for appropriateness and detection of problems Adherence error Inappropriate patient behaviour regarding adherence to a prescribed medication regimen 93 Medication errors 94 Precautions to reduce medication errors 95 Relationship between medication errors and adverse drug reactions l. III. Medication II. Adverse drug errors that do Medication reactions that not result in errors that are not the patient harm result in result of a and near patient medication misses harm error Medication Adverse drug errors reactions I. Medication errors that do not result in patient harm and ‘near misses’ Near misses – errors with potential for harm but detected before they reach the patient. Near misses may indicate failure in systems predisposing to error ‘harm waiting to happen’ e.g. - wrong dose of a drug calculated for a patient in renal failure, but corrected prior to administration - Oncology ward: A patient was documented to be allergic to penicillin. Patient presented with a swollen throat reaction. Augmentin was prescribed but it was not given as this was spotted by the ward pharmacist. - Respiratory ward: The patient has a documented allergy to morphine. Oromorph was prescribed and given to the patient who refused to take it because of his allergy.  Examples from practice.. Oncology ward A patient was documented to be allergic to penicillin. Patient presented with a swollen throat reaction. Augmentin was prescribed but it was not given as this was spotted by the ward pharmacist. Respiratory ward The patient has a documented allergy to morphine. Oromorph was prescribed and given to the patient who refused to take it because of his allergy.  II. Medication errors that result in patient harm Prescribing a non steroidal anti- inflammatory drug to a patient with a documented history of peptic ulcer disease, who suffers a gastrointestinal bleed as a result Dispensing the wrong formulation of an anti-epileptic treatment resulting in loss of seizure control III. An adverse drug reaction that is not the result of a medication error Known or predictable side effects of medicines e.g. a patient who experiences a hypersensitivity reaction to penicillin who was not previously known to be allergic to penicillin A patient who experiences hair loss following a course of cancer chemotherapy 101 Medicines administration Calculations 102 SI units Name Symbol Factor 100 deci- d 10 -1 centi- c 10 -2 milli- m 10 -3 micro- µ (write micro) 10 -6 nano- n (writenano) 10 -9 103  Weight / mass Body weight is usually measured in kilograms (kg). Average adult body weight 70kg. Drug dosage is generally expressed in grams (g), milligrams (mg), micrograms or nanograms. These units are related as follows. Important to be able to convert. 1 kg 1000g 1g 1000mg 1mg 1000microgram 1microgram 1000nanogram 104  Examples What is 0.0625mg of digoxin expressed in micrograms? Dose in micrograms = 0.0625mg x 1000=62.5microgram Often drug doses are expressed unit mass of drug per unit mass of patient, e.g. 0.5mg/kg four times daily. This may also be expressed as 2mg/kg/day in four divided doses, or every 6 hours. Example: A patient weighing 60kg is prescribed gentamicin 2mg per kg per day, to be administered every eight hours. What is the size, in milligrams, of each dose? Daily dose of gentamicin = 60mg x 2 = 120mg Every 8 hours = 3 times daily (24 hrs divided by 8) Therefore each dose = 120mg / 3 = 40mg 105  Dosing and formulations in children Dosing - higher blood-brain barrier permeability - longer half-life for elimination than adults - often small children have no linear dose- per-kg correlation with adults - paediatric dosing regimen cannot simply be extrapolated from adult data - Surface area calculated using a nomogram Formulations - appropriateness of a formulation to achieve safe and accurate dose administration - taste preferences in children - novel formulations with dose adjustment - reduction of risk of medication errors 106 - enhance adherence to medication Vials Powder in Dilution in vial larger reconstituted volume to liquid in e.g. vial infusion bag Multi-dose vials e.g. insulin 107  Ampoules Ampoule - Single use - Can lead to glass particles in solution - Less expensive than vial 108  Dosage based on Units (U) A unit may be defined as a measurement of a specific drug. A unit is not interchangeable with any other measurement. Usually applicable for medicines of biological nature e.g. insulin, heparin, It is recommended to write the term “unit” Insulin concentration of 100units/mL is the most commonly used. 1mL insulin syringe 100 Units U-100 109  Volume Volumes are usually expressed as litres (L) or millilitres (mL) 1 L = 1000mL To convert L to mL multiply by 1000 To convert mL to L divide by 1000 Example: how many mL are there in 0.5 litres? 0.5 L = 0.5 x 1000mL = 500mL 110  Concentration There are several methods of expressing the concentration of a drug in a given fluid: A. Mass/weight in certain volume e.g. mg/mL B. Percentage weight in volume % (w/v). This is the number of grams of drug dissolved in 100mL of solution. 0.9% sodium chloride contains 0.9g of sodium chloride in 100mL of solution. C. Parts per ‘n’ 1:10 means there is 1g in 10mL 1: 100 means there is 1g in 100mL 1: 1000 means there is 1g in 1000mL 1: 10,000 means there is 1g in 10,000mL D. Percentage volume in volume % (v/v) = volume of solute / total volume E. Moles and millimoles per Litre A mole or millimole refers to a certain number of atoms or molecules. Moles of different compounds have different masses/weights. 111 Calculating volume Example: – Mr N is prescribed 25mg spironolactone in liquid form (5mg/ml). What volume should he take? Concentration = Dose / Volume Therefore: Volume required = Dose / concentration Also, Dose = Concentration x volume 112 Calculating volume – Example: – A35kg 8-yr old boy is prescribed amoxicillin at 30mg/kg intravenously. The drug is available as a 500mg/mL preparation. How much volume is required? – Dose required = 30mg/kg x 35kg (= 1050mg) – Volume required = dose required / concentration = 1050mg / 500mg/mL = 2.1mL 113  Example A patient is prescribed 60mg of gentamicin. The vial contains 80mg in 2mL. How many mL are required to deliver the prescribed dose? 80mg = 2mL 60mg = 2/80 x 60 = 1.5mL 114 Calculating volume – Syringe drivers Typically 0.1 to 20 ml/hr 115 Calculating rate Rate required = Volume required / time But usually need to count volume first i.e. volume = dose / concentration 116 Calculating rate Example: – Following a bolus, Mr N (80kg) is prescribed 10mg/kg amiodarone over 24 hours. Intravenous amiodarone is made to a dilution to 500mg/500mL. Give the rate (mL/min) required. 117 Calculating rate Example: – Mr N (80kg) is prescribed 10mg/kg amiodarone over 24 hours. Intravenous amiodarone is made to a dilution to 500mg/500mL. Give the rate (mL/min) required. To do this you need to know: Dose required in total What volume would this be How much volume per unit time Note, unit time has changed here from hr to min 118 Calculating rate Example: – Mr N (80kg) is prescribed 10mg/kg amiodarone over 24 hours. Intravenous amiodarone is made to a dilution to 500mg/500mL. Give the rate required. (mL/min) Dose required = 10mg/kg x 80kg = 800mg Volume required = Dose required / conc = 800mg / 500mg/500mL = 800mg / 1mg/mL = 800mL Rate required = Volume required / time = 800mL / 24hrs = 800mL / 24x60mins = 0.56mL/min 119  Flow rate calculations When a gravity IV infusion system is used the amount of fluid delivered to the patient is calculated by the number of drops per minute Administration sets for clear fluid deliver about 20 drops per mL, this is an estimate and depends on the fluid and whether drugs are added to the fluid. Paediatric administration sets deliver about 60 drops per mL. The figure used for the administration of blood is 15drops per mL. Check the drops per mL for the specific set. 120 Infusion sets 121  Flow rate calculations Prescribed volume (mL) x drops per mL Drops per minute = _______________________________________ Prescribed time (hr) x 60 Where a drug dose is prescribed in weight per minute the following formula can be used: Amount of drug per minute x volume x drops per mL Drops per minute = _________________________________________________ Amount of drug in infusion Always take care of the units Try to reason the calculation 122  Example 800mg of dopamine is added to a 500mL bag of dextrose 5%. What rate should be set for a 70kg man prescribed 10micrograms per kilogram per minute, using a paediatric set which delivers 60 drops per mL? 10microgram/kg/min 10microgram x 70 = 700microgram/min 800mg = 800,000micrograms 800,000micrograms = 500mL 700micrograms = 500x700 / 800,000 = 0.4375 mL 1mL = 60 drops 0.4375 mL = 26.25 drops per minute 123 Treating cancer pain 124