3. INTRODUCTION
• Adverse drug reactions are unwanted effects caused by normal therapeutic doses.
• Drugs are great mimics of disease, and adverse drug reactions present with diverse
clinical signs and symptoms.
• The classification proposed by Rawlins and Thompson (1977) divides reactions into
type A and type B
• Type A reactions, which constitute approximately 80% of adverse drug reactions,
are usually a consequence of the drug’s primary pharmacological effect (e.g.
bleeding from warfarin) or a low therapeutic index (e.g. nausea from digoxin), and
they are therefore predictable.
• They are dose-related and usually mild, although they may be serious or even fatal
(e.g. intracranial bleeding from warfarin).
• Such reactions are usually due to inappropriate dosage, especially when drug
elimination is impaired.
• The term ‘side effects’ is often applied to minor type A reactions
4. INTRODUCTION
• Type B (‘idiosyncratic’) reactions are not predictable from the drug’s
main pharmacological action, are not dose-related and are severe,
with a considerable mortality.
• The underlying pathophysiology of type B reactions is poorly if at all
understood, and often has a genetic or immunological basis.
• Type B reactions occur infrequently (1:1000–1:10 000 treated
subjects being typical).
6. INTRODUCTION
Three further minor categories of adverse drug reaction have been
proposed:
1. type C – continuous reactions due to long-term drug use (e.g.
neuroleptic-related tardive dyskinesia or analgesic nephropathy)
2. type D – delayed reactions (e.g. alkylating agents leading to
carcinogenesis, or retinoid-associated teratogenesis)
3. type E end-of-use reactions, such as adrenocortical insufficiency
following withdrawal of glucocorticosteroids, or withdrawal syndromes
following discontinuation of treatment with benzodiazepines
7. IDENTIFICATION OF THE DRUG AT FAULT
• It is often difficult to decide whether a clinical event is drug related,
and even when this is probable, it may be difficult to determine which
drug is responsible, as patients are often taking multiple drugs.
One or more of several possible approaches may be appropriate.
1. A careful drug history is essential:
Did the clinical event and the time course of its development fit with
the duration of suspected drug treatment and known adverse drug
effects?
Did the adverse effect reverse upon drug withdrawal and, upon
rechallenge with the drug, reappear?
Were other possible causes reasonably excluded?
8. IDENTIFICATION OF THE DRUG AT FAULT
2. Provocation testing.
• This involves giving a very small amount of the suspected drug and seeing
whether a reaction ensues,
• Provocation tests should only be undertaken under expert guidance, after
obtaining informed consent, and with resuscitation facilities available.
3. Serological testing and lymphocytes testing.
• Serological testing is rarely helpful, circulating antibodies to the drug do
not mean that they are necessarily the cause of the symptoms.
4. The best approach in patients on multiple drug therapy is to stop all
potentially causal drugs and reintroduce them one by one until the drug at
fault is discovered
12. INTRODUCTION
Drug interaction is the modification of the action of one drug by another.
There are three kinds of mechanism:
1. Pharmaceutical
2. Pharmacodynamic
3. Pharmacokinetic.
• Pharmaceutical interactions occur by chemical reaction or physical interaction when
drugs are mixed.
• Pharmacodynamic interactions occur when different drugs each influence the same
physiological function, the result of adding a second such drug during treatment with
another may be to increase the effect of the first (e.g. alcohol increases sleepiness
caused by benzodiazepines).
• Conversely, for drugs with opposing actions, the result may be to reduce the effect of
the first (e.g. indometacin increases blood pressure in hypertensive patients treated
with an antihypertensive drug such as losartan)
13. INTRODUCTION
• Pharmacokinetic interactions occur when one drug affects the
pharmocokinetics of another (e.g. by reducing its elimination from
the body or by inhibiting its metabolism)
• Drug interaction is important because, whereas judicious use of more
than one drug at a time can greatly benefit patients, adverse
interactions are not uncommon, and may be catastrophic, yet are
often avoidable.
• Multiple drug use (‘polypharmacy’) is extremely common, so the
potential for drug interaction is enormous
14. USEFUL INTERACTIONS
INCREASED EFFECT
• Drugs can be used in combination to enhance their effectiveness.
• Disease is often caused by complex processes, and drugs that influence
different components of the disease mechanism may have additive
effects (e.g. an antiplatelet drug with a fibrinolytic in treating MI)
• Combinations of antimicrobial drugs are used to prevent the selection of
drug-resistant organisms
• Some combinations of drugs have a more than additive effect (‘synergy’).
• Several antibacterial combinations are synergistic, including
sulfamethoxazole with trimethoprim (co-trimoxazole)
15. USEFUL INTERACTIONS
MINIMIZE SIDE EFFECTS
• There are many situations (e.g. hypertension) where low doses of two
drugs may be better tolerated, as well as more effective, than larger
doses of a single agent.
• Sometimes drugs with similar therapeutic effects have opposing
undesirable metabolic effects, which can to some extent cancel out when
the drugs are used together.
• The combination of a loop diuretic (e.g. furosemide) with a potassium-
sparing diuretic (e.g. spironolactone) provides an example
16. USEFUL INTERACTIONS
BLOCK ACUTELY AN UNWANTED (TOXIC) EFFECT
• Drugs can be used to block an undesired or toxic effect, as for
example when an anaesthetist uses a cholinesterase inhibitor to
reverse neuromuscular blockade,
• or when antidotes such as naloxone are used to treat opioid overdose
• Uses of vitamin K or of fresh plasma to reverse the effect of warfarin
17. HARMFUL INTERACTIONS
• It is impossible to memorize reliably the many clinically important
drug interactions, and prescribers should use suitable references (e.g.
the British National Formulary) to check for potentially harmful
interactions.
• There are certain drugs with steep dose–response curves and serious
dose-related toxicities for which drug interactions are especially liable
to cause harm and where special caution is required with concurrent
therapy
18. SEVERITY OF ADVERSE DRUG INTERACTIONS
• Adverse drug interactions are diverse, including unwanted pregnancy
(from failure of the contraceptive pill due to concomitant medication),
• Hypertensive stroke (from hypertensive crisis in patients on
monoamine oxidase inhibitors),
• Gastrointestinal or cerebral haemorrhage (in patients receiving
warfarin),
• Cardiac arrhythmias (e.g. secondary to interactions leading to
electrolyte disturbance or prolongation of the QTc)
• Adverse interactions can be severe
Other examples include the use of a β2 agonist with a glucocorticoid in the treatment of asthma (to cause bronchodilation and suppress inflammation, respectively
Drug resistance via synthesis of a microbial enzyme that degrades antibiotic (e.g. penicillinase producing staphylococci) can be countered by using a combination
of the antibiotic with an inhibitor of the enzyme: co-amoxiclav is a combination of clavulanic acid, an inhibitor of penicillinase, with amoxicillin.
Several drugs used in cancer chemotherapy are also synergistic, e.g. cisplatin plus paclitaxel
Predictable adverse effects can sometimes be averted by the use of drug combinations. Isoniazid neuropathy is caused by pyridoxine deficiency, and is prevented by the prophylactic use of this vitamin. The combination of a peripheral dopa decarboxylase inhibitor (e.g. carbidopa) with levodopa permits an equivalent therapeutic effect to be achieved with a lower dose of levodopa than is needed when it is used as a single agent, while reducing dose-related peripheral side effects of nausea and vomiting
