Pharmacology, Therapeutics and medicines management

Sue Ayers Advanced Pharmacists Palliative Medicine

March 2011

Index of learning outcomes - 1Pharmacokinetics and PharmacodynamicsPharmacogeneticsDose adjustments in frail, elderly and

children Dose adjustment in renal failureDose adjustment in Liver Failure Dose adjustment in disease progression and

at the end of life

Index of learning outcomes - 2Drug 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 - 3Polypharmacy Understanding medicines Medicine related adverse event reporting Alternative routes of administration Drugs in syringe driversDrug interactions Tolerance, dependence, addiction,

discontinuation reactions Accessing drugs in the community

Pharmacokinetics/dynamicsPharmacokinetics 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 barriersMany 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 barriersCarrier-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 formFree 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 toMelanin – Chloroquine ( particularly in the

retina) Tetracyclines – bones and teeth Amiodarone – liver and lung

Routes of administration Routes – advantages and disadvantagesFrom 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, cholestyramineOral Vancomycin/nystatin

Bioavailability proportion of drug that enters into the

systemic circulation after oral administration doesn't indicate rate of absorption just total

amountUsually 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 secretionsIn body water drugs exist as free and bound,

ionised and unionised forms depending on Ph Drugs move across compartmentsBBBis 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.aspxBNF http://www.medicines.org.uk/emc/ (SPC) Local organisational prescribing policy/guideline/formularyCommissioners’/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 weightHeparin 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/kgEthanol, phenytoin 0.55Paracetamol, diazepam 1-2Morphine, digoxin 2-5Nortriptyline >10Lipid insoluble drugs mainly stay in plasma

and interstitial fluid . Most don’t cross BBBLipid soluble drugs reach all compartments

and may go into fat/tissue ( Vd > total body volume)

Metabolism

http://www.youtube.com/watch?v=xtI0pMEZy7cMainly 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 hydrogencarried 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 reactionsusually 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 ADRhttp://medicine.iupui.edu/clinpharm/ddis/

table.aspGenetic polymorphisms

Enzyme Drug affected

Inducer Effect

CYP1A2 Duloxetine SmokingReduced effect(approx 50% lower

plasma concentrations)

CYP2C9 Celecoxib Carbamazepine Reduced effect

CYP2C19 Diazepam Carbamazepine Reduced effect

CYP3A4 MidazolamAlfentanilFentanylOxycodone

CarbamazepineHigh dose dexamethasone

Reduced effect

Enzyme Drug affected

Inhibitor Effect

CYP1A2 Duloxetine CiprofloxacinPotentially toxic levels - avoid

CYP2C9 CelecoxibAmiodaroneFluconazole

Increased risk of AEs

CYP2C19 Diazepam OmeprazoleIncreased risk of sedation

CYP2D6

CodeineTramadol

Venlafaxine

ParoxetineFluoxetine

Reduced or no effect

Increased risk of AEs

CYP3A4Midazolam

Fentanyl

ClarithromycinBicalutamideGrapefruit juice

Increased risk of AEs

Increased absorption

PHARMACOGENETICSPHARMACOGENETICS is the study of is the study of how variation in an individual gene how variation in an individual gene affects the response to drugs which affects the response to drugs which can lead to adverse drug reactions, can lead to adverse drug reactions, drug toxicity, therapeutic failure and drug toxicity, therapeutic failure and drug interactions.drug interactions.

TERMINOLOGYTERMINOLOGY

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 reactionToxicityLack of effectDrug 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 PMUltra Metabolisers are at risk of life-threatening adverse drug reactions as codeine is metabolised at a very high rate.

Many drug interactions will go unrecognisedIf there is an unexpected change in patient’s

condition, suspect drug interaction as well as disease

Many drug interactions can develop insidiouslyOne size (dose) does not fit all!

Pharmacogenetics becoming more important

ExcretionRenal – 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 kidsDiscussion ( 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 budgetDiscussion 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) ContractsSLAsCommissioning

Prescribing issuesGMC - 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-and-

ethics/medicines-ethics-and-practice-guide.asp

LOCAL MEDICINES MANAGEMENT POLICY !

Prescribing issues 2Clinical 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/personal/ 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/Prescriptioncosts.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 CDOxycontin 20mg in 2 ml InjectionZomorph 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 dateIf issued by a dentist, "for dental treatment only"The name and address of the patientThe dose of the drug to be takenIn the case of preparations, the form and, where appropriate, the strength of the preparationEither 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 shipmanhttp://www.dh.gov.uk/en/

Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4097904 ( Crown Report )

Safer Management of controlled drugs http://www.dh.gov.uk/en/AdvanceSearchResult/

index.htm?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 ( non- immune 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#search="anaphylaxis” Policies! Information Naloxone – use in palliative care Verbal orders

Unlicensed Drugs /Drugs beyond licenseSee PCF3Local policy Terminology Off label Unlicensed Drug Unlicensed use Information for patient

Clinical Trials Good Clinical Practice http://www.mhra.gov.uk/Howweregulate/

Medicines/Inspectionandstandards/GoodClinicalPractice/index.htm

FAQs http://www.mhra.gov.uk/Howweregulate/

Medicines/Inspectionandstandards/GoodClinicalPractice/Frequentlyaskedquestions/index.htm

Polypharmacy/ understanding medicinesDiscussion

Classifications of Adverse Drug ReactionsClassification According to Severity

a) Mild – maybe not even noticed by patient. eg Raised LFTs with lots of drugs.

b) Moderate – requires corrective measures, but not hospitalisation. eg antibiotic rash.

c) Major – organ damage and hospitalisation likely. eg cholestatic jaundice with chlorpromazine.

d) Life threatening. eg pulmonary embolus caused by oral contraceptives.

Classifications of Adverse Drug Reactions

Classification According to IncidenceEU 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/Reportingsafetyproblems/Reportingsuspectedadversedrugreactions/index.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 – SDSDPalliative Care Mattershttp://www.pallcare.info/mod.php?

mod=sdrivers&menu=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