17TYPE C Adverse effects that occur with prolonged but not short duration therapy.

For example,
phenothiazine-induced tardive dyskinesia.

TYPE D Occur some time after discontinuation of treatment.

TYPE E Effects occur on withdrawal of a drug, especially when treatment is stopped abruptly, e.g. the
benzodiazepine withdrawal syndrome, adrenocortical insufficiency after steroid treatment.

18Type G adverse reactions involve irreversible genetic damage.

Carcinogens: Some drugs such as azathioprine, an immunosuppressant, have been found to be

carcinogens – azathioprine increases the risk of developing non-Hodgkins lymphoma.
Cyclophosphamide linked with bladder cancer

Genotoxins: Some drugs, fungal infections and solvents used in drug manufacture may be genotoxic
i.e. alter DNA synthesis in vivo. Certain anti-cancer drugs are also genotoxic

Teratogens: Some drugs, when taken during pregnancy can damage the fetus e.g. isotretinoin for
acne or ACE inhibitors for hypertension or heart failure

31The inability of the FDA to effectively warn healthcare providers and patients about drug
interactions and our inability to translate existing knowledge into changes in prescribing have
resulted in huge economic consequences for the pharmaceutical industry and the loss from the
marketplace of effective drugs, including terfenadine, mibefradil, astemizole, grepafloxacin, and
cisapride.

These five drugs were removed from the market or restricted in their use because it became clear
that they continued to be prescribed in an unsafe manner, even after multiple warning letters were
disseminated by the manufacturer and the FDA to health care professionals concerning their proper
use. Each of these drugs has value in the pharmaceutical marketplace, and each has value to
patients. However, because the manufacturer and the FDA could not prevent co-prescription of
these drugs with interacting drugs resulting in fatal interactions, the risk associated with continued
widespread availability could not be justified.

35Adverse drug reactions are a major clinical problem. Studies have found that around 6.5% of
hospital admissions are due to adverse drug reactions, with 10 000 of all admissions to hospital
being due to ADRs. Furthermore 10 to 20% of patients will experience an adverse reaction during
their stay in hospital. Of these approx 7% will be serious and 0.1-0.3% fatal.

It is therefore clear to see that, adverse drug reactions increase hospital admission rates, increase
morbidity and mortality and thus significantly increase health care costs.

Up to 40% patients receiving drugs in the community are though to experience ADRs. It is difficult to
study ADRs in the community and there are very few well designed studies

Ref for 4) In a 1979 study in general practice 41% of 817 patients surveyed were thought to have
certainly or probably experienced an ADR.
1225 admissions related to ADR 6.5%

ADR directly related to admission in 80% cases

76% patients > 65 years old

Mean hospital stay 8 days

2.3% (28 patients) died as direct result of ADR

15 GI bleeding

17 Aspirin implicated (alone or combination)

5 Renal failure (diuretic and/or ACE)

ADRs responsible for death of 0.15% of patients

72% reactions defined as avoidable

95% ADR’s defined as type A

36Less severe reactions

A patient may decide to stop taking their medication if they are experiencing an adverse reaction to
it. This non-compliance may lead to re-emergence of the original disease and can be particularly
important if the treatment is prophylactic. E.g malaria prophylaxis, the oral contraceptive.

For example, if a patient has an antibiotic allergy, this limits the options for treating infections.

For example a first-line drug may have to be stopped due to an adverse reaction, and a less effective
second-line drug started.

Obviously experiencing an adverse reaction is not pleasant so drug therapy can affect the patients
quality of life. In some cases medicines may have a greater impact on the patient than the symptoms
of the disease itself. e.g. Drugs used to treat hypertension often produce adverse effects while
hypertension itself often has no symptoms.

Drug-induced disease is rarely specific and usually mimics naturally occurring disease thus causing
diagnostic problems.

40Dose optimisation E.g.. reducing doses once responded to treatment – high dose steroids
reducing as per BTS. Risks of unnecessary lengths of course steroids adrenal suppression. CHM
Current Problems in Pharmacovigilance, volume 31, May 2006

Avoid / reduce interactions

Many drugs interact with warfarin

NB herbal interactions. St Johns Wort reducing efficacy of theophylline, etc mechanism. CHM
Current Problems in Pharmacovigilance
Food stuff - warfarin and cranberry juice to increase effect INR, Simvastatin and grapefruit juice,
CHM Current Problems in Pharmacovigilance

Prophylactic therapy PPI cover for low dose aspirin for IHD cover in patients at high risk of GI
problems, to prevent GI bleeds due to low dose aspirin – incidence. Bisphosphonates for patients on
long term oral steroids to prevent osteoporosis (evidence)

Avoid new / black triangle drugs Only given to few 1000 patients allows detection of common ADR’s
but not rare ones. Information on rare or long term ADRs not known.

Avoid prescribing contra-indicated drugs use of a non-selective beta-blocker in an asthmatic ®

bronchospasm

Drug use in an inappropriate clinical indication or medically unnecessary antibiotics for a viral
infection will not cure the infection but will expose patients to the adverse effects of the drug.

Monitoring treatment BMJ 2003;327;1179-1181

e.g. diuretics in CHF patients monitor U+E to ensure not dehydrated or low K, also monitor
symptoms of HF. Optimise dose through robust monitoring – multi disciplinary approach using
specialist nurses, non-medical prescribers, Drs and patient.

Patient counselling BMJ 2006;333:522 telephone counselling patients improves compliance in the
elderly on poly pharmacy (can consider non-compliance as an adverse event).

Better communication on ADR’s between healthcare professionals may reduce unnecessary re-
prescription of discontinued medicines and reduce ADRs in elderly. 27% drugs discontinued in
hospital were re-prescribed in primary care .

Re-prescription after ADR in the elderly Archives of Internal medicine 2006;145(4):284-293

better communications between HCP re ADR’s may reduce unnecessary re-prescription and thereby
reduce the occurrence of ADR’s. 3.

High dose steroids (ensuring patients have steroid cards (multi-disciplinary responsibility to ensure
medicines are used safely). Fatal case of child in Scotland on high dose inhaled steroids, poor
communication. Ref: NeLM

Further information available in BNF

Factors predisposing to pharmacological actions

Pharmacokinetic -Digoxin toxicity due to decreased elimination if renal function impaired

Pharmacodynamic - Indomethacin causing LVF due to water and sodium retention

Drug-drug interaction -Clarithromycin inhibits the metabolism of atorvastatin increasing the risk of
myopathy.

Elderly patients - Altered drug handling, Co-morbidity, PolypharmacyPrescription of 5 drugs

simultaneously increases chance of ADR occurring by 50%
Children - Action and pharmacokinetics different to adults, Not tested in children / ‘off-label use’,
May develop delayed ADRs not seen in adults

Patients with renal and liver impairment

Pregnant or breastfeeding women

41Not all ADRs will be apparent to the patient or the health care professional as ADRs can mimic any
disease process. Always be alert to the possibility of ADRs as a cause of the patients symptoms.
Some common criteria to look out for would be the timing of the reaction with the drug treatment,
did it happen soon after treatment started, after a dosage increase, disappeared when treatment
stopped or reappeared when restarted. Abnormal clinical and laboratory measurements can also be
a good criteria for diagnosing ADR. Patients can be a really important source of information about
ADRs , listen to them and ask questions about how their medication is suiting them

42Up to 40% patients receiving drugs in the community are though to experience ADRs. It is difficult
to study ADRs in the community and there are very few well designed studies

NSAID use is associated with significant morbidity and mortality in the UK each year. There is a
strong association between NSAID use and likelihood for upper GI emergency admission.

Ref for 2) The data recorded in the trial was extrapolated to give the estimated UK figures. The study
was a retrospective survey of case notes of all emergency upper GI admissions per annum
attributable to NSAID use. The study was undertaken at 2 District General Hospitals in the North
West of England (catchment population 550,000). Matched controls were emergency admissions not
caused by upper GI diagnoses. (Blower et al. Emergency admissions for upper gastrointestinal
disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291)