Adverse Reactions
Any substance introduced into the body can pose a risk at normal doses, and all are potentially toxic if given in overdose
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
We will discuss risk in terms of side-effects, adverse drug reactions, and toxicity
Side-effects
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
Examples include drowsiness with the older antihistamines, constipation with opioids etc.
In some situations, a ‘side-effect’ can be a therapeutic effect e.g. antihistamines for sedation, opioids for diarrhoea
Adverse Drug Reactions (ADRs)
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
Type A ‘Predictable’ ADRs: Predicted from pharmacological
reaction and are usually dose-related (eg bradycardia from beta-blocker)
Type A by far the majority of ADRs encountered in clinical practice
With careful selection of drug, dose etc. many Type A ADRs can be avoided
Types of ADRs cont.
Type B: ‘Unpredictable’ ADRs: Unpredictable from
pharmacology of drug and are not dose-dependent; can be very serious
May not be picked up in clinical trials if low incidence
Often involve hypersensitivity reactions (eg penicillin anaphylaxis, malignant hyperthermia of anaesthesia, agranulocytosis with clozapine)
Sometimes reclassified as Type A after a period of clinical use if mechanism is elucidated
Incidence of ADRs
Many surveillance studies have been performed both in hospital and community
In addition meta-analyses and systematic reviews
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.
In both cases, the great majority of ADRs were deemed preventable
The economic costs of ADRs are very high
Patient Risk Factors for ADRs
Age (young, elderly, renal/hepatic function)
Disease State e.g. CHF, HIV
Gender: females approx. 1.5 x greater risk
Patient Risk Factors for ADRs cont.
Genetics: different phenotypes for handling drugs
Immunological factors: some patients hypersensitive
Number of drugs patient is taking: an obvious risk factor, especially in the elderly
Drug Risk Factors for ADRs
Narrow therapeutic index e.g. digoxin, lithium
Route of administration e.g. iv drugs can
produce immediate effects
Formulation/bioavailability: as discussed previously
Drug Risk Factors for ADRs cont.
Additives/excipients: patients may be hypersensitive to these rather than the active drug
In general, patients may not receive sufficient information about side-effects, ADRs etc. in advance
Identification of ADRs
Establishing causal relationships difficult
Accurate drug history required (including non-prescription and complementary products
Temporal relationship needs to be established (many ADRs can be ‘delayed’ reactions)
Identification of ADRs cont.
Detailed medical history required
‘Dechallenge’ and ‘rechallenge’ may or may not be possible (or ethical!)
ADR examples
Iron containing preparations given orally – 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
Vitamin A containing preparations– Rough skin– Dry hair– Enlarged liver– Teratogenic
These adverse reactions only occur at very large doses (e.g. several times usual therapeutic dose)
Pharmacovigilance
ADR reporting systems
Followed from thalidomide tragedy in 1960s
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.)
Also several national reporting systems
Voluntary Reporting Scheme in NZ
Reporting form in MIMS etc
Sent to Centre for Adverse Reaction Monitoring (CARM) - based at University of Otago
Reports assessed by Medical Assessor, with reference to prescribers, to produce a database of ADRs
Voluntary Reporting Scheme in NZ
Reports to Medicines Adverse Reactions Committee at MoH
Annual report by Medsafe
A good scheme but main problem with all voluntary schemes is ‘under-reporting’
Intensive Reporting
Intensive Medicines Monitoring Programme (IMMP); also based at Otago
A small number (about six – see MIMS) of newly marketed medicines on the scheme at any one time
Intensive Reporting cont.
All prescriptions for patients on these agents are followed – pharmacist records kept
Successful in early identification of new ADRs (e.g. ACE inhibitor cough)
Only a handful of such schemes worldwide, NZ reputation very high
Poisoning (Toxicology)
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
Maintenance of ventilation/blood pressure
Reducing absorption- emptying stomach by emesis or washouts- substances to bind poison
Increasing elimination- renal elimination by altering pH of urine- haemoperfusion
Ensure hydration, electrolyte balance
Individual Agents contd.
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
Iron - iron chelating agent desferrioxamine IV as antidote
Drug Interactions
Mostly drug-drug interactions (DDIs), but
Also drug-food, drug-alcohol interactions
Don’t forget complementary therapies and non-prescription medicines
Not all DDI’s are ‘bad’ – e.g. sometimes we use a DDI to enhance effects of one of the agents
Estimated approx. 20% of ADRs due to DDIs
Drug Interactions cont.
Many theoretical interactions but really we want to know those of therapeutic significance
Many clinically important drug interactions involve the effect of one drug on the metabolism of another
Drug-nutrient interactions
Specific drug-nutrient interactions listed in ‘Dietitians New Zealand Inc. Clinical Handbook’
Interaction explained briefly, including a mechanism and a practical recommendation
Several other interaction texts exist including ‘Stockley’s Drug Interactions’
Object or Precipitant
Drug whose effect or action is altered by introduction of another agent is the object drug
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):
Digoxin Lithium Warfarin Aminoglycosides Cytotoxics Levodopa Verapamil Sulphonylureas
More Drugs of Concern
Patient dependent on therapeutic effect: Immunosuppressants (e.g. cyclosporin) Glucocorticoids Oral contraceptives Antiepileptics Antipsychotics Antiarrhythmics Antiretrovirals
Enzyme inducers or inhibitors: 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
Occur before drugs introduced to the body e.g. absorption of benzodiazepines onto rubber, or absorption of carbamazepine to an enteral feed tube
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.
Exposure time and number of drugs mixed important
Usually picked up by pharmacist or checking BNF etc.
2. Pharmacodynamic Interactions
Direct competition at receptor sites- salbutamol/metoprolol- morphine/naloxone
Additive effects at receptor sites - e.g. use of two NSAIDs concurrently
2. Pharmacodynamic Interactions cont.
Indirect effects at site of action
- amiloride plus potassium supplements (hyperkalaemia)
- NSAIDs and warfarin (increased risk of bleeding)
3. Pharmacokinetic Interactions
Absorption
– 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.
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.
Metabolism The great majority of drug interactions of clinical significance
involve the effect of one drug on the metabolism of another
Phase I metabolosm in the liver is mediated through the Cytochrome P450 mixed oxidase system
In fact Cytochrome P450 is comprised of nearly 60 isoenzymes, each expressed from an individual gene
We are just starting to elucidate the importance of genetic determination of each individual’s CYP profile
CYP Profiling
Four main families of CYP450 enzymes
Divided into sub-families; Sub-family enzymes numbered
For example CYP1A2 etc.
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
Well known enzyme inhibitors include cimetidine; erythromycin, clarithromycin; ciprofloxacin; azoles e.g. fluconazole; allopurinol, antivirals
By inhibiting CYP enzymes, they will reduce the metabolism of object drugs using the same metabolic pathway
Enzyme Inhibitors cont.
If the object drug has a low therapeutic index then adverse effects may occur
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)
Similar concerns apply to theophylline, cyclosporin, phenytoin, oc’s etc. as object drugs
Enzyme Inducers
Well known enzyme inducers include rifampicin, barbiturates, carbamazepine, phenytoin, St John’s Wort; also alcohol and cigarette smoking
Involves production of additional enzyme so takes place gradually over several days or weeks
Enzyme Inducers cont.
Enzyme induction increases metabolism of the object drug and decreases its pharmacological effects
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
Grapefruit contains flavonoids (CYP3A4 inhibitor in intestine) – increases bioavailability of felodipine, statins
Alcohol and CNS drugs (additive or synergistic effects with tricyclics, sedatives, opioids etc.)
Complementary medicines (eg St John’s Wort) – enzyme inhibitor: care with cyclosporin etc.