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2 Drug therapy 161-163

Home > 1 PRINCIPLES OF MEDICAL PRACTICE > 2 Drug therapy > EVIDENCE-BASED MEDICINE IN DRUG THERAPY
EVIDENCE-BASED MEDICINE IN DRUG THERAPY
For many years doctors have tried to use the available evidence when making decisions about the use of drugs or other therapeutic measures; this started happening as long ago as the 18th century and perhaps before. However, in the early 1990s it was pointed out that the ways in which they did so were somewhat haphazard. For example, treatment strategies would often be formulated in unsystematic reviews of the published data, using selected pieces of evidence that experts in the field judged to be the most valuable or relevant. Inevitably, bias crept in when such judgements were made. The discipline of evidence-based medicine was therefore invented in order to introduce a more systematic approach to the use of evidence in making therapeutic and other decisions.
This was made possible by:
the development of statistical techniques for the systematic analysis of data
the realisation that it was important to analyse all the available data, both published and unpublished
the development of computerised databases of relevant information, linked to methods by which that information could be traced.

The tenets of evidence-based medicine are that well-formulated questions about medical management, including diagnosis and therapy, can be answered by:
carrying out high-quality, randomised, controlled clinical trials
tracing all the available evidence
analysing the evidence systematically
determining how valid and useful the evidence is
applying the evidence to the management of the individual patient.

It needs to be appreciated that although there are well-established methods for carrying out the first four of these procedures (yielding what is known as 'best evidence'), it is the last that is the most important and the most difficult. This is because the evidence on which decisions are made is usually derived from large populations, which may not have included patients like those you want to treat; even if the trials were representative of your patients, there is so much interindividual variability that mean values taken from studies of populations may not be applicable to individuals. Methods for dealing with this are available, but are not as well developed or easily applied as the methods for obtaining the best evidence. In addition, there are many therapeutic problems for which adequate evidence is not available at all; in such cases one uses what evidence there is, indifferent though it may be.
In this chapter the ways in which evidence-based medicine can inform drug therapy are described. However, the principles apply equally well to other forms of patient care, including examination, investigation and other forms of treatment.
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BENEFICIAL EFFECTS AND THE NUMBER NEEDED TO TREAT (NNT)
Benefit in drug therapy is often expressed as the so-called number needed to treat (NNT), which is the number of patients that you would need to treat in order to prevent one clinical event (for example, a stroke or a pregnancy). A simple example illustrates how this is calculated. Of 239 patients with the acute pain of third molar extraction, 122 were given placebo, of whom 9 (7.4%) had at least 50% pain relief by 6 hours, compared with 65 (55.6%) of the 117 patients who were given ibuprofen; the difference was therefore 55.6-7.4 = 48.2%, or an effect size of 0.482. This is known as the absolute risk reduction, and the NNT is the inverse of this: 1/0.482 = 2.1. In other words, 1 out of every 2 people who take a single dose of ibuprofen will have better than 50% pain relief in the 6 hours after the dose. The 95% confidence interval of this estimate (the calculation of which is more complicated) was 1.7-2.6; in other words, the mean estimate of the NNT was 2.1 and there was a 95% chance that the true value lay between 1.7 and 2.6.
When a drug is given repeatedly, rather than as a single dose, the duration of therapy also has to be stated. For example, in a systematic analysis of the use of warfarin to prevent strokes in patients with atrial fibrillation there were 53 strokes in 1450 patients who took warfarin (3.66%) and 133 in 1450 patients who took placebo (9.17%). The effect size was thus 9.17-3.66 = 5.51% (0.0551) and the NNT was 18 (1/0.0551). The confidence interval was 14-27. So, on the basis of these results, if you treat 18 patients with warfarin for 1 year, you will prevent one stroke (see EBM panel, p. 402). Note that these numbers cannot be multiplied up to longer durations of treatment. In other words, this analysis does not imply that if you treat 18 patients for 2 years you will prevent two strokes; a longer trial would be needed to find out what the actual value was.
For a further perspective on the meaning of the NNT, consider oral contraception. On average a woman who has unprotected sex for 1 year has a 40% chance of falling pregnant, while a woman who takes some form of oral contraception has a 3% chance; this 37% difference translates into an NNT of 2.7 (1/0.37). Now because oral contraception is so effective you might expect the NNT to be very close to 1, but that is not so, since the NNT takes into account the rate that occurs without treatment. In other words, if you treat 100 women for a year with an oral contraceptive, you will prevent 100/2.7 (i.e. 37) pregnancies. But 97 of the women taking the treatment do not fall pregnant; that is because the other 60 women would not have fallen pregnant anyway, even without treatment. Of course, that means that they have taken the treatment without benefit and may have had adverse effects as well; however, it would not have been possible to identify these women, either in advance or even retrospectively.
ADVERSE EFFECTS AND THE NUMBER NEEDED TO HARM (NNH)
The other side of the coin, the number needed to harm (NNH), can be similarly calculated from data on adverse effects of drugs. For example, in a meta-analysis of 13 trials of the effect of thiazide diuretics in essential hypertension, 205 out of 3275 patients taking a thiazide had erectile impotence, compared with 67 out of 5295 patients taking placebo; the NNH for this effect is 20 (see Box 2.3).
2.3 CALCULATION OF NNH, RISK RATIO AND ODDS RATIO
(A) A THEORETICAL CASE
Group Number with adverse event Number without adverse event Total
Active treatment a b a+b
Placebo c d c+d
Total a+c b+d a+b+c+d
1. Calculation of number needed to harm (NNH)
Rate of event in treated group = a/(a+b)
Rate of event in placebo group = c/(c+d)
Difference (absolute harm increase) = a/(a+b) - c/(c+d)
NNH = 1/[a/(a+b) - c/(c+d)]
2. Calculation of risk ratio (RR)
Rate of event in treated group = a/(a+b)
Rate of event in placebo group = c/(c+d)
Risk ratio = [a/(a+b)]/[c/(c+d)]
3. Calculation of odds ratio (OR)
Odds of event in treated group = a/b
Odds of event in placebo group = c/d
Odds ratio = (a/b)/(c/d)
(b) A real case*
Drug 205 3070 3275
Placebo 67 5228 5295
Total 272 8298 8570
1. Calculation of number needed to harm (NNH)
Rate of event in treated group = 205/3275
Rate of event in placebo group = 67/5295
Difference (absolute harm increase) = 205/3275 - 67/5295 = 0.0499 NNH = 20
2. Calculation of risk ratio (RR)
Rate of event in treated group = 205/3275
Rate of event in placebo group = 67/5295
Relative risk = [205/3275]/[67/5295] = 5.0 (i.e. a fivefold risk)
3. Calculation of odds ratio (OR)
Odds of event in treated group = 205/3070
Odds of event in placebo group = 67/5228
Odds ratio = [205/3070]/[67/5228] = 5.2 (i.e. relative odds of about 5 to 1 on)

*Erectile impotence with thiazide diuretics in hypertension over a mean of 4 years, a meta-analysis of 13 RCTs (Hypertension 1999; 34:710).
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THE BENEFIT TO HARM RATIO ASSESSED FROM THE NNT AND NNH
Although you might expect to be able to express the benefit to harm ratio as the simple ratio of the NNT to the NNH, the comparison is not straightforward, since the quality of the benefit and the severity of the harm also need to be considered. How, for example, do you compare the benefit of long-term oral anticoagulation in patients with atrial fibrillation (the prevention of embolic stroke) with the harm that anticoagulation can cause (gastrointestinal haemorrhage)?
However, knowing the numbers can help. Consider, for instance, tamoxifen, which prolongs survival in breast cancer (by an anti-oestrogenic action) and reduces the risk of myocardial infarction (by an oestrogenic effect on blood lipids), but can cause endometrial cancer and venous thromboembolism:
NNT to prevent one death = 17
NNT to prevent one myocardial infarction = 29
NNH for one case of endometrial cancer = 143
NNH for one venous thromboembolism = 130.

These figures suggest that if you treat 1000 women with breast cancer for 2-5 years you will prevent about 60 deaths (1000/17) and 34 myocardial infarctions, at the cost of 7 cases of endometrial cancer and 7 cases of venous thromboembolism, clearly a favourable benefit to harm ratio. Of course, calculations of this sort yield probabilities that relate to the patients that have been studied in clinical trials. They do not necessarily apply to the whole population and they certainly do not tell you what the outcome will be in the individual case.
There are other ways of expressing results of this kind. For example, you can calculate the risk ratio (RR) or odds ratio (OR), each with its confidence interval (see Box 2.3). The larger the effect, the higher the odds ratio is relative to the risk ratio; at incidences of up to about 15% the risk ratio and odds ratio are very similar, but at higher incidences the odds ratio starts to over-estimate the risk ratio considerably. Note that two treatments may have exactly the same risk ratio but different values of NNH. For example, a treatment that increased the risk of an adverse event from 1% to 2% would have a risk ratio of 2 but an NNH of 100 (1/0.01), while a treatment that increased the risk of an adverse event from 25% to 50% would also have a risk ratio of 2 but an NNH of 4 (1/0.25), a much more important effect. When it was reported that third-generation progestogens approximately doubled the risk of deep venous thrombosis compared with older progestogens, the announcement caused some women to panic; what they did not appreciate was that the baseline risk was very low and the NNH therefore very high.
OBTAINING THE BEST EVIDENCE
2.4 SOME METHODS OF OBTAINING EVIDENCE IN DRUG THERAPY
Prospective, randomised, double-blind, placebo-controlled trial
Prospective, randomised, double-blind, comparative trial (drug vs drug)
Systematic review (meta-analysis)
Systematic review (other types of analysis)
Cohort study
Case-control study
Point prevalence study
Subgroup analysis of a large trial (generates hypotheses for further trials)
N-of-one trial
Other trials (e.g. non-randomised, non-controlled, historical controls, retrospective analysis)
Non-systematic review
Case report


Although the well-designed, large, randomised clinical trial (RCT), preferably placebo-controlled, is the gold standard for obtaining the best evidence, there are other ways. Some of these are listed in Box 2.4, roughly in the order of the quality of evidence they yield. A well-designed RCT is more reliable than a meta-analysis of the same size; however, a very large meta-analysis (i.e. one that is much bigger than the largest RCT) may provide better evidence. Furthermore, depending on the quality of the design and conduct, the evidence that any of these forms of study provides can vary; for instance, a well-conducted cohort study may provide better evidence than a poorly designed RCT.
One of these methods is worthy of further mention, the N-of-one (or controlled single-patient) trial. As mentioned above, it may be difficult to extrapolate from the results of large randomised clinical trials to the practical application of drug therapy in the individual patient. In some cases, evidence from large RCTs may not even be available (if, for example, the disease is rare). In such cases an N-of-one trial may help. Here the patient is given either the active drug or a matching placebo at different times and double-blind, and the response to each is noted; thus, in N-of-one trials patients act as their own controls. This type of trial is useful only in the symptomatic treatment of chronic stable conditions, if the course of the disease is predictable, if the treatment has a rapid and easily measured therapeutic effect, and if the effect of a single dose of the drug is not long-lasting.

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Home > 1 PRINCIPLES OF MEDICAL PRACTICE > 2 Drug therapy > PRACTICAL PRESCRIBING
PRACTICAL PRESCRIBING
WHEN TO PRESCRIBE A DRUG
Drug therapy is not always necessary. For example, a mild tremor in Parkinson's disease may not be unduly troublesome; even though drug treatment may alleviate the tremor, it may also cause unwanted effects, outweighing the benefit. Do not be tempted to prescribe a drug simply to end a consultation. If a patient expects drug therapy, discuss the pros and cons. Try to estimate the benefit to harm ratio and prescribe only if you think it is favourable.
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2.5 EXAMPLES OF CHOOSING A THERAPEUTIC CLASS OF DRUG
Indication Therapeutic class
Acute attack of asthma Bronchodilators
Diabetes mellitus Oral hypoglycaemic drugs
Insulin
Congestive cardiac failure Diuretics
Angiotensin-converting enzyme (ACE) inhibitors
Vasodilators
Hypertension Diuretics
ACE inhibitors
Beta-adrenoceptor antagonists (ß-blockers)
Calcium antagonists

2.6 EXAMPLES OF CHOOSING A GROUP OF DRUGS FROM WITHIN A CLASS
Therapeutic class Therapeutic group
Anticoagulants Coumarins/warfarin
Heparins
Diuretics Thiazides
Loop diuretics
Potassium-sparing diuretics
Antibiotics Penicillins
Cephalosporins
Tetracyclines
Aminoglycosides
Macrolides
Quinolones

2.7 EXAMPLES OF CONTRAINDICATIONS TO ANTIBIOTICS
Antibiotic Example of contraindication
Cephalosporins Allergy
Penicillins Allergy
Quinolones Pregnancy and children (teratogenic in animals)
Sulphonamides Late pregnancy (risk of kernicterus in neonate)
Tetracyclines Children (affects growing bones and teeth)
Renal impairment (e.g. elderly people)

HOW TO CHOOSE A DRUG TO PRESCRIBE
If you decide to prescribe a drug, the first step will be to choose the therapeutic class. Sometimes the choice is restricted, sometimes wide, as a few examples illustrate (see Box 2.5).
Having chosen the class of drug, the next step is to choose the group of drugs within that class. Again the choice may be restricted or wide (see Box 2.6). The choice of an anticoagulant depends on whether short-term or long-term treatment is indicated. The choice of a diuretic in the treatment of cardiac failure depends on the severity of the problem, whether acute or chronic therapy is indicated, the convenience of the timing of the diuresis, and potassium balance. The choice of an antibiotic depends on the sensitivities of the infecting organism, the site of infection and contraindications, as some examples show (see Box 2.7).
Drug interactions can also affect therapy, as in the case of antibiotics (see Box 2.8).
The last step is to choose a particular drug from within the group. In some cases the choice is unimportant. For example, all thiazide diuretics have equal efficacy and adverse effects. In contrast, the choice of a specific penicillin is important and will depend on the type of organism (see Box 2.9).
2.8 EXAMPLES OF DRUG INTERACTIONS WITH ANTIBIOTICS
Antibiotic Interacting drug Mechanism Effect
Gentamicin Furosemide (frusemide) Additive Ototoxicity
Chloramphenicol Warfarin Inhibition of metabolism Potentiation of anticoagulation
Metronidazole Alcohol Inhibition of aldehyde dehydrogenase 'Disulfiram reaction'
Metronidazole Warfarin Inhibition of metabolism Potentiation of anticoagulation
Rifampicin Oestrogens (oral contraceptives) Induction of metabolism Reduced contraceptive effect
Rifampicin Warfarin Induction of metabolism Reduced effect of warfarin
Tetracycline Antacids Chelation Reduced effect of tetracycline
Tetracycline Warfarin Altered clotting factor activity Potentiation of anticoagulation

2.9 EXAMPLES OF CHOOSING A PARTICULAR DRUG FROM WITHIN A GROUP
Therapeutic group Drug
Thiazide diuretics Bendroflumethiazide (bendrofluazide)
Cyclopenthiazide
Hydrochlorothiazide
Hydroflumethiazide
Polythiazide
Penicillins Benzylpenicillin
Penicillin V (phenoxymethylpenicillin)
Amoxicillin
Co-amoxiclav (amoxicillin + clavulanic acid)
Ampicillin
Flucloxacillin
Ticarcillin

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How to make a rational choice
Many factors dictate the choice of a particular drug:
Absorption. Bumetanide is better absorbed than furosemide (frusemide). Oral bumetanide may be effective in congestive cardiac failure if oral furosemide has failed; alternatively, use intravenous furosemide.
Distribution. Some antibiotics are well distributed to a particular tissue; for example, tetracyclines are concentrated in the bile, and lincomycin and clindamycin in bones.
Metabolism. In severe liver disease (for example, hepatic cirrhosis) it is advisable to avoid drugs that are extensively metabolised: for example, opiate analgesics. Genetic factors may influence the extent of metabolism of a drug. Although many examples of such variability have been described, these factors do not have a large impact on drug prescribing; however, some important examples are listed in Box 2.10.
Excretion. In renal insufficiency it is advisable to avoid drugs that are extensively excreted; for example, avoid the aminoglycoside antibiotics if alternative antibiotics are suitable.
Efficacy. Insulin is more efficacious at lowering the blood sugar than the oral hypoglycaemic drugs.
Features of the disease. Choose an antibiotic to match the known or suspected sensitivity of the infective organism: for example, amoxicillin for a patient with a community-acquired bronchopneumonia, because the likely organism will be the pneumococcus (Streptococcus pneumoniae). Sputum culture, with identification of the organism and its sensitivity to different antibiotics, will help.
Severity of disease. Mild pain will generally respond to aspirin or paracetamol; more severe pain may require more potent analgesics, such as codeine phosphate or even morphine. Moderate hypertension often responds to a single drug, such as a thiazide diuretic or a ß-adrenoceptor antagonist (ß-blocker); more severe hypertension may require a combination of drugs.
Coexisting diseases. In hypertension coexisting left ventricular failure would prompt the use of a diuretic combined with an ACE inhibitor; coexisting angina pectoris without heart failure would prompt the use of a ß-blocker.
Avoiding adverse effects. In asthma avoid ß-blockers. In penicillin hypersensitivity choose an alternative drug (for example, a cephalosporin in bronchopneumonia). Genetic factors may increase the risk of an adverse drug reaction; some important examples are listed in Box 2.10.
Avoiding adverse drug interactions. Avoid aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), which can cause gastrointestinal bleeding, in patients taking warfarin. Avoid tetracyclines, sulphonamides, chloramphenicol and the antifungal imidazoles (e.g. ketoconazole) in patients taking warfarin because they inhibit its metabolism.
Patient concordance. Atenolol, which can be taken once daily, is often prescribed instead of short-acting ß-blockers, in the hope that minimising the frequency of drug administration will improve patient concordance (compliance).
Cost. If two drugs are of equal efficacy and safety, one would generally choose the cheaper. However, pharmacoeconomics is a complicated subject beyond the scope of this text, and the true costs of drug therapy cannot always be calculated merely on the basis of the relative costs of two drugs.

2.10 SOME EXAMPLES OF GENETIC FACTORS THAT CAUSE VARIABILITY IN DRUG RESPONSE
Process Example of drug affected Clinical outcome
Acetylation Isoniazid Better response and increased risk of some adverse effects (e.g. peripheral neuropathy) in slow acetylators
Oxidation (CYP2D6) Nortriptyline Increased risk of toxicity in poor metabolisers
Oxidation (CYP2C18) Proguanil (active metabolite cycloguanil) Reduced efficacy in poor metabolisers
Sulphoxidation Penicillamine Increased risk of toxicity in poor metabolisers
Pseudocholinesterase activity Suxamethonium Prolonged duration of effect in pseudocholinesterase deficiency
Glucose-6-phosphate dehydrogenase (G6PD) activity Many antimalarial drugs (e.g. chloroquine, quinine) Risk of haemolysis in G6PD deficiency
Porphyria Enzyme-inducing drugs (e.g. carbamazepine, rifampicin) Increased risk of an acute attack

CHOOSING THE ROUTE OF ADMINISTRATION
There are several reasons for choosing a particular route of administration, as some examples illustrate (see Box 2.11).
CHOOSING A FORMULATION
Oral formulations include tablets, capsules, granules, elixirs and suspensions. Drugs for injection come as lyophilised powders for reconstitution before injection or as solutions ready for injection; solutions come in single-dose ampoules, single-dose or multiple-dose vials, and half-litre or litre bottles for infusion.
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2.11 REASONS FOR CHOOSING A PARTICULAR ROUTE OF ADMINISTRATION
Reason Example
Only one route possible Dopamine (intravenous)
Glibenclamide (oral)
Patient concordance Intramuscular depot injections of phenothiazines and thioxanthenes in schizophrenia
Poor absorption Intravenous furosemide (frusemide) in heart failure
Vomiting Phenothiazines (rectal)
Sumatriptan (sublingual)
Avoiding first-pass metabolism Glyceryl trinitrate (sublingual)
Rapid action Glyceryl trinitrate (sublingual)
Sumatriptan (sublingual)
Direct access to the site of action Inhaled bronchodilators in asthma
Rectal corticosteroids in ulcerative colitis
Local application to skin, eyes etc.
Ease of access Benzodiazepines in status epilepticus (e.g. rectal diazepam if intravenous access is difficult)
Subcutaneous fluids (hypodermoclysis)
Controlled release Insulin (subcutaneous)

Some examples show how the choice of formulation can be important.
Potassium salts are available as modified-release formulations, as effervescent tablets that dissolve in water for drinking, or as elixirs immediately ready to drink. Patient preference may dictate the choice, but it would be logical to choose a soluble formulation in a patient with gastrointestinal hurry, in whom the modified-release formulation might pass through the gut unabsorbed.
Lithium salts and theophylline come in several different ordinary and modified-release formulations, each with different absorption characteristics. A formulation that produces adequate plasma lithium or theophylline concentrations in one patient may not be suitable for another, and it is sometimes worth changing the formulation if plasma concentrations are suboptimal. These are examples of drugs that should be prescribed by specific brand name rather than the non-proprietary name.
Iron salts are available as tablets for twice- or thrice-daily administration or as modified-release formulations for once-daily administration. Adverse effects are fewer with the modified-release formulations but the iron is more erratically absorbed. It is usual to start with an ordinary formulation of iron and change to a modified-release formulation if adverse effects are intolerable.
CHOOSING A DOSAGE REGIMEN
The dose of the drug and the frequency and timing of its administration constitute the dosage regimen. Each prescription should be treated as an experiment in which you try to find the regimen that produces the best therapeutic effect with minimal adverse effects, according to some simple principles:
Generally, start with a dosage at the lower end of the recommended dosage range. Exceptions to this rule include corticosteroids and carbimazole, which are begun in high dosages and then reduced to maintenance dosages. Some drugs are given in a loading dose (for example, digoxin, warfarin and amiodarone), followed by a maintenance dose.
Increase the dosage slowly, monitoring the therapeutic effect at regular intervals and looking for adverse effects.
If adverse effects occur, reduce the dosage or try another drug; in some cases lower dosages may be possible by combining drugs (for example, azathioprine reduces corticosteroid dosage requirements in immunosuppression).
Think of drug interactions and avoid potentially dangerous combinations.
Remember that pharmacokinetic and pharmacodynamic variability can alter dosage requirements (see below).
Take particular care with drugs that have a low therapeutic index.

Pharmacokinetic variability
Because absorption, distribution and elimination of drugs vary from patient to patient, flexibility in dosages is necessary. The examples in Box 2.12 show how to respond to differences or changes in pharmacokinetics.
2.12 THERAPEUTIC APPROACHES TO PHARMACOKINETIC PROBLEMS
Pharmacokinetic problem Therapeutic approach
Poor absorption Increase the dose
Choose another route of administration
Use another drug
Altered tissue distribution One-off doses may have to be altered
Usually does not affect chronic therapy, unless distribution to the target tissue is altered
Altered protein binding Usually does not affect long-term doses (but does alter steady-state total plasma drug concentration)
Reduced renal elimination (see Box 2.14) Reduce dosage (use creatinine clearance as a guide)
Reduced hepatic elimination (see Box 2.15) Low-clearance drugs: reduce oral and intravenous doses
High-clearance drugs: reduce oral (but not intravenous) doses

Pharmacodynamic variability
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Figure 2.1 Dose-response curves for bumetanide and furosemide (frusemide). The two drugs have different potencies but the same efficacy. The rate of diuretic excretion reflects the luminal concentration of diuretic.
Pharmacological responses are usually governed by the dose-response curve. An example is seen in Figure 2.1, which shows the effect of two loop diuretics, bumetanide and furosemide (frusemide), on urinary sodium excretion. The two diuretics have different potencies, which can be dealt with by using different dosages; however, they both have the same efficacy, so that comparable dosages should produce the same diuretic effect.
Variability in dose-responsiveness dictates flexibility in prescribing. If a therapeutic effect does not occur with the first dosage chosen, an effect may be produced by making small increases within the therapeutic dosage range. Of course, increasing the dosage will also increase the risk of dose-related adverse effects. Certain diseases can alter a dose-response curve (for example, there is resistance to digoxin in hyperthyroidism) and the pharmacodynamics of one drug can be affected by another drug.
CHOOSING THE FREQUENCY OF DRUG ADMINISTRATION
It is thought that patient concordance with therapy is improved if drugs are given only once or twice daily, rather than three or four times, although the evidence that this is true is scanty. However, it makes sense to simplify the therapeutic regimen, and in general, therefore, try to choose drugs that can be given no more than twice daily. A modified-release formulation may be useful in this respect. In some special cases the frequency of drug administration is an important consideration in therapy (see Box 2.13).
CHOOSING THE TIME OF DRUG ADMINISTRATION
For many drugs the time of administration is unimportant, but there are occasionally pharmacokinetic or therapeutic reasons for giving drugs at particular times (see Box 2.13). Meal times do not usually affect drug administration, since although food may reduce the speed of absorption of a drug it generally does not reduce the extent of absorption. Tetracyclines are an exception; their absorption is greatly reduced by divalent and trivalent cations, and they should not be taken with food or antacids. Food may sometimes help reduce adverse gastrointestinal effects; for example, the effects of aspirin on the stomach may be reduced by taking it with food.
ALTERING DRUG DOSAGES IN SPECIAL CIRCUMSTANCES
Altering dosages in renal insufficiency
2.13 SOME SPECIAL EXAMPLES OF FREQUENCY AND TIMING OF DRUG ADMINISTRATION
Drug Recommended frequency or timing Reasons
Furosemide (frusemide) Once in the morning Kidney refractory to a second dose within 6 hrs; night-time diuresis undesirable
Corticosteroids Once in the morning Minimises inhibitory effects on adrenal function
Salmeterol Once at night Prevents early morning symptoms
Antidepressants Once at night Allows adverse effects to occur during sleep
Digoxin Once at night Allows blood samples for plasma concentration measurement to be taken 12 hrs later
Long-acting nitrates Nitrate-free period of 12 hrs in each 24 hrs To avoid tolerance
Tetracyclines 2 hrs before or after food Divalent and trivalent cations chelate tetracyclines
Opiates In anticipation of pain Better relief in chronic pain
Glyceryl trinitrate When required According to symptoms
Levodopa Adjusted according to response (usually several times a day) Dictated by the duration of action (often wears off quickly during long-term therapy)

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If a drug is more than 50% eliminated unchanged by the kidneys or has active metabolites that are eliminated by the kidneys, the maintenance dosage must be altered in renal insufficiency; it is not usually necessary to alter a one-off dose. Creatinine clearance can be used as a guide to reducing maintenance dosages; the serum creatinine concentration can also be used, but it is a less reliable indicator of renal function and does not rise above the reference range until renal function is impaired by at least 50%.
In some cases dosages should be reduced because the pharmacological effects interact with renal impairment (for example, ACE inhibitors worsen potassium retention). Some drugs should be avoided entirely in renal insufficiency, for either pharmacokinetic or pharmacodynamic reasons (see Box 2.14).
Diuretics are relatively ineffective in severe renal insufficiency, partly because they cannot gain access to their site of action, the luminal epithelium. Thiazide diuretics should therefore not be used and high dosages of loop diuretics may be required for efficacy. Potassium-sparing diuretics should not be used because of the increased risk of hyperkalaemia.
2.14 SOME DRUGS WHOSE DOSAGES ARE AFFECTED BY RENAL INSUFFICIENCY
Mild renal insufficiency (creatinine clearance 20-50 ml/min or serum creatinine 150-300 µmol/l)
ACE inhibitors (monitor carefully; increase dosage if renal function does not worsen with low doses)
Aminoglycosides
Chlorpropamide
Digoxin
Fibrates
Lithium
Zidovudine
Moderate renal insufficiency (creatinine clearance 10-20 ml/min or serum creatinine 300-700 µmol/l)
Some ß-blockers (e.g. atenolol, sotalol)
Opioid analgesics
Severe renal insufficiency (creatinine clearance <10>700 µmol/l; many of these patients receive renal replacement therapy, which may affect drug pharmacokinetics)
Azathioprine
Cephalosporins
Cimetidine
Isoniazid
Penicillins
Sulphonylurea hypoglycaemic drugs (gliclazide, glipizide, gliquidone)
Drugs to avoid in severe renal insufficiency
Chloramphenicol
Chloroquine
Fibrates
Lithium-even in moderate renal insufficiency
Mesalazine-even in mild renal insufficiency
Metformin-even in mild renal insufficiency
Methotrexate-even in moderate renal insufficiency
NSAIDs-even in mild renal insufficiency
Sulphonylurea hypoglycaemic drugs (chlorpropamide, glibenclamide)
Tetracyclines (except doxycycline and minocycline)-even in mild renal insufficiency


Altering dosages in hepatic failure
The liver has a large functional capacity, and chronic hepatic insufficiency usually has to be considerable before it affects drug dosages. However, hepatic drug clearance may be reduced in acute hepatitis, in hepatic congestion due to cardiac failure, and if there is intrahepatic arteriovenous shunting (for example, in hepatic cirrhosis). In chronic liver disease, jaundice, ascites, a prolonged prothrombin time, hypoalbuminaemia, malnutrition and encephalopathy all make clinically important impairment of drug metabolism more likely.
In contrast to renal insufficiency there is no easy way of calculating changes in dosage in patients with impaired hepatic function, because there are no good tests of hepatic drug-metabolising capacity or of biliary excretion. Dosages of drugs that are metabolised by the liver should therefore be altered according to the therapeutic response, and with careful clinical monitoring for signs of adverse effects.
If a drug has a high rate of hepatic clearance (see Box 2.15), it will be mostly cleared during its first passage through the liver (the so-called 'first-pass' effect). In such cases hepatic impairment increases the amount of drug that escapes metabolism in the liver after oral administration, reducing oral dosage requirements but not altering intravenous dosage requirements. For example, clomethiazole is normally extensively metabolised pre-systemically by the liver, and this is reduced by chronic liver disease such as alcoholic cirrhosis. When using oral clomethiazole in a patient with cirrhosis, take care to ensure that overdosage, with the risk of respiratory depression, does not occur.
2.15 SOME DRUGS OF LOW AND HIGH HEPATIC CLEARANCE RATES
Low
Aspirin
Codeine
Diazepam
Isoniazid
Nortriptyline
Paracetamol
Phenobarbital
Phenytoin
Procainamide
Quinidine
Theophylline
Warfarin
High
Clomethiazole
Glyceryl trinitrate
Labetalol
Lidocaine (lignocaine)
Morphine
Pethidine
Propranolol
Simvastatin


2.16 SOME DRUGS WHOSE ACTIONS ARE INCREASED IN LIVER DISEASE
Drug Adverse effect
Oral anticoagulants Increased anticoagulation (reduced clotting factor synthesis)
Metformin Lactic acidosis
Chloramphenicol Bone marrow suppression
NSAIDs Gastrointestinal bleeding
Sulphonylureas Hypoglycaemia

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ISSUES IN OLDER PEOPLE
ALTERING DRUG DOSAGES
Drug handling and the response to drugs change as you get older, and there is much more variability in drug response in elderly people than in younger people, because people age at different rates. This means that responses to drugs are much less predictable, and so dosage regimens of some drugs are different. Adverse drug reactions are more likely in old people; frail old people are particularly at risk, partly because they tend to have poorer renal function and smaller livers and partly because they are less able to maintain their homeostatic control mechanisms than younger people or fit old people.
Polypharmacy is common in old people and the scope for drug interactions is large; the error rate in taking drugs is about 60% in patients over 60 years of age, and the rate of error increases markedly if more than three drugs are prescribed.
Choice of formulation is very important. Many old people find it difficult to swallow tablets, and the more frail and the more ill they are, the more difficult it becomes. For example, many potassium tablets are large and can be difficult to swallow. Tablets or capsules can adhere to the oesophageal mucosa, and to avoid hold-up tablets should be swilled down with at least 60 ml of water. Elixirs may be preferable, but not all drugs are available as elixirs and they may have their own problems. For example, the taste of a potassium elixir may not be acceptable.
Drug distribution may be altered in old people. Dosages should be adjusted for body weight, particularly for drugs with a low therapeutic index. Old people have an increased proportion of body fat, and lipid-soluble drugs tend to accumulate to a greater extent than in younger patients.
Drug metabolism may be reduced in old people-for example, clomethiazole, lidocaine (lignocaine), nifedipine, phenobarbital, propranolol and theophylline. Dosages of these drugs should therefore be reduced. Renal function falls with age, and drugs that are mainly excreted in the urine, or that have active metabolites that are excreted, may require dosage reductions (see above). Some drugs are best avoided in old people. For example, tetracyclines accumulate when renal function is poor, causing nausea and vomiting, which in turn cause dehydration and further deterioration in renal function.
Drug sensitivity may be altered (usually increased) in old age. Old people are more sensitive to the effects of digoxin, probably because of increased sensitivity of their sodium/potassium pump. This, combined with reduced renal function and an increased susceptibility to potassium loss due to diuretics, makes them more liable to digoxin toxicity. In contrast, there is reduced sensitivity of ß-adrenoceptors in old people, and this may reduce some of the pharmacological effects of ß-adrenoceptor agonists and antagonists. Altered sensitivity to drugs in old people may be due to altered physiological responses. For example, reduced baroreceptor function can lead to increased hypotension after the administration of antihypertensive drugs. Other examples include increased sensitivity to the anticoagulant effects of warfarin and increased responsiveness of the brain to centrally active drugs-for example, antidepressants, hypnotics, neuroleptic drugs, sedatives and tranquillisers. Some of these principles are illustrated in Figure 2.2, which shows the difference in nifedipine pharmacokinetics and pharmacodynamic responses between young and old men. After an intravenous dose of nifedipine (2.5 mg) the old men had higher plasma nifedipine concentrations and a fall in blood pressure; the difference in blood pressure response was partly due to the difference in plasma concentration but mostly due to a difference in baroreceptor reflexes, as shown by the difference in heart rate response.
In general, when prescribing drugs for old people, try to use as few drugs as possible, start with low dosages, and increase the dosages carefully only if required. Choose easily swallowed formulations and keep therapy as simple as possible (for example, with once-daily drugs and formulations). Take greater care in frail old people than in fit old people.






Figure 2.2 Differences between young men and old men given an intravenous dose of nifedipine. A Old men have higher plasma concentrations than young men. B and C Old men have a greater fall in blood pressure and a smaller rise in heart rate than young men.
The pharmacological effects of some drugs are altered in liver disease, with increased risk of adverse effects (see Box 2.16).
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WHEN TO STOP DRUG TREATMENT
A single dose of aspirin may be enough to treat a headache, or a single dose of diamorphine may be sufficient to treat the pain of myocardial infarction. In contrast, life-long therapy is usually required for the treatment of diabetes mellitus, essential hypertension, hypothyroidism and pernicious anaemia.
However, there may be difficulty with treatments of intermediate duration. For example, it is still not clear for how long treatment with warfarin should be continued in the treatment of deep venous thrombosis and pulmonary embolism (see p. 565). The duration of treatment of infections with antibiotics varies from infection to infection, and depends on the infecting organism, the site of infection and the response to treatment. For example, uncomplicated urinary tract infection with cystitis usually requires treatment for only a few days, pyelonephritis requires treatment for 1-2 weeks, and acute prostatitis for 4-6 weeks. When you start a drug treatment it is wise to plan the likely duration of therapy. You should also review long-term treatment at regular intervals to assess whether continued treatment is required. A hospital admission is often an opportunity for revising drug therapy, and it is not uncommon for drugs to be withdrawn in the interim or even permanently following an acute severe illness.

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Home > 1 PRINCIPLES OF MEDICAL PRACTICE > 2 Drug therapy > ADVERSE DRUG REACTIONS
ADVERSE DRUG REACTIONS
An adverse drug effect may be due to either a toxic effect or a side-effect. A toxic effect is an adverse effect that arises through an exaggeration of the same pharmacological effect that is responsible for the therapeutic effect of the drug-for example, hypokalaemia due to diuretic therapy-and is therefore dose-related. A side-effect is an adverse effect that arises through some pharmacological action other than that which produces the therapeutic effect; such effects may be dose-related (for example, anticholinergic effects of tricyclic antidepressants) or not dose-related (for example, a rash associated with an antibiotic). The term 'dverse effects' covers all types of unwanted effects. A classification and examples of important adverse drug effects are given in Box 2.17.
2.17 EXAMPLES OF ADVERSE EFFECTS CLASSIFIED BY CAUSE
Mechanism Example
1. Dose-related effects
Pharmaceutical variation Changing modified-release formulations (e.g. lithium)
Pharmacokinetic variation
Pharmacogenetic variation Suxamethonium apnoea
Hepatic disease Sedation due to clomethiazole
Renal disease Digoxin toxicity
Wrong route of administration Intrathecal vincristine
Pharmacodynamic variation
Pharmacogenetic variation Porphyria
Hepatic disease Encephalopathy due to opioid analgesics
Altered fluid and electrolyte balance Digoxin toxicity due to hypokalaemia
2. Non-dose-related effects
Acute hypersensitivity reactions Anaphylaxis (e.g. penicillin)
Anaphylactoid (non-allergic) reactions Polyethoxylated castor oil (used as a solvent for some i.v. drugs)
Immediate pseudoallergic reactions Aspirin-induced asthma
Pharmacogenetic variation Haemolysis in G6PD deficiency
3. Dose-related and time-related effects
Long-term adaptive changes Tardive dyskinesia (e.g. phenothiazines)
Pharmacogenetic variation Acute porphyria (enzyme inducers)
Effects related to over-rapid infusion Red man syndrome (vancomycin)
4. Time-related (not dose-related) effects
Delayed hypersensitivity reactions (Gell and Thrombocytopenia (e.g. quinine; type II)
Coombs types II, III and IV) Interstitial nephritis (e.g. penicillin; type III)
Contact dermatitis (e.g. antihistamines; type IV)
Delayed pseudoallergic reactions Ampicillin rash
5. Withdrawal effects
Following down-regulation of receptors Opiate withdrawal syndrome
Following up-regulation of receptors ß-blocker withdrawal syndrome (myocardial ischaemia, tachycardia)
6. Failure of therapy
Pharmaceutical Inadequate formulations
Chemical instability (e.g. glyceryl trinitrate)
Pharmacokinetic Drug interactions (e.g. oral contraceptives and rifampicin)
Pharmacodynamic Pharmacological tolerance (non-receptor-mediated) (e.g. nitrates)
7. Genetic/genomic mechanisms
Gametic Azoospermia due to sulfasalazine
Teratogenic Vaginal adenocarcinoma with diethylstilbestrol
Carcinogenic Lymphoma with ciclosporin

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Dose-related toxic effects can be avoided by using dosages at the lower end of the recommended range and increasing cautiously, monitoring carefully for therapeutic and adverse effects. Dose-related side-effects may not be avoidable; if they occur despite careful dosage adjustment, it may be necessary to use a different drug. Adverse effects that are due to long-term therapy cannot necessarily be avoided; careful monitoring will help to minimise their impact. Delayed effects can be minimised by reducing the length of exposure to a drug or avoided by not using drugs that are known to have delayed effects.

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Home > 1 PRINCIPLES OF MEDICAL PRACTICE > 2 Drug therapy > DRUG INTERACTIONS
DRUG INTERACTIONS
A drug interaction occurs when the effects of one drug (the object drug) are altered (increased or decreased) by the effects of another drug (the precipitant drug). Although a drug interaction usually results in an adverse effect, in some cases it may prove beneficial-for example, the pharmacodynamic synergy between diuretics and ACE inhibitors in the treatment of hypertension. The classification of drug interactions by mechanism is shown in Box 2.18.
PHARMACEUTICAL INTERACTIONS
Pharmaceutical interactions are physico-chemical interactions, either of a drug with an intravenous infusion solution or of two drugs in the same solution, resulting in the loss of activity of the drugs involved. Pharmaceutical interactions are too numerous to remember in detail, but they can be simply avoided:
by giving intravenous drugs by bolus injection, if possible, or via an infusion burette
by using only dextrose or saline for drug infusion
by not mixing drugs in the same infusion solution, unless the mixture is known to be safe (e.g. potassium chloride can be given with insulin).

2.18 CLASSIFICATION OF DRUG INTERACTIONS BY MECHANISM
Example
Mechanism Object drug Precipitant drug Result
Pharmaceutical Sodium bicarbonate Calcium gluconate Precipitation of calcium carbonate
Pharmacokinetic
Reduced absorption Tetracyclines Calcium, aluminium, magnesium salts Reduced tetracycline absorption
Reduced protein binding Phenytoin Aspirin Reduced phenytoin plasma concentration with same therapeutic effect
Reduced metabolism (CYP3A4) Terfenadine Grapefruit juice Cardiac arrhythmias
Reduced metabolism (CYP2C19) Phenytoin Ticlopidine Phenytoin toxicity
Reduced metabolism (CYP2D6) Clozapine Paroxetine Clozapine toxicity
Reduced metabolism (other enzymes) Azathioprine Allopurinol Azathioprine toxicity
Increased metabolism Ciclosporin St John's wort Loss of immunosuppression
Reduced renal elimination Lithium Diuretics Lithium toxicity
Pharmacodynamic
Direct antagonism Opiates Naloxone Reversal of opiate effects
Direct potentiation Alcohol Antidepressants Increased sedation
Indirect potentiation Anti-arrhythmic drugs Diuretics Cardiac arrhythmias (hypokalaemia)

PHARMACOKINETIC INTERACTIONS
Pharmacokinetic interactions occur when the absorption, distribution or elimination (metabolism or excretion) of the object drug is altered by the precipitant drug.
Absorption interactions
Absorption interactions are usually not important. Exceptions include impaired absorption of tetracyclines by chelation with divalent and trivalent cations. Metoclopramide increases the rate of gastric emptying and this hastens the absorption of analgesics in the treatment of an acute attack of migraine, a beneficial effect.
Distribution interactions: protein-binding displacement
Protein-binding displacement causes an increase in the circulating concentration of unbound drug. However, this is only important if the object drug is highly protein-bound (greater than 90%) and is not widely distributed to body tissues. In practice, this limits important interactions of this type to warfarin and phenytoin. When these drugs are displaced their clearance rate increases in proportion to the degree of displacement and so at steady state the total concentration of drug in the plasma falls to a new equilibrium value, and the unbound concentration is the same as it was before the precipitant drug was introduced, in spite of an increase in the unbound fraction. This means that, provided the patient can 'weather' the increase, if any, in unbound concentration of the object drug for as long as it takes to reach the new steady state, such an interaction will not be clinically important.
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Metabolism interactions
Drug interactions involving metabolism are important interactions. They occur when the metabolism of an object drug is either inhibited or increased by a precipitant drug. There are two phases of drug metabolism. Phase I metabolic reactions (for example, dealkylation, deamination, hydroxylation, sulphoxidation) are carried out by isoenzymes of the mixed-function oxidase system and are subject to interactions. Phase II reactions are conjugations (for example, acetylation, methylation, glucuronidation, sulphatation), which are not affected by interactions.
Induction of drug metabolism
Induction of the metabolism of a drug reduces the amount of drug in the body and therefore reduces its effects. This can result, for example, in pregnancy despite what would otherwise have been adequate oral contraception.
Inhibition of drug metabolism
Inhibition of drug metabolism occurs through inhibition of either the mixed-function oxidase reactions or other specific metabolic pathways.
Examples of the former include the inhibition of warfarin metabolism by chloramphenicol, cimetidine, ketoconazole, metronidazole and quinolones, inhibition of phenytoin metabolism by isoniazid, and inhibition of theophylline metabolism by quinolone and macrolide antibiotics (for example, erythromycin).
Examples of the latter include the inhibition by allopurinol of the metabolism of azathioprine and 6-mercaptopurine by xanthine oxidase and of dietary amines by monoamine oxidase inhibitors.
Excretion interactions
Competition for renal tubular secretion reduces drug excretion. For example, probenecid inhibits the tubular secretion of penicillin, increasing the blood concentration of penicillin and prolonging its therapeutic effects, a beneficial interaction. Amiodarone, quinidine and verapamil inhibit the tubular secretion of digoxin by inhibiting the transport protein P glycoprotein, increasing plasma digoxin concentrations and causing toxicity. Salicylates inhibit the active secretion of methotrexate. Diuretics inhibit the renal excretion of lithium.
PHARMACODYNAMIC INTERACTIONS
In pharmacodynamic interactions the effect of a drug is altered at its site of action. Such interactions are either direct or indirect.
Direct pharmacodynamic interactions
Direct pharmacodynamic interactions occur when two drugs either act on the same site (antagonism or synergism) or act on two different sites with a similar end result. For example, naloxone reverses the effects of opiates and vitamin K reverses the effects of warfarin (beneficial antagonistic interactions). The anticoagulant effects of warfarin are increased in direct synergistic interactions with anabolic steroids and tetracyclines. Any drug that has a depressant action on central nervous function can potentiate the effect of another such drug, whether or not the two drugs have effects on the same receptors; for example, alcohol potentiates the action of any other centrally acting drug.
Indirect pharmacodynamic interactions
In indirect pharmacodynamic interactions a pharmacological, therapeutic or toxic effect of the precipitant drug in some way alters the therapeutic or toxic effect of the object drug, but the two effects are not themselves related and do not themselves interact.
The effects of anticoagulants can be increased by three indirect effects: reduced platelet aggregation (for example, by salicylates, dipyridamole, ticlopidine and NSAIDs) or thrombocytopenia; gastrointestinal ulceration (for example, NSAIDs); and increased fibrinolysis (for example, metformin).
Alterations in fluid and electrolyte balance by diuretics increase the effects of cardiac glycosides and class I anti-arrhythmic drugs (for example, lidocaine (lignocaine), quinidine, procainamide and phenytoin).
AVOIDING ADVERSE DRUG INTERACTIONS
The simple way of avoiding adverse drug interactions is to avoid combinations that are known to be dangerous. If that is not possible, the dosage of the object drug should be reduced in advance of starting the precipitant drug and the precipitant drug should be introduced slowly. When a theoretical interaction is anticipated on the basis of the known properties of two drugs, even if it has not been previously described, careful monitoring will help recognise adverse effects early.

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Home > 1 PRINCIPLES OF MEDICAL PRACTICE > 2 Drug therapy > WRITING A DRUG PRESCRIPTION
WRITING A DRUG PRESCRIPTION
2.19 INFORMATION TO BE GIVEN ON A PRESCRIPTION OUTSIDE HOSPITAL
The date
The patient's name, initials and address
The age of a child if under 12
The name of the drug, preferably in capitals (use generic names when possible)
The formulation to be prescribed
The strength of the formulation
The dose
The frequency of administration
The route of administration
The doctor's name, address and signature


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Figure 2.3 An example of a prescription for a prescription-only medicine (digoxin).
A prescription should be a precise, accurate, clear and readable set of instructions, sufficient for a nurse to administer a drug accurately in hospital, or for a pharmacist to provide a patient with both the correct drug and the instructions on how to take it (see Fig. 2.3). The information that should be written on a prescription is given in Box 2.19.
WRITING DRUG DOSES
Quantities of 1 gram or more should be written in grams. For example, write 2 g.
Quantities of less than 1 gram but more than 1 milligram should be written in milligrams. For example, write 100 mg, not 0.1 g.
Quantities of less than 1 milligram should be written in micrograms or nanograms as appropriate. Do not abbreviate micrograms or nanograms. For example, write 100 micrograms, not 0.1 mg, 100 µg, 100 mcg or 100 ug.
If a decimal point cannot be avoided for values less than 1, write a zero before it. For example, write 0.5 ml, not .5 ml.
For liquid medicines given orally the dose should be stated as the number of milligrams in either 5 ml or 10 ml of solution. For example, write paracetamol oral suspension 250 mg in 5 ml.

PRESCRIBING CONTROLLED DRUGS
2.20 REQUIREMENTS FOR PRESCRIPTIONS FOR CONTROLLED DRUGS
Written completely in the prescriber's handwriting in ink
Signed and dated by the prescriber
The prescriber's address specified
The name and address of the patient specified
The form and strength (if appropriate) of the drug stated
The total quantity of the drug or the number of dose units to be dispensed stated in both words and figures
The exact size of each dose stated in both words and figures




Figure 2.4 An example of a prescription for a controlled drug (morphine).
Because of the problems of drug addiction and misuse of drugs, in the United Kingdom problem drugs are the subject of the Misuse of Drugs Act 1971, the Misuse of Drugs (Notification of and Supply to Addicts) Regulations 1973 and the Misuse of Drugs Regulations 1985. The requirements for the prescription of controlled drugs are listed in Box 2.20 and a sample prescription for a controlled drug is shown in Figure 2.4. Doctors in other countries should make themselves familiar with local regulations.
ABBREVIATIONS
Some abbreviations that are used in prescribing are listed in Box 2.21. Other abbreviations should be avoided and instructions should be written in plain English.
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2.21 ACCEPTABLE ABBREVIATIONS IN PRESCRIPTIONS
Abbreviation Latin meaning English translation
b.d. or b.i.d. Bis in die Twice a day
gutt. Guttae Drops
i.m. - Intramuscular(ly)
i.v. - Intravenous(ly)
o.d. Omni die (Once) every day
o.m. Omni mane (Once) every morning
o.n. Omni nocte1 (Once) every night
p.o. Per os By mouth
PR Per rectum By the anal route
p.r.n. Pro re nata Whenever required
PV Per vaginam By the vaginal route
q.d.s. Quater die sumendum Four times a day
s.c. - Subcutaneous(ly)
stat. Statim Immediately
t.d.s. Ter die sumendum2 Three times a day

1Sometimes written simply as mane or nocte.
2The abbreviations t.i.d. or q.i.d. (ter or quater in die) are sometimes used instead.

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Home > 1 PRINCIPLES OF MEDICAL PRACTICE > 2 Drug therapy > DRUG NOMENCLATURE
DRUG NOMENCLATURE
Drugs have different kinds of name:
the chemical name, whose form generally follows the rules issued by the International Union of Pure and Applied Chemistry (IUPAC)
the approved (official or generic) name, which is usually the International Non-proprietary Name (INN), recommended or proposed by the World Health Organisation, but may be some locally approved name (for example, the British Approved Name (BAN) or United States Adopted Name (USAN))
the proprietary name (brand name or trade name), given to it by a pharmaceutical manufacturer.
For example:
chemical name: (R)-1-(3,4-dihydroxyphenyl)-2-methylaminoethanol
International Non-proprietary Name: epinephrine; British Approved Name: adrenaline
proprietary names: EpiPen® for intramuscular injection and Eppy® or Simplene® eye drops.

Since the chemical name is generally, as in this case, unsuitable for routine prescribing, either the approved name or proprietary name is used. Which should one choose? For some drugs the question is trivial, since only one proprietary formulation exists; for example, donepezil is currently available in the UK only as Aricept®.
However, several proprietary formulations of the same chemical entity may become available when the patent expires on a drug with a previously unique proprietary name. For instance, amoxicillin was first marketed as Amoxil®. When the patent expired the number of proprietary brands multiplied. This can cause prescribing and dispensing problems. For example, in the UK, whether the prescriber writes 'donepezil BP' or 'Aricept', the patient will receive Aricept®. However, if the prescriber writes 'amoxicillin BP', the pharmacist may dispense any proprietary formulation, provided that it conforms to the description laid out in the BP (British Pharmacopoeia), and will generally dispense the cheapest available.
By writing the proprietary name the prescriber can ensure that a particular formulation of a drug is prescribed. However, in some hospitals (in the UK, for example) the hospital pharmacy may stock only one formulation, and even if the hospital doctor writes 'Amoxil' on an inpatient prescription chart the pharmacist may dispense some other approved formulation for which the hospital will have negotiated an economic deal with the supplier.
There are advantages and disadvantages to the prescribing of drugs by their generic (non-proprietary) as opposed to their proprietary names. The advantages relate to:
Awareness of the prescription. The name of the compound often indicates to what class it belongs, usually by virtue of its suffix: e.g. -statin (HMG CoA reductase inhibitors), -olol (ß-blockers, although beware stanozolol), -floxacin (quinolone antibiotics).
Drug stocks. If, say, 'Almodan' rather than 'amoxicillin' is prescribed and an outside pharmacy stocks only Amoxil®, the pharmacist cannot legally dispense the prescription without first consulting the doctor; clearly this can cause inconvenience to all concerned and might result in delayed treatment.
Expense. It is generally cheaper to prescribe by the approved name, since the pharmacist will dispense the cheapest variant held in stock.

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The disadvantages of prescribing by non-proprietary name relate to:
Remembering names. Proprietary names are chosen by pharmaceutical companies because they are catchy, usually easier to remember than the corresponding generic name, and shorter and easier to spell (compare, for example, 'Librium' with 'chlordiazepoxide'). Furthermore, a single proprietary name will do when the formulation may in fact contain two or more drugs (compare, for example, 'Fefol' with 'ferrous sulphate plus folic acid'). However, in recent years there has been a move in the UK to counteract this problem by giving single approved names to some common combinations of drugs; for example, the combination of dihydrocodeine with paracetamol (acetaminophen) is known as co-dydramol.
Quality of product. For a few drugs a change in tablet excipients (the non-therapeutic components) has significant effects on the absorption of the drug from the formulation; important examples include lithium salts, nifedipine and theophylline, which should always be prescribed by brand name.
Continuity of treatment. Patients not infrequently become confused if the drug they are being given changes its form with every prescription; continuity can be achieved by prescribing the same proprietary formulation every time.

In hospital it is usually better to prescribe by approved name, since the pharmacy will dispense whatever formulation is held in stock. The proprietary name can be used when a combination product is prescribed for which no single approved name exists (for example, 'Fefol'). In general practice it is also usually best to prescribe by approved name. Many practitioners prefer to prescribe by proprietary name and in some cases (for example, lithium salts, nifedipine and theophylline) should do so. However, doctors who make the effort to prescribe when possible by approved name will generally find it just as easy as prescribing by proprietary name.
2.22 SOME DRUG NAMES WHOSE BANs AND INNs ARE CONSIDERED TO BE SIGNIFICANTLY DIFFERENT
British Approved Name (BAN) International Non-proprietary Name (INN)
Acrosoxacin Rosoxacin
Adrenaline Epinephrine
Amethocaine Tetracaine
Bendrofluazide Bendroflumethiazide
Benzhexol Trihexyphenidyl
Chlorpheniramine Chlorphenamine
Dicyclomine Dicycloverine
Dothiepin Dosulepin
Eformoterol Formoterol
Flurandrenolone Fludroxycortide
Frusemide Furosemide
Hydroxyurea Hydroxycarbamide
Lignocaine Lidocaine
Methotrimeprazine Levomepromazine
Methylene blue Methylthioninium chloride
Mitozantrone Mitoxantrone
Mustine Chlormethine
Nicoumalone Acenocoumarol
Noradrenaline Norepinephrine
Oxpentifylline Pentoxifylline
Procaine penicillin Procaine benzylpenicillin
Salcatonin Calcitonin (salmon)
Thymoxamine Moxisylyte
Thyroxine sodium Levothyroxine sodium
Trimeprazine Alimemazine

2.23 USUAL THERAPEUTIC AND TOXIC PLASMA CONCENTRATIONS OF COMMONLY MEASURED DRUGS
Concentration below which a therapeutic effect is unlikely Concentration above which a toxic effect is more likely
Drug Optimal sampling time Mass units Molar units Mass units Molar units
Aspirin (salicylate)
Analgesic Just before next dose 20 mg/l 0.15 mmol/l 300 mg/l 2.2µmol/l
Anti-inflammatory Just before next dose 150 mg/l 1.1 mmol/l 300 mg/l 2.2µmol/l
Carbamazepine Just before next dose 4 mg/l 17 mmol/l 10 mg/l 42µmol/l
Cardiac glycosides
Digitoxin Just before next dose 15µg/l 20 nmol/l 30µg/l 39 nmol/l
Digoxin 11 hrs after last dose 0.8µg/l 1.0 nmol/l 2µg/l 2.6 nmol/l
Ciclosporin* Just before next dose 125µg/l 104 nmol/l 200µg/l 166 nmol/l
Lithium 12 hrs after last dose - 0.4 mmol/l - 1.0 mmol/l
Phenytoin Just before next dose 10 mg/l 40 mmol/l 20 mg/l 80µmol/l
Theophylline Just before next dose 10 mg/l 55 mmol/l 20 mg/l 110µmol/l


*Measured in whole blood by specific radioimmunoassay or high-performance liquid chromatography (HPLC).
Notes
Care should be taken in comparing results between different laboratories (particularly with ciclosporin).
The concentration below which a therapeutic effect is unlikely and the concentration above which a toxic effect is more likely together constitute a target range within which satisfactory therapy is likely to be achieved; however, dosages should be adjusted according to the clinical response, not the concentration, which should only be used as a guide.
Note the units used when interpreting results. Laboratories may report in mass units or molar units or both; µg/l = ng/ml; mg/l = µg/ml.
Remember that pharmacokinetics differ from individual to individual; for within-patient comparisons always use the same time after the last dose.
Remember that pharmacodynamics differ from individual to individual and that different individuals respond differently to the same concentration of drug; other factors that can alter the individual response should be considered.
For paracetamol see Figure 3.3, page 171.
For aminoglycosides consult your laboratory.

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There is currently some difficulty in countries of the European Union over certain drug names, following the issue of directives from Brussels (particularly directive 92/27/EEC), requiring member states to use the International Non-proprietary Names rather than locally approved names such as the British Approved Names. In the UK this has little or no effect in most cases, since most of the International Non-proprietary Names are identical or very similar to the corresponding British Approved Names. However, in a few cases (see Box 2.22) the names are considered to be different enough to warrant extra care. In this textbook we have used the International Non-proprietary Names (with the British Approved Names in parentheses in cases that might cause confusion). The only exceptions are adrenaline and noradrenaline, for which we have used the British Approved Names, the corresponding International Non-proprietary Names being epinephrine and norepinephrine; this is because it is thought that in these cases changing to the International Names could be dangerous for patients.

pages 161 - 163


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