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Pharmacology, Therapeutics and medicines management Sue Ayers Advanced Pharmacists Palliative Medicine March 2011 Index of learning outcomes - 1 Pharmacokinetics and Pharmacodynamics Pharmacogenetics Dose adjustments in frail, elderly and children Dose adjustment in renal failure Dose adjustment in Liver Failure Dose adjustment in disease progression and at the end of life Index of learning outcomes - 2 Drug formularies in palliative care Managing a pharmacy budget Prescribing issues ( non CDs) Prescribing issues (CDs) CD legislation Unlicensed drugs Drugs beyond licence Drugs in clinical trials Index of learning outcomes - 3 Polypharmacy Understanding medicines Medicine related adverse event reporting Alternative routes of administration Drugs in syringe drivers Drug interactions Tolerance, dependence, addiction, discontinuation reactions Accessing drugs in the community Pharmacokinetics/dynamics Pharmacokinetics may be simply defined as what the body does to the drug, as opposed to pharmacodynamics which may be defined as what the drug does to the body. Movement of drugs across cellular barriers To traverse cellular barriers (e.g. gastrointestinal mucosa, renal tubule, blood–brain barrier, placenta), drugs have to cross lipid membranes. Drugs cross lipid membranes mainly (a) by passive diffusional transfer and (b) by carrier-mediated transfer. The main factor for rate of passive diffusional transfer across membranes is a drug’s lipid solubility. Molecular weight less important. Pharmacokinetics - Processes Distribution - cellular barriers, protein binding, “compartments”, ADME Movement of drugs across cellular barriers Many drugs are weak acids or weak bases; state of ionisation varies with pH according to the Henderson– Hasselbalch equation. Weak acids or bases - only the uncharged species can diffuse across lipid membranes; this gives rise to pH partition. pH partition means that weak acids tend to accumulate in compartments of relatively high pH, whereas weak bases do the reverse. Movement of drugs across cellular barriers Carrier-mediated transport (e.g. in the renal tubule, blood–brain barrier, gastrointestinal epithelium) is important for some drugs that are chemically related to endogenous substances. Plasma Protein Binding At therapeutic plasma concentrations many drugs exist mainly in bound form Free drug in aqueous solution can be less than 1% Albumin – most important. 2 bi9nding sites. Binds many acidic drugs (warfarin/NSAIDs) and some basic drugs ( TCAs/chlorpromazine) Beta – globulin and acid glycoprotein – bind basic drugs ( quinine) Amount bound depends on concentration of free drug affinity of binding sites concentration of protein Plasma Protein Binding Usual concentration of albumin is 0.6mmol/l 2 binding sites per molecule – binding capacity for drugs is 1.2mmol/l Most drugs therapeutic plasma level < 1.2 mmol/l so binding sites not saturated and fraction unbound not dependant on drug concentration Important if therapeutic concentration nearing saturation ( sulphonamides and tolbutamide) doubling dose can more than double free concentration Displacement from binding sites is only relevant when binding sites saturated ( less important drug interaction) Extensive protein binding slows elimination ( Met or excretion by glomerular filtration) Partition into body fat and other tissues Fat is a large, non polar compartment only relevant for a few drugs Most drugs have a low fat:water partition coefficient Morphine – lipid soluble enough to enter BBB but lipid:water partition coefficient is only 0.4 so sequestration into fat not important Thiopental ( f:w coefficient = 10 ) distributes into fat so no good as an induction anaesthetic Fat has low blood supply <2% cardiac output – limits drug accumulation when given acutely as slow to accumulate , but chronic administration of lipid soluble drugs ( Benzos) may accumulate ( or insecticides) Other Tissues drugs bind to Melanin – Chloroquine ( particularly in the retina) Tetracyclines – bones and teeth Amiodarone – liver and lung Routes of administration Routes – advantages and disadvantages From intestine Passive transport mainly rate determined by ionisation and lipid solubility. Strong bases ( pKa >10) and strong acid ( pKa <3) are not adsorbed as they are sully ionised ( curare) Carrier – mediated transport . Levodopa ( via phenylalanine carrier) Fluorouracil ( via pyrimidine carrier thyamine and uracil) Iron via carriers in jejunal mucosa and calcium via vitamin D dependant carrier Factors affecting GI absorption Motility Splanchnic blood flow ( increased by food) Particle size and formulation ( Extended release preparations ) Physiochemical properties – milk and tetracyclines, cholestyramine Oral Vancomycin/nystatin Bioavailability proportion of drug that enters into the systemic circulation after oral administration doesn't indicate rate of absorption just total amount Usually a percentage range ( variable! Not accurate) Drug licensing authorities use bio-equivalence - ie new substance behaves similarly to another without clinical harm to substitute it. ( Zomorph/MST) Distribution Body Water ( 50 – 70%) in four compartments Extracellular fluid – plasma 4.5% body weight, interstitial fluid 16% bw, lymph 1.2% Intracellular fluid 30 – 40% bw Transcellular fluid 2.5%bw - csf, eye, peritoneal, pleural, synovial and digestive secretions In body water drugs exist as free and bound, ionised and unionised forms depending on Ph Drugs move across compartments BBBis particularly important Blood Brain Barrier Domperidone doesn’t cross – Chemoreceptor Trigger Zone has leaky barrier – acts there. Can use with parkinson’s patients on dopamine antagonists that do cross BBB Methylnaltrexone (Relistor) Increased permeability – liver disease, bradykinin and enkephalins General Prescribing Prescription forms – types Legal requirements ad best practice: http://www.nhsbsa.nhs.uk/PrescriptionServices.aspx BNF http://www.medicines.org.uk/emc/ (SPC) Local organisational prescribing policy/guideline/formulary Commissioners’/contractors prescribing policy/guidelines Volume of distribution ( Vd) The volume of fluid that is required to contain the total amount ( Q) of drug in the body at the same concentration as that present in the plasma ( Cp) Vd = Q/Cp Vd tables in PCF3 Plasma volume = 0.05l/kg body weight Heparin Vd 0.05 – 0.1 (mainly in plasma) Extracellular fluid 0.2l/kg Theophylline 0.4 – 0.7 Volume of distribution ( Vd) Total body water 0.55 l/kg Ethanol, phenytoin 0.55 Paracetamol, diazepam 1-2 Morphine, digoxin 2-5 Nortriptyline >10 Lipid insoluble drugs mainly stay in plasma and interstitial fluid . Most don’t cross BBB Lipid soluble drugs reach all compartments and may go into fat/tissue ( Vd > total body volume) Metabolism http://www.youtube.com/watch?v=xtI0pMEZy7c Mainly liver ( gut/lungs) –”First pass metabolism” Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization, addition of oxygen or removal of hydrogen carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a cytochrome P450 ( CYP3a4 metabolises 50% drugs, then 2D6 and 2C9 or 8 ) Can get genetic variation Metabolism Phase II reactions usually known as conjugation reactions (e.g., with glucuronic acid, sulfonates, glutathione or amino acids) are usually detoxication in nature. Products of conjugation reactions have increased molecular weight and are usually inactive unlike Phase I reactions which often produce active metabolites. Morphine goes straight to Phase II - M3G and M6G In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults Can get genetic variation Metabolism – drug interactions and genetics Enzyme inducers ( phenobarbitone, carbamazepine, rifampicin, smoking) Can occur within 2-3 days – 2 weeks and take same time to return to normal once stopped Enzyme inhibitors ( ciprofloxacin, erythromycin, cimetidine) Can occur immediately. Care if drug has narrow therapeutic window . Look for CYP450 interaction if cant explain ADR http://medicine.iupui.edu/clinpharm/ddis/table.asp Genetic polymorphisms Enzyme Drug affected Inducer Effect CYP1A2 Duloxetine Smoking Reduced effect (approx 50% lower plasma concentrations) CYP2C9 Celecoxib Carbamazepine Reduced effect CYP2C19 Diazepam Carbamazepine Reduced effect CYP3A4 Midazolam Alfentanil Fentanyl Oxycodone Carbamazepine High dose dexamethasone Reduced effect Enzyme Drug affected Inhibitor Effect CYP1A2 Duloxetine Ciprofloxacin Potentially toxic levels avoid CYP2C9 Celecoxib Amiodarone Fluconazole Increased risk of AEs CYP2C19 Diazepam Omeprazole Increased risk of sedation CYP2D6 Codeine Tramadol Paroxetine Fluoxetine Increased risk of AEs Venlafaxine Midazolam CYP3A4 Fentanyl Reduced or no effect Clarithromycin Bicalutamide Grapefruit juice Increased risk of AEs Increased absorption TERMINOLOGY PHARMACOGENETICS is the study of how variation in an individual gene affects the response to drugs which can lead to adverse drug reactions, drug toxicity, therapeutic failure and drug interactions. POLYMORPHISMS refer to commonly occurring genetic variants (i.e. differences in DNA sequences). In most cases, a polymorphism is of little clinical consequence. However, a polymorphism in a critical coding or non-coding region can lead to altered protein synthesis with clinical implications such as abnormal drug responses. Genetic variability can affect an individual’s response to drug treatment by influencing pharmacokinetic and pharmacodynamic processes, e.g. cytochrome P450 isoenzymes, drug receptors, or transport proteins Several polymorphisms that affect drug metabolism have been identified ( poor hydroxylators and slow acetylators) Functional changes as a result of a polymorphism can have profound effects: Adverse drug reaction Toxicity Lack of effect Drug interaction Isoenzymes CYP2D6, CYP2C9 and CYP2C19 display high levels of polymorphism These have been shown to affect the response of individuals to many drugs Codeine Metabolised by CYP2D6 to morphine. PMs derive no analgesia from codeine. Drugs that inhibit CYP2D6 will mimic PM Ultra Metabolisers are at risk of lifethreatening adverse drug reactions as codeine is metabolised at a very high rate. Many drug interactions will go unrecognised If there is an unexpected change in patient’s condition, suspect drug interaction as well as disease Many drug interactions can develop insidiously One size (dose) does not fit all! Pharmacogenetics becoming more important Excretion Renal – most drugs Biliary – ( lipid soluble – diethylstilbestrol) – enterohepatic circulation increases bioavailability Half life ( T1/2) Time to steady state concentration = 3 to 5 half lives Use PCF3 tables Steady State Concentration Dose adjustment in frail, elderly and kids Discussion ( this lecture does not cover paediatric dosing) Dose adjustment in renal impairment See separate Drugs and Renal Disease Lecture -Sue Ayers, April 2006 ( to be circulated via email) Yorkshire Registrar Guidelines - Drug use in renal impairment BNF/SPC/AYP –( ASK YOUR PHARMACIST) Renal friendly opioids? Dose adjustment in Liver Disease See separate lecture ( To be circulated via email) BASIC PRINCIPLES : Dose adjustment in disease progression and at the end of life Discussion Drug formularies in palliative care Discussion Managing a pharmacy budget Discussion EL94 (14) annex B and EL 95 ( Circulated by email) PBC ( Practice based commisioning) PBR ( Payment by results) HRG ( Health Resources Groups) Tariff and non-tariff drugs ( high cost) Contracts SLAs Commissioning Prescribing issues GMC - Good Medical Practice: Providing good clinical care and Good Medical Practice: Maintaining & improving your performance Other professional standards – NMC http://www.nmc-uk.org/Publications/Standards/ RPS – MEP - http://www.rpharms.com/law-andethics/medicines-ethics-and-practice-guide.asp LOCAL MEDICINES MANAGEMENT POLICY ! Prescribing issues 2 Clinical Governance/ Risk Management NPSA http://www.npsa.nhs.uk/ MHRA http://www.mhra.gov.uk/index.htm Taking drugs abroad http://www.homeoffice.gov.uk/drugs/licensing/perso nal/ plus consulate of country visiting! “letter from your prescribing doctor or drug worker, which must confirm your name, travel itinerary, names of prescribed controlled drugs, dosages and total amounts of each to be carried” Personal License >3months supply Prescribing Issues – 3 Prescribing stationary FP10 – EXEMPTION http://www.nhs.uk/NHSEngland/Healthcosts/Pages/P rescriptioncosts.aspx Near miss and drug incident reporting systems Standard Resources to support prescribing OSCE fun !! The ultimate syringe driver /breakthrough calculation The domiciliary syringe driver writing nightmare! The “what schedule is this CD” game What schedule is this CD Oxycontin 20mg in 2 ml Injection Zomorph 10mg capsules Lorazepam 1mg tablets Buprenorphine 10mcg/hr patch Oramorph 10mg/5mls liquid Buprenorphine 35mcg/hr patch Temazepam 20mg tablets Co-codamol 30/500 soluble tablets Midazolam 10mg in 2ml Injection FP10s for Controlled Drugs Comply with the requirements of the Misuse of Drugs Act. ( Handwritten or computer generated since 1995) In practice there are only extra requirements for Schedule 2 and Schedule 3 controlled drugs. Prescriptions for Schedule 4 and Schedule 5 controlled drugs just have to meet the requirements for writing prescriptions for POMs. FP10s for temazepam do not have to comply with the above requirements. Validity of prescriptions for schedule 2, 3 & 4 controlled drugs is now restricted to 28 Schedule 2 and 3 CDs - Rx The prescriber's usual signature and the date If issued by a dentist, "for dental treatment only" The name and address of the patient The dose of the drug to be taken In the case of preparations, the form and, where appropriate, the strength of the preparation Either the total quantity of the preparation or the number of dose units in both words and figures “strong recommendation” that the maximum quantity is limited to 30 days for schedule 2, 3 & 4 controlled drugs. CDs post shipman http://www.dh.gov.uk/en/Publicationsandstatistics/P ublications/PublicationsPolicyAndGuidance/DH_409 7904 ( Crown Report ) Safer Management of controlled drugs http://www.dh.gov.uk/en/AdvanceSearchResult/index.h tm?searchTerms=controlled+drugs Accountable Officer Registers Patent held register? SOPs Classifications of Adverse Drug Reactions Mechanism (Type A vs Type B) Type A: Dose dependent and predictable. (intolerance/side effects). About 80% of ADRs Examples: Sedation with antipsychotic drugs. Hypokalaemia with diuretics. Liver failure with paracetamol overdose Theophylline toxicity when ciprofloxacin started Other Classifications Type B: Not related to dose and usually not related to the pharmacology of the drug. Unpredictable Examples: Allergic rash with amoxycillin (immune reaction – “allergy” or “hypersensitivity”) Renal failure with contrast dye for scans ( nonimmune reaction - “idiosyncratic” ) Type C: Chronic effects ( Benzo addiction) Type D: Delayed effects ( carcinogens/teratogens) Type E: End-of-treatment effects ( opiate withdrawal, beta blocker withdrawal – BP increase) Type F: Failure of therapy ( Oral contraceptive and drug interaction) Anaphylaxis and emergency boxes http://www.resus.org.uk/pages/anapost1.pdf#sea rch="anaphylaxis” Policies! Information Naloxone – use in palliative care Verbal orders Unlicensed Drugs /Drugs beyond license See PCF3 Local policy Terminology Off label Unlicensed Drug Unlicensed use Information for patient Clinical Trials Good Clinical Practice http://www.mhra.gov.uk/Howweregulate/Medicines/Ins pectionandstandards/GoodClinicalPractice/index.htm FAQs http://www.mhra.gov.uk/Howweregulate/Medicines/Ins pectionandstandards/GoodClinicalPractice/Frequentlya skedquestions/index.htm Polypharmacy/ understanding medicines Discussion Classifications of Adverse Drug Reactions Classification According to Severity a) b) c) d) Mild – maybe not even noticed by patient. eg Raised LFTs with lots of drugs. Moderate – requires corrective measures, but not hospitalisation. eg antibiotic rash. Major – organ damage and hospitalisation likely. eg cholestatic jaundice with chlorpromazine. Life threatening. eg pulmonary embolus caused by oral contraceptives. Classifications of Adverse Drug Reactions Classification According to Incidence EU classification:Used now for new SPC ( data sheets for medicines) Very common More than 10% Example: Drowsiness with carbamazepine. Common 1-10% Example: Fluid retention with carbamazepine. Uncommon 0.1-1% Example: Diarrhoea with carbamazepine. Rare 0.01-0.1% Example: Depression with carbamazepine. Very Rare Less than 0.01% Example: Arrhythmias with carbamazepine. The risk for an individual of dying during the year from any cause at all in the UK is about 1.1%. Organized by the Committee on Safety of Medicines (CSM) http://www.mhra.gov.uk/Safetyinformation/Reportingsafet yproblems/Reportingsuspectedadversedrugreactions/ind ex.htm “Yellow Cards” found at the back of the BNF or on-line https://yellowcard.mhra.gov.uk/ Can be completed by doctor, pharmacist or nurse etc ….. caring for the patient … OR THE PATIENT!!!! ( on-line) Facility to report available on SystmOne .. What Should be Reported? All reactions to new drugs (they have an inverted black triangle next to them in BNF or MIMS). Any serious reaction to all other drugs. Includes all prescription and OTC medicines. Includes vaccines, herbal products, blood products, dental and surgical materials, X-ray contrast media. Not nutrition products or dressings. ( Device reporting : MHRA website) Drugs in syringe drivers Resources Syringe Driver Handbook Palliativedrugs.com – SDSD Palliative Care Matters http://www.pallcare.info/mod.php?mod=sdrivers&men u=14 Mixing drugs in syringe drivers - issues Choice of syringe driver devices Drug interactions Discussion Resources Tolerance,dependance,addiction, discontinuation reactions Discussion Accessing drugs in the community Discussion