Transcript Pharmacology for Nurse Prescribing

Adverse Reactions,
Pharmacovigilance and Interactions
Adverse Reactions
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Any substance introduced into the body can pose a
risk at normal doses, and all are potentially toxic if
given in overdose
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However, we should keep in mind that the great
majority of treatments are safe and effective if the
principles of pharmacology and pharmacokinetics are
carefully applied
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We will discuss risk in terms of side-effects, adverse
drug reactions, and toxicity
Side-effects
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A consequence of the pharmacological mechanism of
action of the drug – usually due to presence of
receptors in a number of tissues or lack of receptor
specificity
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Examples include drowsiness with the older
antihistamines, constipation with opioids etc.
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In some situations, a ‘side-effect’ can be a therapeutic
effect e.g. antihistamines for sedation, opioids for
diarrhoea
Adverse Drug Reactions (ADRs)
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An ADR is any response to a drug that is
undesirable and unintended and that occurs
at doses used in humans, for prophylaxis,
diagnosis or therapy, excluding therapeutic
failure
WHO definition
Types of ADRs
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Type A
‘Predictable’ ADRs: Predicted from pharmacological
reaction and are usually dose-related (eg bradycardia
from beta-blocker)
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Type A by far the majority of ADRs encountered in
clinical practice
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With careful selection of drug, dose etc. many Type A
ADRs can be avoided
Types of ADRs cont.
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Type B:
‘Unpredictable’ ADRs: Unpredictable from
pharmacology of drug and are not dose-dependent;
can be very serious
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May not be picked up in clinical trials if low incidence
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Often involve hypersensitivity reactions (eg penicillin
anaphylaxis, malignant hyperthermia of anaesthesia,
agranulocytosis with clozapine)
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Sometimes reclassified as Type A after a period of
clinical use if mechanism is elucidated
Incidence of ADRs
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Many surveillance studies have been
performed both in hospital and community
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In addition meta-analyses and systematic
reviews
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ADRs responsible for hospital admissions
average about 5% (range 2-12%); in the
community the range is far greater (2-40%)
reflecting the complexity of data gathering and
the criteria used
Incidence of ADRs cont.
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In both cases, the great majority of ADRs
were deemed preventable
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The economic costs of ADRs are very high
Patient Risk Factors for ADRs
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Age (young, elderly, renal/hepatic function)
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Disease State e.g. CHF, HIV
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Gender: females approx. 1.5 x greater risk
Patient Risk Factors for ADRs cont.
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Genetics: different phenotypes for handling drugs
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Immunological factors: some patients
hypersensitive
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Number of drugs patient is taking: an obvious risk
factor, especially in the elderly
Drug Risk Factors for ADRs
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Narrow therapeutic index e.g. digoxin, lithium
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Route of administration e.g. iv drugs can
produce immediate effects
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Formulation/bioavailability: as discussed
previously
Drug Risk Factors for ADRs cont.
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Additives/excipients: patients may be
hypersensitive to these rather than the active
drug
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In general, patients may not receive sufficient
information about side-effects, ADRs etc. in
advance
Identification of ADRs
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Establishing causal relationships difficult
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Accurate drug history required (including nonprescription and complementary products
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Temporal relationship needs to be established
(many ADRs can be ‘delayed’ reactions)
Identification of ADRs cont.
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Detailed medical history required
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‘Dechallenge’ and ‘rechallenge’ may or may not
be possible (or ethical!)
ADR examples
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Iron containing preparations given orally
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GI irritation and pain
Nausea appears to be dose related
Altered bowel habit, either diarrhoea or constipation
These side effects can occur at common
therapeutic doses
Choice of which Iron preparation prescribed
should be guided by that individual’s response
to that particular preparation (try a fully funded
type first)
ADR examples
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Vitamin A containing preparations
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Rough skin
Dry hair
Enlarged liver
Teratogenic
These adverse reactions only occur at very
large doses (e.g. several times usual
therapeutic dose)
Pharmacovigilance
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ADR reporting systems
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Followed from thalidomide tragedy in 1960s
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Data on safety gathered by pharmaceutical companies
from pre-clinical testing, clinical trials and
postmarketing surveillance studies (case studies,
cohort studies, case-control studies etc.)
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Also several national reporting systems
Voluntary Reporting Scheme in NZ
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Reporting form in MIMS etc
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Sent to Centre for Adverse Reaction
Monitoring (CARM) - based at University of
Otago
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Reports assessed by Medical Assessor, with
reference to prescribers, to produce a
database of ADRs
Voluntary Reporting Scheme in NZ
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Reports to Medicines Adverse Reactions
Committee at MoH
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Annual report by Medsafe
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A good scheme but main problem with all
voluntary schemes is ‘under-reporting’
Intensive Reporting
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Intensive Medicines Monitoring Programme
(IMMP); also based at Otago
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A small number (about six – see MIMS) of
newly marketed medicines on the scheme at
any one time
Intensive Reporting cont.
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All prescriptions for patients on these agents
are followed – pharmacist records kept
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Successful in early identification of new ADRs
(e.g. ACE inhibitor cough)
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Only a handful of such schemes worldwide,
NZ reputation very high
Poisoning (Toxicology)
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Due to toxic effects (overdosage) of drugs and other
agents
Both accidental and deliberate causes
Children at special risk – especially of Iron or
Paracetamol overdose
Drugs often in combinations, making treatment difficult
High number of acute medical admissions
Treatment: non-specific measures
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Maintenance of ventilation/blood pressure
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Reducing absorption
- emptying stomach by emesis or washouts
- substances to bind poison
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Increasing elimination
- renal elimination by altering pH of urine
- haemoperfusion
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Ensure hydration, electrolyte balance
Individual Agents contd.
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Paracetamol - causes liver damage which
may be fatal, due to production of toxic
metabolite when normal liver enzyme system
is saturated (at about 10g of paracetamol).
Methionine (orally) or n-acetylcysteine
(infusion) may be effective antidotes if
administered early
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Iron - iron chelating agent desferrioxamine IV
as antidote
Drug Interactions
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Mostly drug-drug interactions (DDIs), but
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Also drug-food, drug-alcohol interactions
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Don’t forget complementary therapies and nonprescription medicines
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Not all DDI’s are ‘bad’ – e.g. sometimes we use a DDI
to enhance effects of one of the agents
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Estimated approx. 20% of ADRs due to DDIs
Drug Interactions cont.
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Many theoretical interactions but really we
want to know those of therapeutic
significance
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Many clinically important drug interactions
involve the effect of one drug on the
metabolism of another
Drug-nutrient interactions
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Specific drug-nutrient interactions listed in
‘Dietitians New Zealand Inc. Clinical Handbook’
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Interaction explained briefly, including a
mechanism and a practical recommendation
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Several other interaction texts exist including
‘Stockley’s Drug Interactions’
Object or Precipitant
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Drug whose effect or action is altered by
introduction of another agent is the object drug
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Drug which alters or precipitates a change in
the effect of the other drug is the precipitant
drug
Any Particular Drugs?
Special care must be taken with patient on low
therapeutic index/steep dose-response curve
medicines (consider how these medicines will
‘mix’ with what you are prescribing):
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Digoxin
Lithium
Warfarin
Aminoglycosides
Cytotoxics
Levodopa
Verapamil
Sulphonylureas
More Drugs of Concern
Patient dependent on therapeutic effect:
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Immunosuppressants (e.g. cyclosporin)
Glucocorticoids
Oral contraceptives
Antiepileptics
Antipsychotics
Antiarrhythmics
Antiretrovirals
Enzyme inducers or inhibitors:
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Inhibitors e.g. cimetidine, erythromycin
Inducers e.g. barbiturates, antiepileptics, rifampicin
Mechanisms
1. Pharmaceutical incompatabilities
2. Pharmacodynamic interactions
3. Pharmacokinetic interactions (ADME)
1. Pharmaceutical Incompatibilities
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Occur before drugs introduced to the body e.g.
absorption of benzodiazepines onto rubber, or
absorption of carbamazepine to an enteral feed tube
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Often involves precipitation of additives to intravenous
fluids and other formulations e.g. precipitation of certain
antibiotics in IV fluids, neomycin in aqueous cream etc.
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Exposure time and number of drugs mixed important
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Usually picked up by pharmacist or checking BNF etc.
2. Pharmacodynamic Interactions
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Direct competition at receptor sites
- salbutamol/metoprolol
- morphine/naloxone
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Additive effects at receptor sites
- e.g. use of two NSAIDs concurrently
2. Pharmacodynamic Interactions
cont.
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Indirect effects at site of action
- amiloride plus potassium supplements
(hyperkalaemia)
- NSAIDs and warfarin (increased risk of
bleeding)
3. Pharmacokinetic Interactions
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Absorption
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Chelation describes the process where two
separate parts of a mixture will bind strongly to each
other
Many metal ions (as supplements or antacids ) will
bind drugs, thereby preventing them from being
absorbed.
E.g. antacids, Ca or Fe containing products given at
the same time as doxycycline will prevent
absorption of the antibiotic.
3. Pharmacokinetic Interactions cont.
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Absorption
- Gastric emptying and motility
Drugs with anticholinergic effects (e.g, tricyclic
antidepressants) reduce gastric emptying and
decrease bioavailability of levodopa
Metoclopramide increases gastric emptying
and speeds absorption of paracetamol
Pharmacokinetic Interactions cont.
Distribution
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Generally not clinically significant
Pharmacokinetic Interactions cont.
Metabolism
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The great majority of drug interactions of clinical significance
involve the effect of one drug on the metabolism of another
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Phase I metabolosm in the liver is mediated through the
Cytochrome P450 mixed oxidase system
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In fact Cytochrome P450 is comprised of nearly 60 isoenzymes,
each expressed from an individual gene
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We are just starting to elucidate the importance of genetic
determination of each individual’s CYP profile
CYP Profiling
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Four main families of CYP450 enzymes
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Divided into sub-families; Sub-family enzymes numbered
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For example CYP1A2 etc.
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It is beyond this course to give further detail but CYP2D6
is well studied and shows inter-individual variability and
CYP3A4 is involved in the metabolism of many drugs (it
is found both in liver and intestinal epithelium)
Enzyme Inhibitors
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Well known enzyme inhibitors include
cimetidine; erythromycin, clarithromycin;
ciprofloxacin; azoles e.g. fluconazole;
allopurinol, antivirals
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By inhibiting CYP enzymes, they will reduce
the metabolism of object drugs using the same
metabolic pathway
Enzyme Inhibitors cont.
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If the object drug has a low therapeutic index
then adverse effects may occur
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For example, if warfarin is the object drug, the
risk of bleeding is markedly increased due to
rise in blood levels of warfarin (not being
metabolised)
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Similar concerns apply to theophylline,
cyclosporin, phenytoin, oc’s etc. as object
drugs
Enzyme Inducers
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Well known enzyme inducers include
rifampicin, barbiturates, carbamazepine,
phenytoin, St John’s Wort; also alcohol and
cigarette smoking
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Involves production of additional enzyme so
takes place gradually over several days or
weeks
Enzyme Inducers cont.
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Enzyme induction increases metabolism of the
object drug and decreases its pharmacological
effects
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For therapeutically important object drugs (e.g.
cyclosporin, oral contraceptives,
corticocosteroids, warfarin) there is a risk of
therapeutic failure
Pharmacokinetic Interactions cont.
Excretion
 Changes in urinary pH
- At alkaline pH weak acids are not reabsorbed and
therefore excreted (eg salicylates)
- At acid pH weak bases are not reabsorbed and
therefore excreted (eg amphetamines)
- Urine acidification or alkalinisation used to treat
poisoning – or to try to mask drugs used in sports or for
illicit drug screening!
Pharmacokinetic Interactions cont.
Excretion
Changes in active excretion
- some drugs compete for the same active transport
system in the kidney tubule
- examples include probenecid (excreted preferentially)
and penicillins or antiretrovirals; methotrexate and
NSAIDs (excreted preferentially)
Drug-Food, Drug-Alcohol
Interactions
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Grapefruit contains flavonoids (CYP3A4
inhibitor in intestine) – increases
bioavailability of felodipine, statins
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Alcohol and CNS drugs (additive or
synergistic effects with tricyclics, sedatives,
opioids etc.)
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Complementary medicines (eg St John’s
Wort) – enzyme inhibitor: care with
cyclosporin etc.
Drug-Food, Drug-Alcohol
Interactions cont.
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Vit K – Warfarin (antagonism of warfarin
effects)
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MAOIs and certain foods containing tyramine
(cheese etc.) – increase blood pressure
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Disulfiram, metronidazole and alcohol (build
up of acetaldehyde due to alcohol
dehydrogenase inhibition)