Transcript Document
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