18 Therapeutics and prescriptions

The purpose of drug therapy is to cure or ameliorate disease, or to alleviate symptoms. However, all drugs also have adverse effects and drug therapy is not always necessary. The good prescriber: The good prescriber prescribes only when the balance of benefit to harm is favourable. The choice of drug should be based on an understanding of the relevant pathophysiology and pharmacology, and the dose regimen must take into account the particular circumstances of each patient. The response to treatment should be monitored and the prescription reviewed if adverse effects emerge.

The knowledge and experience required to become a good prescriber may take many years to accrue and, for the newcomer to medicine, merely gaining some familiarity with the wide range of available treatments may seem daunting. This chapter provides concise summaries of some important and common drugs, including the mode of action, major side-effects, contraindications and interactions, and a guide to their use in everyday practice. Also included is some basic advice on writing prescriptions and on prescribing in renal impairment, hepatic impairment and the elderly. Neither the list of drugs nor the information on their side-effects and interactions is exhaustive, and we would advise readers to refer to the British National Formulary or other national equivalent for more detailed and regularly updated guidance.

WRITING A DRUG PRESCRIPTION

A prescription should be a precise, accurate, clear, 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. The information that should be written on a prescription is given in Box 18.1. Some abbreviations used in prescribing are listed in Box 18.2. Other abbreviations should be avoided and instructions should, whenever possible, be written in plain English. Because of the problems of drug addiction and misuse of drugs, drugs likely to be abused are, in the UK, 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 18.3. Doctors in other countries should make themselves familiar with local regulations.

18.2 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 mane¹	(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 sumendum²	Four times a day
s.c.	—	Subcutaneous(ly)
stat.	Statim	Immediately
t.d.s.	Ter die sumendum²	Three times a day

1 Sometimes written simply as ‘mane’ or ‘nocte’.

2 The abbreviations t.i.d. and q.i.d. (ter/quater in die) are sometimes used instead; do not use q.d. to mean once a day.

ALTERING DOSAGES IN RENAL INSUFFICIENCY

If a drug is more than 50% eliminated unchanged by the kidneys or has active metabolites that are eliminated by the kidneys (Box 18.4), the maintenance dosage must be altered in renal insufficiency, although it is not usually necessary to alter a one-off dose. Creatinine clearance can be used as a guide to reducing maintenance dosages.

18.4 DRUGS WHOSE DOSAGES ARE AFFECTED BY RENAL INSUFFICIENCY ¹

Mild renal insufficiency (creatinine clearance 20–50 ml/min)

Moderate renal insufficiency (creatinine clearance 10–20 ml/min)

• Some β-blockers (e.g. atenolol, sotalol)

• Opioid analgesics

Severe renal insufficiency (creatinine clearance <10 ml/min)²

• Sulphonylureas (gliclazide)

¹ These guidelines mirror those recommended in the British National Formulary.

² Many of these patients receive renal replacement therapy, which can affect drug pharmacokinetics.

Some drugs should be avoided entirely in renal insufficiency, for either pharmacokinetic or pharmacodynamic reasons (Box 18.5).

Diuretics are relatively ineffective in severe renal insufficiency, partly because they cannot gain access to their site of action, the luminal epithelium. High dosages of loop diuretics may be required for efficacy. Potassium-sparing diuretics should not be used, because of the increased risk of hyperkalaemia.

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. In chronic liver disease, jaundice, ascites, a prolonged PT, 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. 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 (Box 18.6), it will be mostly cleared during its first passage through the liver (so-called ‘first-pass’ metabolism). 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 i.v. dosage requirements. The pharmacological effects of some drugs are altered in liver disease, with increased risks of adverse effects (Box 18.7).

18.6 SOME DRUGS WITH HIGH HEPATIC CLEARANCE RATES

• Clomethiazole	• Morphine
• Glyceryl trinitrate	• Pethidine
• Labetalol	• Propranolol
• Lidocaine	• Simvastatin

18.7 SOME DRUGS WHOSE ACTIONS ARE INCREASEDIN LIVER DISEASE

Drug	Adverse effect
Oral anticoagulants	Increased anticoagulation (reduced clotting factor synthesis)
Metformin	Lactic acidosis
Chloramphenicol	Bone marrow suppression
NSAIDs	GI bleeding
Sulphonylureas	Hypoglycaemia

ALTERING DOSAGES IN OLDER PEOPLE

Both drug handling and responses to drugs change as people age, and there is much more variability in drug response in elderly people than in younger people. Adverse drug reactions are particularly likely in frail older people, 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 older people.

Inappropriate polypharmacy is common in older people and the scope for drug interactions is large; in patients >60 yrs of age the error rate in taking drugs is ∼60%, and this increases markedly if more than three drugs are prescribed.

Many older people find it difficult to swallow tablets, and the more frail they are, the more difficult this becomes. Tablets or capsules can adhere to the oesophageal mucosa, and tablets should be swilled down with at least 60 ml of water to avoid hold-up.

Drug distribution is sometimes altered in older people and dosages should be adjusted for body weight, particularly for drugs with a low therapeutic index. Older people have an increased proportion of body fat, and lipid-soluble drugs tend to accumulate to a greater extent than in younger patients.

The metabolism of some drugs (e.g. clomethiazole, nifedipine, propranolol, theophylline) is reduced in older people and dosages of these drugs should be reduced.

Renal function falls with age, and drugs with predominantly renal excretion may require dosage reductions (see above). Serum creatinine may be deceptively reassuring because of reduced muscle mass in old age; creatinine clearance should therefore be calculated using an equation such as Cockcroft–Gault.

In general, when prescribing for older 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).

DRUGS COMMONLY USED FOR INFECTIOUS DISEASES

The optimal selection of antimicrobial therapy requires knowledge of:

• The infecting organism (or most likely pathogen, given the clinical and geographical context).

• Local patterns of antimicrobial resistance.

• The relevant pharmacokinetics.

• The clinical status of the patient.

ANTIBACTERIAL AGENTS

BETA-LACTAM ANTIBIOTICS (PENICILLINS, CEPHALOSPORINS, CARBAPENEMS)

Mode of action: Exert a bactericidal effect by disrupting bacterial cell wall synthesis.

Penicillins

Indications:

• Natural penicillins (phenoxymethylpenicillin and benzylpenicillin): streptococcal infections including throat infections, otitis media, erysipelas, cellulitis, endocarditis; meningococcal infections; anthrax, diphtheria, syphilis, gas gangrene, leptospirosis.

• Flucloxacillin: staphylococcal infections including impetigo, cellulitis, osteomyelitis, septic arthritis, wound infections, endocarditis, pneumonia.

• Aminopenicillins (ampicillin and amoxicillin): exacerbations of chronic bronchitis, pneumonia, treatment and prophylaxis of endocarditis, urinary tract infection (UTI), otitis media, sinusitis, dental abscess, listerial meningitis.

Clinical use: Very cheap, well tolerated, safe and easy to use, but re-sistance is increasing. Natural penicillins are primarily effective against Gram-positive organisms (except staphylococci) and anaerobic organisms (Fig. 18.1).

• Phenoxymethylpenicillin (oral 250–500 mg 6-hourly): widely used for simple skin, ear and oral infections, but should not be given in serious infections due to unreliable oral absorption.

• Benzylpenicillin (i.v. 1.2–2.4 g 6-hourly): first-line treatment for streptococcal endocarditis (with gentamicin) and cellulitis (with flucloxacillin). It is also highly effective in meningococcal meningitis/sepsis, but less effective in pneumococcal meningitis; for this reason, a broad-spectrum cephalosporin is often preferred as empirical therapy for meningitis (p. 667).

• Flucloxacillin (oral/i.v. 500 mg–1 g 6-hourly): the mainstay of treatment for most staphylococcal infections (Fig. 18.2), but meticillin-resistant Staph. aureus (MRSA) is an increasing problem. If MRSA is suspected (low threshold in serious or hospital-acquired infections), vancomycin should be used in preference.

Fig. 18.1 Antibacterial spectrum of Natural Penicillin.

Fig. 18.2 Antibacterial spectrum of flucloxacillin.

Aminopenicillins have similar activity to natural penicillins with additional Gram-negative cover against Enterobacteriaceae and haemophilus (Fig. 18.3). Addition of the β lactamase inhibitor, clavulanic acid (producing ‘co-amoxiclav’), prevents resistance due to bacterial β-lactamase production and extends the spectrum of activity.

• Amoxicillin (oral/i.v. 500 mg–1 g 8-hourly) and co-amoxiclav (oral 375–625 mg 8-hourly; i.v. 1.2 g 8-hourly) are widely used in the treatment of uncomplicated community-acquired pneumonia, exacerbations of chronic bronchitis and UTI.

• Ampicillin (i.v. 2 g 4-hourly) should be added to empirical therapy for bacterial meningitis where listerial infection is suspected (e.g. in patients >50 yrs).

Fig. 18.3 Antibacterial spectrum of amoxicillin.

Side-effects: Hypersensitivity reactions (generalised allergy to penicillin occurs in 0.7–10% of cases and anaphylaxis in <0.2%); diarrhoea (including antibiotic-associated colitis). Over 90% of patients with infectious mononucleosis develop a rash if given aminopenicillins; this does not imply lasting allergy. Cholestatic jaundice may occur with co-amoxiclav.

Cephalosporins

Indications: Include sepsis, pneumonia, meningitis, biliary infections, UTIs, peritonitis.

Clinical use:

• First-generation compounds (e.g. cefalexin: oral 250 mg 6-hourly): excellent activity against Gram-positive organisms but limited Gram-negative cover. They may be helpful in some urinary, skin and soft tissue infections but are rarely first-line treatment.

• Second-generation cephalosporins (e.g. cefuroxime): retain Gram-positive activity but have extended Gram-negative activity and some activity against anaerobes (Fig. 18.4). Oral cefuroxime (250–500 mg 12-hourly) has good activity against common respiratory pathogens but is poorly absorbed. I.V. cefuroxime (750 mg–1.5 g 8-hourly) is widely used with metronidazole in the treatment of colorectal and biliary tract infection and for prophylaxis in colorectal and hepatobiliary surgery.

• Third-generation cephalosporins: further improve anti-Gram-negative cover but are very expensive and only available i.v. Ceftriaxone (i.v. 1–2 g daily) and cefotaxime (i.v. 1–2 g 6–12-hourly) retain good activity against Strep. pyogenes, haemolytic streptococci and many staphylococci; they are widely used in serious infections including sepsis, meningitis, severe community-acquired pneumonia and acute pyelonephritis. Ceftazidime (e.g. i.v. 1 g 8-hourly) has particularly good antipseudomonal activity but less Gram-positive effectiveness; it has an important role in the treatment of hospital-acquired pneumonia and sepsis.

Fig. 18.4 Antibacterial spectrum of cefuroxime.

Side-effects: Many of the first-generation drugs are potentially nephrotoxic. Second- and third-generation cephalosporins have a low incidence of allergy and a very low rate of anaphylaxis, even in patients with established penicillin allergy; however, their broad spectrum of activity predisposes to antibiotic-associated colitis.

Clinical use: Very effective against Gram-negative organisms (Fig. 18.6), including Pseudomonas aeruginosa, and useful in Gram-negative sepsis or serious infections arising from the urinary or biliary tract. They also have some Gram-positive activity and show impressive synergy with penicillins; the combination of gentamicin and penicillin is frequently used in the treatment of endocarditis. They must be administered by injection (e.g. gentamicin i.v./i.m. 3–5 mg/kg 8-hourly), as absorption from the GI tract is negligible. Careful monitoring of renal function and drug levels can help to minimise oto- and nephrotoxicity.