RATIONAL APPROACH TO THERAPEUTICS

Drugs should only be prescribed when they are necessary, and in all cases the benefit of administering the medicine should be considered in relation to the risks involved. Bad prescribing habits lead to ineffective and unsafe treatment, exacerbation or prolongation of illness, distress and harm to the patient, and higher cost.

The following steps will help to remind prescribers of the rational approach to therapeutics.

1. Define the patient’s problem
2. Specify the therapeutic objective
3. Selecting therapeutic strategies

(a) Non-pharmacological treatment

(b) Pharmacological treatment

• Selecting the correct group of drugs

• Selecting the drug from the chosen group

• Verifying the suitability of the chosen pharmaceutical treatment for each patient

• Prescription writing

• Giving information, instructions and warnings

• Monitoring treatment

VARIATION IN DOSE RESPONSE

Success in drug treatment depends not only on the correct choice of drug but on the correct dose regimen. Unfortunately drug treatment frequently fails because the dose is too small or produces adverse effects because it is too large. This is because most texts, teachers and other drug information sources continue to recommend standard doses.

The concept of a standard or ‘average’ adult dose for every medicine is firmly rooted in the mind of most prescribers. After the initial ‘dose ranging’ studies on new drugs, manufacturers recommend a dosage that appears to produce the desired response in the majority of subjects. These studies are usually done on healthy, young male Caucasian volunteers, rather than on older men and women with illnesses and of different ethnic and environmental backgrounds. The use of standard doses in the marketing literature suggest that standard responses are the rule, but in reality there is considerable variation in drug response. As a result many prescribed doses are far too low or too high, leading to treatment failure or toxicity. There are many reasons for this variation which include adherence (see below), drug formulation, body weight and age, composition, variation in absorption, distribution, metabolism and excretion, variation in pharmacodynamics, disease variables, genetic and environmental variables.

Drug formulation

Poorly formulated drugs may fail to disintegrate or to dissolve. Enteric-coated drugs are particularly problematic, and have been known to pass through the gastrointestinal tract intact. Some drugs like digoxin or phenytoin have a track record of formulation problems, and dissolution profiles can vary not only from manufacturer to manufacturer but from batch to batch of the same company. The problem is worse if there is a narrow therapeutic to toxic ratio, as changes in absorption can produce sudden changes in drug concentration. For such drugs quality control surveillance should be carried out.

Body weight and age

Although the concept of varying the dose with the body weight or age of children has a long tradition, adult doses have been assumed to be the same irrespective of size or shape. Yet adult weights vary two to threefold, while a large fat mass can store large excesses of highly lipid soluble drugs compared to lean patients of the same weight.

Age changes can also be important. Adolescents may oxidize some drugs relatively more rapidly than adults, while the elderly may have reduced renal function and eliminate some drugs more slowly.

Physiological and pharmacokinetic variables

Drug absorption rates may vary widely between individuals and within the same individual at different times and in different physiological states. Drugs taken after a meal are delivered to the small intestine much more slowly than in the fasting state, leading to much lower drug concentrations. In the case of drugs like paracetamol with a high rate of metabolism on ‘first pass’ through the liver, this may render a standard dose completely ineffective. In pregnancy gastric emptying is also delayed, while some drugs may increase or decrease gastric emptying and affect absorption of other drugs.

Drug distribution

Drug distribution varies widely: fat soluble drugs are stored in adipose tissue, water soluble drugs are distributed chiefly in the extracellular space, acidic drugs bind strongly to plasma albumin and basic drugs to muscle cells. Hence variation in plasma albumin levels, fat content or muscle mass may all contribute to dose variation. With very highly albumin bound drugs like warfarin, a small change of albumin concentration can produce a big change in free drug and a dramatic change in drug effect.

Drug metabolism and excretion

Drug metabolic rates are determined both by genetic and environmental factors. Drug acetylation shows genetic polymorphism, whereby individuals fall clearly into either fast or slow acetylator types. Drug oxidation, however, is polygenic, and although a small proportion of the population can be classified as very slow oxidizers of some drugs, for most drugs and most subjects there is a normal distribution of drug metabolizing capacity, and much of the variation is under environmental control. Many drugs are eliminated by the kidneys without being metabolized. Renal disease or toxicity of other drugs on the kidney can therefore slow excretion of some drugs.

Pharmacodynamic variables

There is significant variation in receptor response to some drugs, especially central nervous system responses, for example pain and sedation. Some of this is genetic, some due to tolerance, some due to interaction with other drugs and some due to addiction, for example, morphine and alcohol.

Disease variables

Both liver disease and kidney disease can have major effects on drug response, chiefly by the effect on metabolism and elimination respectively (increasing toxicity), but also by their effect on plasma albumin (increased free drug also increasing toxicity). Heart failure can also affect metabolism of drugs with rapid hepatic clearance (for example lidocaine, propranolol). Respiratory disease and hypothyroidism can both impair drug oxidation.

Enviromental variables

Many drugs and environmental toxins can induce the hepatic microsomal enzyme oxidizing system (MEOS) or cytochrome P450 oxygenases, leading to more rapid metabolism and elimination and ineffective treatment. Environmental pollutants, anaesthetic drugs and other compounds such as pesticides can also induce metabolism. Diet and nutritional status also impact on pharmacokinetics. For example in infantile malnutrition and in malnourished elderly populations drug oxidation rates are decreased, while high protein diets, charcoal cooked foods and certain other foods act as metabolizing enzyme inducers. Chronic alcohol use induces oxidation of other drugs, but in the presence of high circulating alcohol concentrations drug metabolism may be inhibited.

ADHERENCE (COMPLIANCE) WITH DRUG TREATMENT

It is often assumed that once the appropriate drug is chosen, the prescription correctly written and the medication correctly dispensed, that it will be taken correctly and treatment will be successful. Unfortunately this is very often not the case, and physicians overlook one of the most important reasons for treatment failure-poor adherence (compliance) with the treatment plan.

There are sometimes valid reasons for poor adherence - the drug may be poorly tolerated, may cause obvious adverse effects or may be prescribed in a toxic dose.

Failure to adhere with such a prescription has been described as ‘intelligent noncompliance’.

Bad prescribing or a dispensing error may also create a problem, which patients may have neither the insight nor the courage to question. Even with rational prescribing, failure to adhere to treatment is common. Factors may be related to the patient, the disease, the doctor, the prescription, the pharmacist or the health system and can often be avoided.

The Following points are recommended to increase patient compliance

• Review the prescription to be sure it is correct.

• Spend time explaining the problem and the reason for the drug.

• Establish a good relationship with the patient, rather than a hurried or brusque manner with little eye contact.

• Explore problems, for example reading the label, getting the prescription filled.

• Insist that patients bring their medication to the clinic ‘for checking’, so that tablet counts can be made unobtrusively.

• Insist that patients learn the names of their tablets, and review their regimen with them. Write notes for them.

• Keep treatment regimens simple.

• Communicate with the pharmacist, to develop teamwork and collaboration in helping and advising the patient.

• Involve the partner or another family member,

• Listen to the patient.

ADVERSE EFFECTS AND INTERACTIONS

Adverse drug reactions

An adverse drug reaction (ADR) may be defined as ‘any response to a drug which is noxious, unintended and occurs at doses normally used for prophylaxis, diagnosis, or therapy...’.

ADRs are therefore unwanted or unintended effects of a medicine, including idiosyncratic effects, which occur during its proper use. They differ from accidental or deliberate excessive dosage or drug maladministration.

Any drug may produce unwanted or unexpected adverse reactions. Detection and recording of these is of vital importance. Doctors and pharmacists are urged to help by reporting adverse reactions to:

Drug Administration and Control Authority of Ethiopia
Planning, Drug information establishment and distribution department
P.o.Box 5681
Fax. 251-1-524122
E-mail: daca@telecom.net.et

Major factors predisposing to adverse effects

It is well known that different patients often respond differently to a given treatment regimen. For example, in a sample of 2422 patients who had been taking combinations of drugs known to interact, only 7 (0.3%) showed any clinical evidence of interactions. In addition to the pharmaceutical properties of the drug therefore, there are characteristics of the patient which predispose to ADRs.

EXTREMES OF AGE. The very old and the very young are more susceptible to ADRs. Drugs which commonly cause problems in the elderly include hypnotics, diuretics, non-steroidal antiinflammatory drugs, antihypertensives, psychotropics and digoxin.

All children, and particularly neonates, differ from adults in the way they respond to drugs. Some drugs are likely to cause problems in neonates (for example morphine), but are generally tolerated in children. Other drugs (for example valproic acid) are associated with increased risk of ADRs in children of all ages. Other drugs associated with problems in children include chloramphenicol (grey baby syndrome), antiarrhythmics (worsening of arrhythmias), aspirin (Reye syndrome).

INTERCURRENT ILLNESS. If besides the condition being treated the patient also suffers from another disease, such as kidney, liver or heart disease, special precautions are necessary to prevent ADRs. Remember also that, as well as the above factors, the genetic make-up of the individual patient may predispose to ADRs.

DRUG INTERACTIONS. Interactions may occur between drugs which compete for the same receptor or act on the same physiological system. They may also occur indirectly when a drug-induced disease or a change in fluid or electrolyte balance alters the response to another drug. Interactions may occur when one drug alters the absorption, distribution or elimination of another drug, such that the amount which reaches the site of action is increased or decreased. Drug-drug interactions are some of the commonest causes of adverse effects. When two drugs are administered to a patient, they may either act independently of each other, or interact with each other. Interaction may increase or decrease the effects of the drugs concerned and may cause unexpected toxicity. As newer and more potent drugs become available, the number of serious drug interactions is likely to increase. Remember that interactions which modify the effects of a drug may involve non-prescription drugs, non-medicinal chemical agents, and social drugs such as alcohol, marijuana, and traditional remedies, as well as certain types of food. The physiological changes in individual patients, caused by such factors as age and gender, also influence the predisposition to ADRs resulting from drug interactions.

Incompatibilities between drugs and IV fluids

Drugs should not be added to blood, amino acid solutions or fat emulsions. Certain drugs, when added to IV fluids, may be inactivated by pH changes, by precipitation or by chemical reaction. Benzylpenicillin and ampicillin lose potency after 6- 8 hours if added to dextrose solutions, due to the acidity of these solutions. Some drugs bind to plastic containers and tubing, for example diazepam and insulin. Aminoglycosides are incompatible with penicillins and heparin. Hydrocortisone is incompatible with heparin, tetracycline, and chloramphenicol.

Adverse effects caused by traditional medicines

Patients who have been or are taking traditional herbal remedies may develop ADRs. It is not always easy to identify the responsible plant or plant constituent. Refer to the drug and toxicology information service if available and/or to suitable literature.

The effect of food on drug absorption

Food delays gastric emptying and reduces the rate of absorption of many drugs; the total amount of drug absorbed may or may not be reduced. However, some drugs are preferably taken with food, either to increase absorption or to decrease the irritant effect on the stomach.

PRESCRIPTION WRITING

A prescription is an instruction from a prescriber to a dispenser. The prescriber is not always a doctor but can also be a paramedical worker, such as a medical assistant, a midwife or a nurse. The dispenser is not always a pharmacist, but can be a pharmacy technician, an assistant or a nurse.

The following guidelines will help to ensure that prescriptions are correctly interpreted and leave no doubt about the intention of the prescriber. The guidelines are relevant for primary care prescribing; they may, however, be adapted for use in hospitals or other specialist units.

Prescription form

The most important requirement is that the prescription be clear. It should be legible and indicate precisely what should be given. The local language is preferred.

The following details should be shown on the form:

• The prescriber’s name, address and telephone number. This will allow either the patient or the dispenser to contact the prescriber for any clarification or potential problem with the prescription.

• Date of the prescription.

• Name, form and strength of the drug. The International Nonproprietary Name of the drug should always be used. If there is a specific reason to prescribe a special brand, the trade name can be added. The pharmaceutical form (for example ‘tablet’, ‘oral solution’, ‘eye ointment’) should also be stated.

• The strength of the drug should be stated in standard units using abbreviations that are consistent with the Systéme Internationale (SI). ‘Microgram’ and ‘nanogram’ should not, however, be abbreviated. Also, ‘units’ should not be abbreviated. Avoid decimals whenever possible. If unavoidable, a zero should be written infront of the decimal point.

• Specific areas for filling in details about the patient including name, address and age.

Directions

Directions specifying the route, dose and frequency should be clear and explicit; use of phrases such as ‘take as directed’ or ‘take as before’ should be avoided. For preparations which are to be taken on an ‘as required’ basis, the minimum dose interval should be stated together with, where relevant, the maximum daily dose.

It is good practice to qualify such prescriptions with the purpose of the medication (for example ‘every 6 hours as required for pain’, ‘at night as required to sleep’).

It is good practice to explain the directions to the patient; these directions will then be reinforced by the label on the medicinal product and possibly by appropriate counseling by the dispenser. It may be worthwhile giving a written note for complicated regimens although it must be borne in mind that the patient may lose the separate note.

Quantity to be dispensed

The quantity of the medicinal product to be supplied should be stated such that it is not confused with either the strength of the product or the dosage directions.

Alternatively, the length of the treatment course may be stated (for example ‘for 5 days’).

Wherever possible, the quantity should be adjusted to match the pack sizes available.

For liquid preparations, the quantity should be stated in millilitres (abbreviated as ‘ml’) or litres (preferably not abbreviated since the letter ‘l’ could be confused with the figure ‘1’).

Narcotics and controlled substances

The prescribing of a medicinal product that is liable to abuse requires special attention and may be subject to specific statutory requirements. Practitioners may need to be authorized to prescribe controlled substances; in such cases it might be necessary to indicate details of the authority on the prescription. In particular, the strength, directions and the quantity of the controlled substance to be dispensed should be stated clearly, with all quantities written in words as well as in figures to prevent alteration. Other details such as patient particulars and date should also be filled in carefully to avoid alteration.