Guidance on Prescribing

Introduction

Rational Prescribing

Drug and Dose Selection

Irrational Prescribing

Common Prescription Abbreviations Used

Medicine Schedules in South Africa

Prescription Writing: Legal Requirements

Prescribing for Children

The ‘Pros and Cons’ of Some Medicinal Preparations

Special Dosage Calculation: Body Surface Area (BSA)

Prescribing during Pregnancy and Breastfeeding

Prescribing in Liver Disease

Prescribing in Renal Disease

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Introduction

In medicine, the word ‘Prescription’ means: “the written instructions from an authorized healthcare provider (e.g. registered medical doctor), to a pharmacist stating the name, form, dosage strength, frequency and duration of a drug(s) to be dispensed to a specific patient”.

Prescribing a drug is the most important tool used by authorized healthcare providers to diagnose, treat and/or prevent  disease. Prescribing, although it may sound easy,  is a complex process that requires: (1) diagnostic skills, (2) knowledge of common medicines, (3) understanding of the basic principles of pathophysiology and pharmacology, (4) communication skills, and (5) the ability to make decisions based on judgments of potential benefit and risks, having taken into account available evidence, availability of medicines, and specific factors relating to the patient being treated and the selected drugs.

The progressive accumulation of clinical data concerning medicines in common usage might be expected to provide sufficient evidence to support most prescribing decisions when, in fact, authorized healthcare providers prescribe in varied circumstances, often in the absence of any directly related evidence.

Rational Prescribing describes a logical (feasible) approach that includes:

• making a correct (differential) diagnosis
• estimating possible prognosis
• establishing the goals of pharmacotherapy
• selecting the most appropriate (safe + cost-effective) treatment, and
• monitoring the effects of that treatment

Rational prescribing also should be adopted with an attempt to:

• maximize clinical effectiveness
• minimize drug-related adverse effects
• avoid wasting scarce healthcare resources, and
• respect patient choice(s)

Drug and Dose Selection

Having considered diagnosis, prognosis and goals of therapy, prescribers often select from several pharmacological options. The best choice should maximize the benefit-harm balance based on drug, patient, and prescriber factors influencing drug selection, taking into account restrictions based on approved indications, availability and costs.

Drug factors

• Pharmacokinetics
• Pharmacodynamics
• Therapeutic efficacy and safety
• Cost-effectiveness

Patient factors

• Known history adverse drug reactions
• Co-morbidities
• Current drug therapy
• Risk for non-compliant/adherence
• Intrapersonal (genetics)

Prescriber factors

• Qualification
• Medication prescribed is within the professional scope of practice
• HPCSA registration/authorization to prescribe medicines
• Familiarity with the medicines
• Possible follow-up and monitoring

Rational prescribing aims to ensure that selection medicine(s) is not a simple formulaic linkage of drugs and doses to particular diagnoses but involves individualizing prescriptions as far as possible, taking account of all drug, patient and prescriber variables.

Irrational Prescribing refers to a process of prescribing a medicine that fails to conform to good standards, and ethics, of treatment. This may manifest in five different ways, namely:

• Under-prescribing: where the medicines required are not prescribed, or an insufficient dosage or treatment duration is issued
• Over-prescribing: where a medicine that is not indicated is prescribed, or, if indicated, the duration of treatment is too long or the quantity of medicine given to patients exceeds the amount required for the current course of therapy
• Incorrect prescribing: when a medicine is given for the wrong diagnosis, the prescription is prepared improperly, or adjustments are not made to incorporate the patient’s co-existing medical, genetic, or environmental conditions
• Extravagant prescribing: when a prescriber issues a more expensive medicine when a less expensive one of comparable safety and efficacy exists, or where a prescriber treats a patient symptomatically instead of unpacking the underlying serious condition, and
• Multiple prescribing: when two or more medicines are prescribed when fewer would have achieved the same effect (i.e. polypharmacy), or where prescribers treat several related conditions when treatment of the underlying (primary) disorder would improve or cure the other conditions

Common Prescription Abbreviations Used

Abbreviation	Meaning
(p.o)	orally
(I.M.)	intramuscular
(I.V)	intravenous
(I.V.I.)	Intravenous infusion
(S.Q.) (S.C.) (sub q)	subcutaneous
(stat)	immediately
(o.d.) (d)	once per day, once daily
(qd)	daily
(q.o.d)	every other day
(b.d.)	twice per day
(t.i.d) (t.d.s)	three times per day
(q.i.d) (q.d.s)	four times per day
(o.m.) (mane)	every morning
(o.n.) (noct)	every night
(a.c.)	before food
(p.c.)	after food
(p.r.n.) (s.o.s.)	when required / when necessary

Medicine Schedules in South Africa

There are four main types of medicine schedules:

Unscheduled medicines

• Unscheduled medicines have a schedule of 0 (S0 medicines)
• These medicines are registered in South Africa
• Available in unrestricted trade
• Available on the shelves at places like pharmacies, supermarkets, health shops or service stations

Over-the-counter medicines (OTC)

• Have a schedule of 1 or a schedule of 2 (S1 and S2 medicines)
• These medicines are registered in South Africa
• S1 and S2: Can be dispensed with or without prescription. Can be repeated,
• Are medicines that can be given to you ‘over the counter’ without a prescription
• Only available at pharmacies
• Can only be dispensed by a pharmacist/pharmacy assistant

Prescription medicines

• Any medicine classified as schedule 3 or higher is a prescription medicine
• These medicines are registered in South Africa
• Will require a prescription from a treating authorized prescriber (like general practitioner, dentist or allied health professional)
• S3, S4 and S5: You can only get a pre-specified amount (6-month repeat prescription), subject to change as per regulatory body
• S6 and higher: NO REPEATS
• Medicine with a high scheduling status (schedule 6 and higher) is treated differently because of its habit-forming nature, potential abuse and risk for adverse effects

Section 21 medicines

• The official South African Health Regulatory Authority may authorize (in writing) any person to sell (hence used) for a specified period to a specified person a specified quantity of a specified medicine
• These medicines are NOT registered in South Africa

Prescription Writing: Legal Requirements

According to the Regulation (33) of the MEDICINES AND RELATED SUBSTANCES ACT (Act No.101 of 1965), as amended:

1. Every prescription for a medicine shall be

• written in legible print
• typewritten or
• prepared with an electronic agent as defined by and in compliance with the Electronic Communications and Transactions Act, 2002 (Act No. 25 of 2002)

2. A prescription shall be signed

• in person , or
• in the case of a prescription prepared in accordance with subregulation (1)(c), with an advanced electronic signature as per Section 13 of the Electronic Communications and Transactions Act, 2002 (Act No. 25 of 2002), by an authorized prescriber

3. A prescription shall at least state the following

• the name, qualification, registration number with the relevant statutory health council and address of the prescriber
• the name, identification number and address of the patient or the name, identification number and address of the person to whom the medicines are delivered in the case of a prescription issued by a veterinarian
• the date of issue of the prescription
• the approved name or the proprietary name of the medicine
• the dosage form
• the strength of the dosage form and the quantity of the medicine to be supplied:
  Provided that-
  - in the case of Schedule 6 substances the quantity to be supplied shall be expressed in figures as well as in words; and
  - where the prescriber has failed to express the quantity in figures as well as in words, the medical practitioner, dentist, veterinarian or pharmacist dispensing the medicine may, after obtaining confirmation from the prescriber, insert the words or figures that have been omitted
• instructions for the administration of the dosage, frequency of administration and the withdrawal period in the case of veterinary medicines for food producing animals
• the age and gender of the patient and, in the case of veterinary medicine, the animal species; and
• the number of times the prescription may be repeated

4. The pharmacist who dispenses a prescription shall verify the authenticity of all prescriptions so dispensed.

5. In the event of a prescription transmitted by fax or communicated verbally a permanent copy of the prescription shall be made for record purposes and shall be followed by the signed prescription as per subregulation (2) within 7 working days from the original transmission or communication.

6. The prescriber shall keep records of the diagnosis relevant to the prescription and where the patient consents, indicate the diagnosis on the prescription.

Prescribing for Children

Children dosage forms and medicines adherence:

Many drugs prepared for children are in the form of liquid preparation, either in form syrup/elixir, suspension or any other liquid preparation, and for that reason, the following must be considered:

• Syrup/Elixir is usually (not always) an alcoholic solution in which the drug molecules are dissolved and evenly distributed. No shaking is required, and unless some of the vehicle has evaporated, the first dose from the bottle and the last dose should contain equivalent amounts of drug
• Suspensions contain undissolved particles of drug that must be distributed throughout the vehicle by shaking. If shaking is not thorough each time a dose is given, the first doses from the bottle may contain less drug than the last doses, with the result that less than the expected plasma concentration or effect of the drug may be achieved early in the course of therapy
• Toxicity may, conversely, occur late in the course of therapy, when it is not expected. This uneven distribution is a potential cause of inefficacy or toxicity in children taking anticonvulsant suspension therapy
• It is essential that the healthcare prescriber know the form in which the drug will be dispensed and provide proper instructions to the pharmacist and the child’s parent (or caregiver)

Measuring oral liquid preparations can be challenging. For example, the measured volume of “teaspoons” can vary depending on the size of the spoon and subjective medicines volume calculation. The healthcare prescriber must encourage parents to obtain a calibrated medicine spoon or syringe from the pharmacy as these devices improve the accuracy of dose measurements and simplify administration of drugs to children.

Adherence (also known as compliance) may be more difficult to achieve in the paediatrics  practice than otherwise, since it involves not only the parent’s conscientious effort to follow directions but also such practical matters as measuring errors, spilling, dislikeness and spitting out.

When evaluating adherence, it is often helpful to ask if an attempt has been made to give a further dose after the child has spilled half of what was offered. The parents or caregivers may not always be able to say with confidence how much of a dose the child actually received. The parents or caregivers must be told whether or not to wake the infant for the ‘every-6-hour’ dose day or night. These matters should be discussed and made clear, and no assumptions should be made about what the parents or caregivers may or may not do.

Nonadherence frequently occurs when an antibiotic, for example, is prescribed to treat a condition like otitis media and the child feels well after 2 or 3 days of therapy. The parents or caregivers may not feel there is any reason to continue giving the medicine even though it was prescribed for a specific period of time (7 days, for example).

Parents education and medicines adherence: The common nonadherence situation should be always anticipated so the parents or caregivers can be told why it is important to continue giving the medicine for the prescribed period even if the child started to feel “better.” Whenever a drug does not achieve its therapeutic effect, the possibility of nonadherence or inaccurate diagnosis should be considered.

Practical and convenient dosage forms and dosing schedules should be chosen to the extent possible. The easier it is to administer and take the medicine and the easier the dosing schedule is to follow, the more likely it is that adherence will be achieved.

Possible adverse effects and drug interactions with other (chronic) medicines and/or any over-the-counter (OTC) medicines or foods should also be discussed.

Drugs with narrow therapeutic index/windows: for such drugs (like digoxin), independent double-checking of dose and volume calculations is widely practiced.

Errors of prescribing: A good rule for avoiding prescribing errors is to:

• Write the dosage strength using a leading “0” plus decimal point (instead of “decimal point” alone) when dealing with doses less than “1 mg or mcg”. For example, digoxin dose must be written as [0.0125mg] instead of [.0125mg]
•  Avoid using the value zero “0” after a decimal point. For example, phenytoin dose must be written as [5mg/kg] instead of [5.0mg/kg]
• Avoid using abbreviations for the acronyms that might be mis-interpreted. For example, international unit (IU) can be misinterpreted as intravenous (IV), also microgram (µg) can be misinterpreted as milligram (mg)
• Avoid using child’s age dosing charts when dealing with children with extreme body weights; under-weight and overweight children, in order to avoid therapy inefficacy or toxicity, and rather use the recommended mg/kg dosing calculation system

The ‘Pros and Cons’ of Some Medicinal Preparations

Preparation	Example	Advantages	Disadvantages
Oral liquid	Syrups	Easy to administer	Preservative can be contraindicated or prohibited
Rectal	Suppositories	Easy to administer	- Local irritation  - Unpredictable absorption
Topical	Cream	Easy to apply	- Local irritation - Local adverse effects
Parenteral	Intramuscular	Instant systemic delivery (in emergencies)	- Deep muscle abscess - Invoke significant anxiety

Special Dosage Calculation: Body Surface Area (BSA)

Calculating the Paediatric dosage according to the child’s body surface area (BSA) is a common practice in oncology, haematology and other clinics.

In order to calculate the doses of the medicines according to the child’s BSA, the following formulae can be used in order to calculate the child BSA:

If the child’s body weight and body height are known:

BSA (m2) =  

If the child’s body weight is only known (body height is unknown):

BSA (m2) =

Prescribing during Pregnancy and Breastfeeding

Prescription and over-the-counter medicines use is challenging practice during pregnancy and breastfeeding for different reasons.

For example, the physiological changes associated with pregnancy and its pathophysiological impact on the pharmacokinetics and pharmacodynamics of medications.

Moreover, the lack of information related to safety (and possible efficacy) data from clinical trials, and the potential risk for both maternal and foetal adverse effects during the use of such medicine should always be considered while prescribing medicines to pregnant populations, during the antenatal and postpartum periods.

Adherence to the safe principles of prescribing together with patient involvement in decision making is essential when prescribing during pregnancy and breastfeeding in order to prevent any unfortunate medical and/or medico-legal consequences.

As per June 2015, the U.S. Food and Drug Administration (FDA) published a report outlining the new (update) standards for how to present information regarding the safety of medications used during pregnancy and breastfeeding. The new content and formatting requirements aimed to provide a more consistent way to include relevant information about the risks and benefits of prescription drugs and biological products used during pregnancy and breastfeeding.

The newly designed labelling system (known as Pregnancy and Lactation Labelling Rule - PLLR) would include the following three subsections:

• Pregnancy: will provide information relevant to the use of the drug in pregnant women, such as dosing and potential risks to the developing fetus, and will require information about whether there is a registry that collects and maintains data on how pregnant women are affected when they use the drug or biological product. Information in drug labelling about the existence of any pregnancy registries has been previously recommended but not required until now.
• Lactation: will provide information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed child.
• Females and Males of Reproductive Potential: will include information about pregnancy testing, contraception and about infertility as it relates to the drug. This information has been included in labelling, but there was no consistent placement for it until now.

(A) Prescribing during Pregnancy

For many years, the FDA had discussed the limitations of the old FDA-pregnancy category system (alphabetical) to classify the reproductive safety of medications, which uses five risk categories (A, B, C, D and X) based on data derived from human and animal studies. While such an old alphabetical system was the main resource used to make decisions regarding the use of medications during pregnancy, many health-related societies and organizations have criticized this old alphabetical system of classification, indicating that this type of drug labelling is often not helpful and, even worse, may be misleading.

Pregnancy and foetal summaries

The pregnancy summary is intended as a brief overview of the reported data reported in pregnancy, both from animal and human studies, whereas the foetal risk summary provides the specific details of the data. Both pregnancy and foetal summaries support the decision regarding risk:benefit ratio and the recommendations supporting the use of medicines during pregnancy.

The foetal risk summary is an analysis of the literature concerning the use of the drug in pregnancy. The intent is to provide healthcare professionals with sufficient data to counsel patients and to arrive at safe conclusions as to the risk:benefit ratio a particular medicine poses for the embryo, foetus, and newborn.

Pregnancy recommendations

The pregnancy recommendations are intended to assist the healthcare professional in determining the level of risk of a specific drug. Such recommendations may ONLY apply to the recommended (posology) therapeutic dose of the drug in a typical patient. In addition to the animal reproduction data and known human pregnancy outcomes, the assessment of risk includes, when relevant, other major factors such as route of medicine administration, pharmacokinetics of medicines, observed pharmacodynamic effect of similar drug class, and the embryo-foetal effects of untreated or undertreated maternal disease. Moreover, drug exposures represent different levels of risk depending on the stage of pregnancy and, thus, timing (in relation to gestational age) of the exposure to medicine is critical in determining risk.

Because short statements of risk assessment and recommendations may not always adequately assess the risk throughout the pregnancy, healthcare professionals are encouraged to review the entire special population and relevant drug monograph before estimating the risk for a specific patient.

Examples of some recommendations

• "Safe”: this drug can be used during pregnancy. Human pregnancy experience, either for the drug itself or drugs in the same class or with similar mechanisms of action is adequate to demonstrate that the embryo-foetal risk is very rare or nonexistent and animal reproduction
• “Caution” and/or “Not recommended”: the use of this drug during pregnancy should only be considered based on proper risk: benefit ratio assessment with close follow-up and monitoring protocol. Either there is no human pregnancy experience, low-evidence regarding risk: benefit, or the few pregnancy exposures have not been associated with developmental toxicity, however animal data and studies may have suggested low, moderate, or high risks for developmental foetal toxicity
• “Contraindicated”: this drug should not be used during the entire pregnancy. Human exposures at any time in pregnancy, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity - teratogenicity (growth restriction, structural anomalies, functional/behavioral deficits, or death), with animal reproduction data, if available, confirm the risk
• “Contraindicated in the first-trimester”: The drug should not be used in the 1st trimester. Human exposures in the 1st trimester, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity - teratogenicity (growth restriction, structural anomalies, functional/ behavioral deficits, or death)
• “Contraindicated in the second- and third-trimesters”: this drug should not be used in the 2nd and 3rd trimesters. Human exposures in the 2nd and 3rd trimesters, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity - teratogenicity (growth restriction, structural anomalies, functional/ behavior deficits, or death)

(B) Prescribing during Breastfeeding

Without a doubt, the health benefits of breastfeeding during the first year of life, post-partum, are important and well-established. Despite the increased amount of clinical data related to the use of medicines during breastfeeding, the vast majority of medical societies had recommended, by default, that the use of medicines during this stage should only be considered when clinically necessary.

Like with pregnancy, breastfeeding has been, historically, excluded from clinical trials due to different, mainly ethical, reasons, making clinical data and recommendations related to the use of medicines during breastfeeding both insufficient and challenging.

Breastfeeding summary

The breastfeeding summary is a brief review of the literature concerning the excretion of the drug into human breast milk and the effects, if any, on a nursing infant. Unfortunately, in many cases, there is insufficient published information about the use of the drug during this stage. Moreover, even when studies do exist, infants often were not allowed to breastfeed.

Healthcare professionals should pay close attention to this distinction (i.e., possible medicine excretion into milk vs. effect(s) of medicine on the nursing infant) when looking for answers.

Breastfeeding recommendations

The breastfeeding recommendations are intended to assist the healthcare professional in determining the level of risk of a specific drug. Such recommendations may ONLY apply to the recommended (posology) therapeutic dose of the drug in a typical patient. Such risks also change during breastfeeding because nearly all reported adverse effects in nursing infants have occurred in infants <6 months of age. The neonate and very young infants are most at risk for toxic effects from drugs present in breast milk. The recommendations for breastfeeding are based on, when known, the toxicity of the drug or similar drugs in adults or children, and the ‘estimated’ amount of drug excreted into breast milk. Although most drugs taken by the mother are probably present in milk, the plasma-to-milk drug concentrations are usually unknown.

Because short statements of risk assessment and recommendations may not always adequately assess the risk during breastfeeding, healthcare professionals are encouraged to review the entire special population and relevant drug monograph before estimating the risk for a specific patient.

Examples of some recommendations

• “Safe” or “Compatible”: this drug can be used during breastfeeding. Either the drug is not excreted in clinically significant amounts into human breast milk, or its use during lactation does not, or is not expected to, cause toxicity in a nursing infant.
• “Caution” and/or “Not recommended”: the use of this drug during breastfeeding should only be considered based on proper risk: benefit ratio assessment with close follow-up and monitoring protocol. Either there is no human data, or the human data are limited. The characteristics of the drug suggest that it could represent a clinically significant risk  (for different levels) to a nursing infant.
• “Contraindicated”: this drug should not be used during breastfeeding or hold breastfeeding. There may or may not be human experience, but the combined data suggest that the drug may cause severe (serious) toxicity in a nursing infant, or breastfeeding is contraindicated because of the maternal condition for which the drug is indicated. Women should either not breastfeed their infants if they are taking the drug or have the condition OR breastfeeding should be held until maternal therapy is completed and the drug has been eliminated.

Prescribing in Liver Disease

Patients with liver disease and impaired hepatic functions often require drug treatment, either for their liver disease and/or its complications, or for pre-existing comorbidities.

Patients with underlying liver disease are at higher risk for developing drug-induced liver injury, such risk can expose these patients to potential drug-drug interactions (DDIs), further deterioration in hepatic impairment and serious adverse effects.

The liver is the main site of drug metabolism. This is primarily a detoxification mechanism whereby the body converts pharmacologically active (lipid-soluble) drugs into less-/non-active (hydrophilic) metabolites, which can then be excreted by the kidneys. On occasions, the liver can also play an important major role in activating prodrugs (a pharmacologically inactive substance that is converted in the body through metabolism into a pharmacologically active drug), and converting those pro-drugs to their active form.

An example of prodrugs include: tamoxifen, clopidogrel, dabigatran etexilate, aripiprazole lauroxil and many others.

Hepatic drug metabolism

Hepatic drug metabolism can be thought of as occurring in three different phases:

• Phase I reaction: include oxidation, reduction and hydrolysis. The most common are oxidation reactions (adding oxygen, or removing hydrogen). Oxidation reactions include dealkylation, hydroxylation, deamination and desulphuration. Most occur via the superfamily of cytochrome P450 (CYP 450) enzymes located in the endoplasmic reticulum. Each CYP isoenzyme (e.g. 3A4, 2C9, 2D6) varies in terms of expression and substrate specificity
• Phase II reaction: involve conjugations, such as glucuronidation, acetylation, sulfation and methylation. Glucuronidation is quantitatively the most important(e.g.glucuronyl transferases, N-acetyl transferases and glutathione-S-transferases). Glucuronidation enzymes are located in both the endoplasmic reticulum and the cytosol
• Phase III: is represented by active drug transport processes across cellular membranes rather than enzyme-catalysed reactions; these include both efflux (e.g. P-glycoprotein - P-gp) and influx (e.g. organic anion transporters - OATs) transporters

As a general prescribing rule, drugs that undergo hepatic metabolism may require dosage adjustment in patients with liver impairment as compared to patients without liver impairment.

The effect of liver disease on drug metabolism depends on various factors, including

• The severity of the liver disease: because of the enormous reserve of the liver parenchyma, impaired hepatic elimination of drugs occurs only in severe disease
• The enzyme responsible for drug metabolism: in general, phase II metabolic enzymes are affected to a lesser extent than phase I enzymes; the effect on the different CYP isoforms also varies. CYP 3A4 metabolizes more than 50% of drugs and its reduction in cirrhotic livers is likely to have negative impacts on both safety and efficacy of medicines
• The type of liver disease: a cholestatic pattern is more likely to affect drug transporter proteins (phase III pathways), whereas phase I metabolism is relatively spared; by contrast, acute hepatic inflammation is more likely to down-regulate CYP 450 enzyme expression. A decrease in hepatic clearance may result in increased drug concentrations in serum and potential toxicity, particularly for drugs with a narrow therapeutic index. For prodrugs, reduced conversion to the active compound results in reduced efficacy of those drugs

Prescriber healthcare professionals should be aware of the way in which drug response can be affected in patients with liver disease or vice versa in order to ensure safe and effective pharmacotherapy. 

Biomarkers of drug-induced liver injury

• Alanine transaminase (ALT): Highly specific for hepatocyte damage. Plasma half‐life of approximately 36–48 hours
• Aspartate transaminase (AST): Released by hepatocytes after damage. Plasma half‐life of 12–24 hours. AST : ALT ratio >1 indicates more significant liver damage than ALT rise alone

Abnormal liver function tests (LFTs)

Patients often have abnormal liver function tests in the absence of hepatobiliary symptoms. Prevalence ranges from as low as 5% to as high as 21% according to a data from the U.K.

It has been suggested that an ALT >2 times the upper limit of normal (ULN) warrants further investigation as do patients with milder abnormalities but with significant risk factors for liver disease. This is a common clinical scenario in primary care.

Common causes of abnormal LFTs may include

• Steatosis/Steatohepatitis (e.g. alcohol- or weight-related)
• Viral hepatitis (e.g. hepatitis C)
• Drug‐induced liver injury (DILI)
• Chronic biliary disease (e.g. primary biliary cirrhosis)
• Autoimmune liver disease
• Iron overload/haemochromatosis
• Metabolic disease (e.g. Wilson’s disease)
• Multisystemic disease

Drug-induced liver injury (DILI)

An idiosyncratic drug‐induced liver injury (DILI) is an adverse drug reaction (ADR is defined as any response to a drug that is noxious, is unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease) that is unexpected on the basis of the pharmacological action of the drug administered.

DILI is more prevalent at the extremes of age, in those who are malnourished or who have pre-existing hepatic conditions. The manifestation of DILI is dependent on environmental triggers in those with genetic susceptibility.

Diagnosis of DILI depends on a high level of suspicion and systematic assessment. DILI may be symptomatic or asymptomatic and be detected by abnormal liver blood tests checked routinely or during drug monitoring. DILI can be defined as:

• ALT >5 times ULN; or
• ALP >2 times ULN; or
• ALT >3 times ULN + bilirubin >2 times ULN.

Assessment of suspected DILI

• Drug with an established history of DILI
• Indication for use of the drug
• Dates of treatment
• Initial biochemical abnormality and trends in liver biochemistry
• Associated systemic features and timing of onset – fever, rash, eosinophilia, cytopenia, arthralgia
• Exclusion of other potential causes

Re‐challenge may occasionally be used to aid diagnosis.
Re‐challenges should be performed with great caution in immune-mediated DILI. Liver biopsy is rarely required unless there is an atypical presentation or a need to assess the degree of chronic damage and prognosis (e.g. methotrexate).

Child-Pugh score

The Child-Pugh score is a system for assessing the prognosis of  — including the required strength of treatment and necessity of liver transplant — of chronic liver disease, primarily cirrhosis. It provides a forecast of the increasing severity of your liver disease and your expected survival rate.

The Child-Pugh score is determined by scoring five clinical measures of liver disease. A score of 1, 2, or 3 is given to each  of the following measures (with 3 being the most severe):

• total bilirubin
• serum albumin
• prothrombin time or INR
• Ascites; and
• hepatic encephalopathy

Interpreting the Child-Pugh score

• Class A (5-6 points) =  mild hepatic impairment/disease ~ with one- to five-year survival rate = 95%
• Class B (7-9 points) = moderate hepatic impairment/disease ~ with one- to five-year survival rate = 75%
• Class C (10-15 points) = severe hepatic impairment/disease ~ one- to five-year survival rate = 50%

Prescribing in Renal Disease

Prescribing to patients with underlying renal impairment is complicated, because renal disease has multiple effects on the pharmacokinetics and the pharmacodynamics of medicines, and these effects are dependent on both the drug and the patients profile. For example, renal disease may be chronic (slowly progressive over months or years) or acute (rapidly evolving), and each scenario requires a different approach to drug dosing.

Understanding how changes to physiology affect the pharmacokinetics and dynamics of a given drug is essential to rational drug use and the optimization of treatment regimens.

Failure to rationally account for the effect of renal disease when selecting appropriate therapy can predispose a patient to treatment failure and/or risk of adverse drug events.

Guidelines for renal dose adjustment in varying stages of renal impairments are not easy to find even by the manufacturer’s drug package insert (PI) and summary of product characteristics (SmPC). Furthermore, dose recommendations in the setting of renal disease are frequently on the basis of limited data, and they may not adequately account for interindividual variability or pathophysiological changes.

Therefore, it is necessary to have a rational approach to prescribing in patients with renal disease. This requires better understanding and good pharmacology knowledge about medicines’ pharmacokinetic and pharmacodynamics principles, drug profile, and patient profile.

Healthcare prescribers need to understand that, either subtherapeutic (risk for therapy failure) or supratherapeutic (risk for toxicity) drug plasma levels related to dosing can occur when appropriate dose adjustments are not considered in patients with underlying renal disease, and both will have negative effects on patient outcomes, including morbidity, prolonged hospitalisation, and potentially, death. Subtherapeutic dosing increases the risk of treatment failure, which may be life threatening (e.g., anti-infectives for pneumonia) or organ-threatening (e.g., immunosuppressants for organ transplantation). The risk of supratherapeutic exposure from drugs (or their active or toxic metabolites) that rely on renal elimination is amplified when the drug has a common nephrotoxic profile, such as aminoglycosides, or a narrow therapeutic index, such as digoxin or lithium. In many cases, accumulation develops over days or weeks, and the onset of drug toxicity is insidious.

The more significant percentage of individuals affected by these agents are the elderly.

Nephrotoxic medications

Nephrotoxic medications can elicit damage to the renal system through different pathophysiological mechanisms, including alteration in its structure and function. There are numerous drugs that go under the category of nephrotoxic medications. Below are some examples:

• Aciclovir
• Aminoglycosides (e.g. amikacin, kanamycin, gentamicin)
• Amphotericin B
• ACE-inhibitors (e.g. enalapril, perindopril, captopril)
• ARBs (e.g. valsartan, losartan)
• Aspirin (salicylic acid derivatives)
• Beta-lactam antimicrobials (e.g. co-amoxiclav)
• Ciclosporin
• Cisplatin
• Lithium
• Metformin
• NSAIDs (e.g aspirin, ibuprofen, naproxen)
• Tenofovir

Nephrotoxic drugs may elicit damage to renal tissue via numerous mechanisms. A few of these mechanisms include impairment of perfusion, inflammation induction, free radicals formation, and many other mechanisms.

• Glomerular Filtration Rate (GFR) Alteration: Examples include the effect of ACE inhibitors, ARBs, ciclosporin, and NSAIDs that affect the intraglomerular haemodynamics via the alteration of the glomerular filtration rate
• Tubular Cell Toxicity: The presence of certain pharmaceutical agents may damage the cells of the proximal tubules via free radical formation, mitochondrial damage, and transport systems damage. Examples include aminoglycosides, amphotericin B, and cisplatin.
• Interstitial Nephritis: NSAIDs and rifampin are common causes of acute interstitial tissue inflammation. Chronic forms result from agents, including analgesics, anticancer drugs, lithium, and calcineurin inhibitors (like tacrolimus).
• Crystal Nephropathy: Antivirals such as aciclovir and antibiotics such as ampicillin have been common etiologies of insoluble crystal formation within renal tissue.

The Cockcroft-Gault formula is the preferred method for estimating renal function when calculating drug doses in patients with renal impairment who are elderly or at extremes of muscle mass.

The Cockcroft-Gault equation (according to the South African Renal Society) is

eCrCl (mL/min) = [140 – age] x Body Weight (kg) x 0.85 (if female) ÷serum Cr (µmol/L) 

The five stages of renal impairment

The five stages of renal impairment and the GFR for each stage, is shown below:

• Stage 1 =  normal or high GFR (GFR > 90 mL/min)
• Stage 2 = mild impairment (GFR = 60-89 mL/min)
• Stage 3 = moderate impairment  (GFR = 30-59 mL/min
• Stage 4 = severe impairment (GFR = 15-29 mL/min)
• Stage 5 = end Stage/established impairment (GFR <15 mL/min)