Adverse Reactions, Pharmacovigilance and Interactions

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.

Distribution

Generally not clinically significant

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.

Drug-Food, Drug-Alcohol Interactions cont.

Vit K – Warfarin (antagonism of warfarin effects)

MAOIs and certain foods containing tyramine (cheese etc.) – increase blood pressure

Disulfiram, metronidazole and alcohol (build up of acetaldehyde due to alcohol dehydrogenase inhibition)