Dispensing 2 (Medication-related problems, Medication Safety, Medication counselling and other pharmacy services

MEDICATION-RELATED PROBLEMS/ DRUG-RELATED PROBLEMS

Drug-Related Problems Pharmacotherapy can effectively improve quality of life, cure, and prevent or alleviate
symptoms in many conditions in late life. Drugs are however powerful and must be handled appropriately. This is
especially important for elderly patients. Adverse effects and other drug-related problems (DRPs) are common in
elderly patients (Hanlon et al. 2003). Drug-related problem has been defined as “an event or circumstance involving
drug treatment that actually or potentially interferes with a patient’s experiencing an optimum outcome of medical
care” (Hepler and Strand 1990). With this definition DRP include e.g. drug use without an indication, drug
interactions, subtherapeutic dosage, overdosage, noncompliance, drug interactions and adverse drug reactions
(ADRs). Therapeutic failure may be due to underuse of medications. Reasons for this could be lack of patient
adherence but also suboptimal prescribing. All medications have risk of adverse effects with varying clinical
consequences and severity. These adverse effects can result from medications taken individually or can result from
pharmacokinetic and pharmacodynamic interactions of medications used in combination. Elderly patients are more
susceptible to ADR than younger patients. This is due to the fact that elderly use many drugs but also due to
physiological changes with increasing age that affects the pharmacokinetics and pharmacodynamics. However, in the
absence of disease, the decline in physiological functions most often causes no symptoms. The potential risk of drug-
drug interactions is increased with the number of drugs used and age. Since the interactions are more common in frail
patients, the consequences are likely to be worse than in younger individuals. If the prescriber is aware of potential
interactions these can many times be avoided by choosing other drugs. If this is not possible, drug dosages have to be
adjusted and pharmacotherapy more cautiously evaluated. Adverse drug reactions are common preventable causes
of emergency medical admissions in the elderly (Chan et al. 2001). It is not only ADRs that might cause problems in
the elderly but also withdrawal events. Adverse drug withdrawal events are related to the removal of a drug.
Hospitalisation accounts for a great part of total cost of care. Studies have shown that 15–22% of the hospitalised
elderly patients are admitted because of DRP (Bero et al. 1991, Roughead et al. 1998, Cooper 1999). Also it is reported
that the majority of adverse drug reactions in the elderly can be prevented (Beijer and de Blaey 2002). It has further
been shown that the majority of hospitalised patients have DRPs (Blix et al. 2004). Use of unnecessary drugs is quite
frequent among elderly and one quarter of these unnecessary drugs are started during hospitalisation (Hajjar et al.
2005). Drug-related problems may increase the need for hospital care and also have impact on mortality. Adverse
drug effects are between the fourth and sixth leading causes of death in USA (Lazarou et al. 1998). There is also a
financial aspect on drug-related problems. For every dollar spent on drugs in US nursing homes facilities, 1.33 dollars
in health care resources are consumed in the treatment of drug-related problems (Bootman et al. 1997).

MEDICATION-RELATED PROBLEMS
When the outcome of medicines use is not optimal, the underlying medication-related problem (MRP) can be
classified according to the criteria set out in Box 1.1 (Hepler and Strand, 1990). Some MRPs are associated with
significant morbidity and mortality. Preventable medication-related hospital admissions in the UK and USA have
been estimated to have a prevalence rate of 4% to 5%, indicating that gains in public health from improving
prescribing, monitoring and adherence to medicines would be sizeable (Howard et al., 2003; Winterstein et al., 2002).
In prospective studies, up to 28% of accident and emergency department visits have been identified as medication
related, of which 70% were deemed preventable (Zed, 2005). Again the most frequently cited causes were non-
adherence and inappropriate prescribing and monitoring.

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In England adverse drug reactions (ADRs) have been identiied as the cause of 6.5% of hospital admissions for
patients older than 16 years. The median bedstay for patients admitted with an ADR was 8 days, representing 4% of
bed capacity.
The projected annual cost to the National Health. Service
(NHS) was £466 million, the equivalent of seven 800- bed
hospitals occupied by patients admitted with an ADR.
More than 70% of the ADRs were determined to have been
avoidable (Pirmohamed et al., 2004). Between 2005 and
2010 more than half a million medication incidents were
reported to the National Patient Safety Agency, and 16% of
these reports involved actual patient harm (Cousins et al.,
2012). In 2004 the direct cost of medication errors in NHS hospitals, defined as preventable events that may cause or
lead to inappropriate medicines use or harm, was estimated to lie between £200 and £400 million per year. To this
should be added the costs arising from litigation (Department of Health, 2004). In care homes, one study found that
more than two-thirds of residents were exposed to one or more medication errors (Barber et al., 2009), whilst in
hospitals a prescribing error rate of almost 9% has been identified (Doran et al., 2010). In addition, nearly a third of
patients are non-adherent 10 days after starting a new medicine for a chronic condition, of whom 45% are intentionally
non-adherent (Barber et al., 2004), a significant contributor to the £150 million per annum estimated avoidable
medicines waste in primary care (York Health Economics Consortium and School of Pharmacy, 2010). The scale of
the misadventure that these findings reveal, coupled with increasing concerns about the costs of drug therapy, creates
an opportunity for a renaissance in clinical pharmacy practice, providing that it realigns strongly with the principles
of medicines optimization. Pharmacists and their teams are uniquely placed to help reduce the level of medication-
related morbidity in primary care by virtue of their skills and accessibility, and by building on relationships with
general practice.

DRUG INTERACTIONS
KEY POINTS
 Drug interactions can cause significant patient harm and are an important cause of morbidity.
 Most clinically important drug interactions occur as a result of either decreased drug activity with diminished
efficacy or increased drug activity with exaggerated or unusual effects.
 Drugs with a narrow therapeutic range, such as theophylline, lithium and digoxin, or a steep dose–response
curve, such as anticoagulants, oral contraceptives and anti-epileptics, are often implicated.
 The most important pharmacokinetic interactions involve drugs that can induce or inhibit enzymes in the
hepatic cytochrome P450 system.
 Pharmacodynamic interactions are difficult to classify, but their effects can often be predicted when the
pharmacology of co-administered drugs is known.
 In many cases potentially interacting drugs can be given concurrently, provided the possibility of interaction
is kept in mind and any necessary changes to dose or therapy are initiated promptly. In some situations,
however, concurrent use of potentially interacting drugs should be avoided altogether.
 Suspected adverse drug interactions should be reported to the appropriate regulatory authority as for other
adverse drug reactions.
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An interaction is said to occur when the effects of one drug are altered by the co-administration of another drug,
herbal medicine, food, drink or other environmental chemical agents (Preston, 2016). The net effect of the combination
may manifest as an additive or enhanced effect of one or more drugs, antagonism of the effect of one or more drugs,
or any other alteration in the effect of one or more drugs.
Clinically significant interactions refer to a combination of therapeutic agents which have direct consequences on
the patient’s condition. Therapeutic benefit can be obtained from certain drug interactions; for example, a combination
of different antihypertensive drugs may be used to improve blood pressure control, or an opioid antagonist may be
used to reverse the effect of an overdose of morphine. This chapter concentrates on clinically significant interactions
which have the potential for undesirable effects on patient care.

EPIDEMIOLOGY
Accurate estimates of the incidence of drug interactions are difficult to obtain because published studies
frequently use different criteria for defining a drug interaction and for distinguishing between clinically significant
and non-significant interactions.
The reported incidence of drug–drug interactions in hospital admissions ranged from 0% to 2.8% in a review
which included nine studies, all of which had some design laws (Jankel and Fitterman, 1993). In the Harvard Medical
Practice Study of adverse events, 20% of events in acute hospital inpatients were drug related. Of these, 8% were
considered to be due to a drug interaction, suggesting that interactions are responsible for less than 2% of adverse
events in this patient group (Leape et al., 1992).
In a 1-year prospective study of patients attending an emergency department, 3.8% resulted from a drug–
drug interaction, and most of these led to hospital admissions (Raschett et al., 1999). In a prospective UK study carried
out on hospital inpatients ADRs were responsible for hospital admission in 6.5% of cases. Drug interactions were
involved in 16.6% of adverse reactions, therefore being directly responsible for leading to hospital admission in
approximately 1% of cases (Pirmohamed et al., 2004). Few studies have attempted to quantify the incidence of drug–
drug interactions in the outpatient hospital setting and in the community. In the early 1990s, a Swedish study
investigated the occurrence of potential drug interactions in primary care and reported an incidence rate of 1.9%
(Linnarsson, 1993). In the outpatient setting, the availability of newer drugs for a variety of chronic conditions has
increased the risk of drug–drug interactions in this patient group. Although the overall incidence of serious adverse
drug interactions is low, it remains a potentially preventable cause of morbidity
and mortality.

SUSCEPTIBLE PATIENTS
The risk of drug interactions increases with the number of drugs used. In a hospital study, the rate of ADRs
in patients taking 6–10 drugs was 7%, rising to 40% in those taking 16–20 drugs, with the exponential rise being largely
attributable to drug interactions (Smith et al., 1969). In a high-risk group of emergency department patients, the risk
of potential adverse drug interaction was 13% in patients taking two drugs and 82% in those taking seven or more
drugs (Goldberg et al., 1996). Although polypharmacy is common and often unavoidable, it places certain patient
groups at increased risk of drug interactions. Patients at particular risk include those with hepatic or renal disease,
those on long-term therapy for chronic disease (e.g. HIV infection, epilepsy, diabetes), patients in intensive care,
transplant recipients, patients undergoing complicated surgical procedures and those with more than one prescriber.
Critically ill and elderly patients are at increased risk not only because they take more medicines but also because of
impaired homeostatic mechanisms that might otherwise counteract some of the unwanted effects.
Interactions may occur in some individuals, but not in others. The effects of interactions involving drug
metabolism may vary greatly in individual patients because of differences in the rates of drug metabolism and in

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susceptibility to microsomal enzyme induction. Certain drugs are frequently implicated in drug interactions and
require careful attention (Box 4.1).

MECHANISMS OF DRUG INTERACTIONS

Drug interactions are conventionally discussed according to the mechanisms involved. These mechanisms
can be conveniently divided into those with a pharmacokinetic basis and those with a pharmacodynamic basis. Drug
interactions often involve more than one mechanism. There are some situations where drugs interact by unique
mechanisms, but the most common mechanisms
are discussed in this section.

I. PHARMACOKINETIC INTERACTIONS
Pharmacokinetic interactions are those that affect the processes by which drugs are absorbed, distributed,
metabolized or excreted. Due to marked inter-individual variability in these processes, these interactions may be
expected, but their extent cannot be easily predicted. Such interactions may result in a change in the drug
concentration at the site of action with subsequent toxicity or decreased efficacy.

1. Absorption
Following oral administration, drugs are absorbed through the mucous membranes of the gastro-intestinal
tract. A number of factors can affect the rate of absorption or the extent of absorption (i.e. the total amount of drug
absorbed).

1.1 Changes in gastro-intestinal pH.

The absorption of a drug across mucous membranes depends on the extent to which it exists in the
non- ionized, lipid-soluble form. The ionization state depends on the pH of its environment, the acid
dissociation constant (pKa) of the drug and formulation factors. Weakly acidic drugs, such as the
salicylates, are better absorbed at low pH because the non-ionized form predominates. An alteration in
gastric pH due to antacids, histamine H2 antagonists or proton pump inhibitors therefore has the
potential to affect the absorption of other drugs. The clinical significance of antacid-induced changes in
gastric pH is not certain, particularly because relatively little drug absorption occurs in the stomach.
Changes in gastric pH tend to affect the rate of absorption rather than the extent of absorption, provided
that the drug is acid labile.
Although antacids could theoretically be expected to markedly influence the absorption of other drugs via
this mechanism, in practice there are very few clinically significant examples. Antacids, histamine H2
antagonists and proton pump inhibitors can significantly decrease the bioavailability of ketoconazole and
itraconazole, which require gastric acidity for optimal absorption, but the absorption of fluconazole and
voriconazole is not significantly altered by changes in gastric pH. The alkalinizing effects of antacids on the
gastro-intestinal tract are transient, and the potential for interaction may be minimized by leaving an interval
of 2–3 hours between the antacid and the potentially interacting drug.

1.2 Adsorption, chelation and other complexing mechanisms.

Certain drugs react directly within the gastro-intestinal tract to form chelates and complexes which are not
absorbed. The drugs most commonly implicated in this type of interaction include tetracyclines and the
quinolone antibiotics that can complex with iron, and antacids containing calcium, magnesium and
aluminum. Tetracyclines can chelate with divalent or trivalent metal cations such as calcium, aluminum,
bismuth and iron to form insoluble complexes, resulting in greatly reduced plasma tetracycline
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concentrations. Bisphosphonates are often co-prescribed with calcium supplements in the treatment of
osteoporosis. If these are taken concomitantly, however, the bioavailability of both is significantly reduced,
with the possibility of therapeutic failure. The absorption of some drugs may be reduced if they are given
with adsorbents such as charcoal or kaolin, or anionic exchange resins such as cholestyramine or colestipol.
The absorption of paracetamol, digoxin, warfarin, calcitriol, thiazide diuretics, raloxifene and levothyroxine
is reduced by cholestyramine. Most chelation and adsorption interactions can be avoided if an interval of 2–3
hours is allowed between doses of the interacting drugs. For cholestyramine the advice is for the patient to
take other drugs at least 1 hour before or 4–6 hours after cholestyramine to reduce possible issues with their
absorption (Joint Formulary Commission, 2017).

1.3 Effects on gastro-intestinal motility.

Because most drugs are largely absorbed in the upper part of the small intestine, drugs that alter the
rate at which the stomach empties its contents can affect absorption. Drugs with anticholinergic effects, such
as tricyclic antidepressants, phenothiazines and some antihistamines, decrease gut motility and delay gastric
emptying. The outcome of the reduced gut motility can be either an increase or a decrease in drugs given
concomitantly. For example, tricyclic antidepressants can increase dicoumarol absorption, probably as a result
of increasing the time available for its dissolution and absorption. Anticholinergic agents used in the
management of movement disorders have been shown to reduce the bioavailability of levodopa by as much
as 50%, possibly as a result of increased metabolism in the intestinal mucosa. Opioids such as diamorphine
and pethidine strongly inhibit gastric emptying and greatly reduce the absorption rate of paracetamol,
without affecting the extent of absorption. Codeine, however, has no significant effect on paracetamol
absorption. Metoclopramide increases gastric emptying and increases the absorption rate of paracetamol, an
effect which is used to therapeutic advantage in the treatment of migraine to ensure rapid analgesic effect.
Although metoclopramide also accelerates the absorption of propranolol, meloquine, lithium and ciclosporin,
this interaction is rarely clinically significant.

1.4 Induction or inhibition of drug transport proteins.

The oral bioavailability of some drugs is limited by the action of drug transporter proteins, which eject
drugs that have diffused across the gut lining back into the gut. At present, the most well-characterized drug
transporter is P-glycoprotein. Digoxin is a substrate of P-glycoprotein, and drugs that inhibit P-glycoprotein,
such as verapamil, may increase digoxin bioavailability with the potential for digoxin toxicity (DuBuske,
2005).

1.5 Malabsorption.
Drugs such as neomycin may cause a malabsorption syndrome leading to reduced absorption of drugs
such as digoxin. Orlistat is a speciic long-acting inhibitor of gastric and pancreatic lipases, thereby preventing
the hydrolysis of dietary fat to free fatty acids and triglycerides. This can theoretically lead to reduced
absorption of fat-soluble drugs co- administered with orlistat. As a result, the Medicines and Healthcare
Products Regulatory Agency (MHRA, 2010) has advised of a possible impact on efficacy of co-administration
of orlistat with levothyroxine, antiepileptic drugs such as valproate sodium and lamotrigine, and
antiretroviral HIV drugs such as efavirenz and lopinavir. Most of the interactions that occur within the gut
result in reduced rather than increased absorption. It is important to recognize that the majority result in
changes in absorption rate, although in some instances the total amount (i.e. extent of drug absorbed) is
affected. For drugs that are given chronically on a multiple-dose regimen, the rate of absorption is usually
unimportant provided the total amount of drug absorbed is not markedly altered. In contrast, delayed
absorption can be clinically significant where the drug affected has a short half-life or where it is important to
achieve high plasma concentrations rapidly, as may be the case with analgesics or hypnotics. Absorption
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interactions can often be avoided by allowing an interval of 2–3 hours between administrations of the
interacting drugs.

2. Drug distribution
Following absorption, a drug undergoes distribution to various tissues, including to its site of action. Many
drugs and their metabolites are highly bound to plasma proteins. Albumin is the main plasma protein to which acidic
drugs such as warfarin are bound, whereas basic drugs such as tricyclic antidepressants, lidocaine, disopyramide and
propranolol are generally bound to α1-acid glycoprotein. During the process of distribution, drug interactions may
occur, principally as a result of displacement from protein-binding sites. A drug displacement interaction is defined
as a reduction in the extent of plasma protein binding of one drug caused by the presence of another drug, resulting
in an increased free or unbound fraction of the displaced drug. Displacement from plasma proteins can be
demonstrated in vitro for many drugs and has been thought to be an important mechanism underlying many
interactions in the past. However, clinical pharmacokinetic studies suggest that, for most drugs, once displacement
from plasma proteins occurs, the concentration of free drug rises temporarily, but falls rapidly back to its previous
steady-state concentration due to metabolism and distribution. The time this takes will depend on the half-life of the
displaced drug. The short-term rise in the free drug concentration is generally of little clinical significance but may
need to be taken into account in therapeutic drug monitoring. For example, if a patient who is taking phenytoin is
given a drug which displaces phenytoin from its binding sites, the total (i.e. free plus bound) plasma phenytoin
concentration will fall even though the free (active) concentration remains the same. There are few examples of
clinically important interactions which are entirely due to protein-binding displacement. It has been postulated that
a sustained change in steady-state free plasma concentration could arise with the parenteral administration of some
drugs which are extensively bound to plasma proteins and non-restrictively cleared; that is, the efficiency of the
eliminating organ is high. Lidocaine has been given as an example of a drug hitting these criteria.

3. Drug metabolism
Most clinically important interactions involve the effect of one drug on the metabolism of another. Metabolism
refers to the process by which drugs and other compounds are biochemically modified to facilitate their degradation
and subsequent removal from the body. The liver is the principal site of drug metabolism, although other organs such
as the gut, kidneys, lung, skin and placenta are involved. Drug metabolism consists of phase I reactions such as
oxidation, hydrolysis and reduction, and phase II reactions, which primarily involve conjugation of the drug with
substances such as glucuronic acid and sulphuric acid. Phase I metabolism generally involves the CYP450 mixed
function oxidase system. The liver is the major site of cytochrome 450- mediated metabolism, but the enterocytes in
the small intestinal epithelium are also potentially important.

CYP450 isoenzymes. The CYP450 system comprises 57 isoenzymes, each derived from the expression of an
individual gene. Because there are many different isoforms of these enzymes, a classification for nomenclature
has been developed, comprising a family number, a subfamily letter, and a number for an individual enzyme
within the subfamily (Wilkinson, 2005). Four main subfamilies of P450 isoenzymes are thought to be
responsible for most (about 90%) of the metabolism of commonly used drugs in humans: CYP1, CYP2, CYP3
and CYP4. The most extensively studied isoenzyme is CYP2D6, also known as debrisoquine hydroxylase.
Although there is overlap, each cytochrome 450 isoenzyme tends to metabolize a discrete range of substrates.
Of the many isoenzymes, a few (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) appear to be
responsible for the human metabolism of most commonly used drugs. The genes that encode specific
cytochrome 450 isoenzymes can vary between individuals and, sometimes, ethnic groups. These variations
(polymorphisms) may affect metabolism of substrate drugs. Inter-individual variability in CYP2D6 activity is
well recognized. It shows a polymodal distribution, and people may be described according to their ability to
metabolize debrisoquine. Poor metabolizers tend to have reduced irst-pass metabolism, increased plasma
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levels and exaggerated pharmacological response to this drug, resulting in postural hypotension. By contrast,
ultra-rapid metabolizers may require considerably higher doses for a standard effect. About 5–10% of
Caucasians and up to 2% of Asian and black people are poor metabolizers. The CYP3A family of P450 enzymes
comprises two isoenzymes, CYP3A4 and CYP3A5, so similar that they cannot be easily distinguished. CYP3A
is probably the most important of all drug-metabolizing enzymes because it is abundant in both the intestinal
epithelium and the liver, and it has the ability to metabolize a multitude of chemically unrelated drugs from
almost every drug class. It is likely that CYP3A is involved in the metabolism of more than half the therapeutic
agents that undergo alteration by oxidation. In contrast with other cytochrome 450 enzymes, CYP3A shows
continuous unimodal distribution, suggesting that genetic factors play a minor role in its regulation.
Nevertheless, the activity of the enzyme can vary markedly among members of a given population. The effect
of a cytochrome 450 isoenzyme on a particular substrate can be altered by interaction with other drugs. Drugs
may be themselves substrates for a cytochrome 450 isoenzyme and/or may inhibit or induce the isoenzyme.
In most instances, oxidation of a particular drug is brought about by several CYP isoenzymes and results in
the production of several metabolites. So, inhibition or induction of a single isoenzyme would have little effect
on plasma levels of the drug. However, if a drug is metabolized primarily by a single cytochrome 450
isoenzyme, inhibition or induction of this enzyme would have a major effect on the plasma concentrations of
the drug. For example, if erythromycin (an inhibitor of CYP3A4) is taken by a patient being given
carbamazepine, which is extensively metabolized by CYP3A4, this may lead to toxicity caused by higher
concentrations of carbamazepine. Table 4.1 gives examples of some drug substrates, inducers and inhibitors
of the major cytochrome 450 isoenzymes.

Enzyme induction. The most powerful enzyme inducers in

clinical use are the antibiotic rifampicin and antiepileptic agents such as barbiturates, phenytoin and
carbamazepine. Some enzyme inducers, notably barbiturates and carbamazepine, can induce their own
metabolism (auto-induction). Cigarette smoking, chronic alcohol use and the herbal preparation St John’s
wort can also induce drug-metabolizing enzymes. Because the process of enzyme induction requires new
protein synthesis, the effect usually develops over several days or weeks after starting an enzyme-inducing
agent. Similarly, the effect generally persists for a similar period following drug withdrawal. Enzyme-
inducing drugs with short half-lives such as rifampicin will induce metabolism more rapidly than inducers
with longer half-lives (e.g. phenytoin) because they reach steady-state concentrations more rapidly. There is
evidence that the enzyme induction process is dose dependent, although some drugs may induce enzymes at
any dose. Enzyme induction usually results in a decreased pharmacological effect of the affected drug. St
John’s wort is now known to be a potent inducer of CYP3A (Mannel, 2004). Thus, when a patient receiving
ciclosporin, tacrolimus, HIV-protease inhibitors, irinotecan or imatinib takes St John’s wort, there is a risk of
therapeutic failure with the affected drug. However, if the affected drug has active metabolites, this may lead
to an increased pharmacological effect. The effects of enzyme induction vary considerably between patients
and are dependent upon age, genetic factors, concurrent drug treatment and disease state. Some examples of
interactions due to enzyme induction are shown in Table 4.2.

Enzyme inhibition. Enzyme inhibition is responsible for many clinically significant interactions. Many drugs
act as inhibitors of cytochrome 450 enzymes (Box 4.2). A strong inhibitor is one that can cause ≥5-fold increase
in the plasma area under the curve (AUC) value or more than 80% decrease in clearance of CYP3A substrates.
A moderate inhibitor is one that can cause ≥2- but <5-fold increase in the AUC value or 50–80% decrease in
clearance of sensitive CYP3A substrates when the inhibitor is given at the highest approved dose and the
shortest dosing interval. A weak inhibitor is one that can cause ≥1.25- but <2-fold increase in the AUC values
or 20–50% decrease in clearance of sensitive CYP3A substrates when the inhibitor is given at the highest
approved dose and the shortest dosing interval. Concurrent administration of an enzyme inhibitor leads to
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reduced metabolism of the drug and hence an increase in the steady-state drug concentration. Enzyme
inhibition appears to be dose related. Inhibition of hepatic metabolism of the affected drug occurs when
sufficient concentrations of the inhibitor are achieved in the liver, and the effects are usually maximal when
the new steady-state plasma concentration is achieved. Thus, for drugs with a short half-life, the effects may
be seen within a few days of administration of the inhibitor. Maximal effects may be delayed for drugs with
a long half-life. The clinical significance of this type of interaction depends on various factors, including
dosage (of both drugs), alterations in pharmacokinetic properties of the affected drug, such as half-life, and
patient characteristics such as disease state. Interactions of this type are again most likely to affect drugs with
a narrow therapeutic range such as theophylline, ciclosporin, oral anticoagulants and phenytoin. For example,
starting treatment with an enzyme inhibitor such as amiodarone in a patient who is taking warfarin could
result in a marked increase in warfarin plasma concentrations and increased bleeding risk. Some examples of
interactions due to enzyme inhibition are shown in Table 4.3. The isoenzyme CYP3A4 in particular is present
in the enterocytes. Thus, after oral administration of a drug, cytochrome 450 enzymes in the intestine and the
liver may reduce the portion of a dose that reaches the systemic circulation, that is, the bioavailability of the
drug. Drug interactions resulting in inhibition or induction of enzymes in the intestinal epithelium can have
significant consequences. For example, by selectively inhibiting CYP3A4 in the enterocyte, grapefruit juice
can markedly increase the bioavailability of some oral CCBs, including felodipine (Wilkinson, 2005). Such an
interaction is usually considered to be a drug metabolism interaction, even though the mechanism involves
an alteration in drug absorption. A single glass of grapefruit juice can cause CYP3A inhibition for 24–48 hours,
and regular consumption may continuously inhibit enzyme activity. Consumption of grapefruit juice is
therefore not recommended in patients who are receiving drugs that are extensively metabolized by CYP3A,
such as simvastatin, tacrolimus and vardenafil. Enzyme inhibition usually results in an increased
pharmacological effect of the affected drug, but in cases where the affected drug is a pro-drug which requires
enzymatic metabolism to active metabolites, a reduced pharmacological effect may result. For example,
clopidogrel is metabolised via CYP2C19 to an active metabolite which is responsible for its antiplatelet effect.
Proton pump inhibitors such as omeprazole are inhibitors of CYP2C19 and may lead to reduced effectiveness
of clopidogrel when used in combination.

Predicting interactions involving metabolism.

drug interactions is not easy for many reasons. First, individual drugs within a therapeutic class may have
different effects on an isoenzyme. For example, the quinolone antibiotics ciprofloxacin and norfloxacin inhibit
CYP1A2 and have been reported to increase plasma theophylline levels, whereas moxiloxacin is a much weaker
inhibitor and appears not to interact in this way. While atorvastatin and simvastatin are metabolised predominantly
by the CYP3A4 enzyme, luvastatin is metabolised by CYP2C9 and pravastatin is not metabolised by the CYP450
system to any signiicant extent. Identification of CYP450 isoenzymes involved in drug metabolism using in vitro
techniques is now an important step in the drug development process. However, findings of in vitro studies are not
always replicated in vivo, and more detailed drug interaction studies may be required to allow early identification of
potential interactions. Nevertheless, some interactions affect only a small proportion of individuals and may not be
identified unless large numbers of volunteers or patients are studied. Suspected drug interactions are often described
initially in published case reports and are then subsequently evaluated in formal studies. For example, published case
reports indicated that commonly used antibiotics such as amoxicillin may reduce the effect of oral contraceptives,
although this interaction has not been demonstrated in formal studies, leading to a change in the
advice provided to patients who take the oral contraceptive pill and non-enzyme-inducing antibiotics. Another factor
complicating the understanding of metabolic drug interactions is the finding that there is a large overlap between the
inhibitors/inducers and substrates of the drug transporter protein P-glycoprotein and those of CYP3A4. Therefore,
both mechanisms may be involved in many of the drug interactions previously thought to be due to effects on
CYP3A4.
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4. Elimination interactions
Most drugs are excreted in either the bile or urine. Blood entering the kidneys is delivered to the glomeruli of
the tubules where molecules small enough to pass across the pores of the glomerular membrane are filtered through
into the lumen of the tubules. Larger molecules, such as plasma proteins and blood cells, are retained. The blood then
lows to other parts of the kidney tubules where drugs and their metabolites are removed, secreted or reabsorbed into
the tubular filtrate by active and passive transport systems. Interactions can occur when drugs interfere with kidney
tubule luid pH, active transport systems or blood flow to the kidney, thereby altering the excretion of other drugs.

4.1 Changes in urinary pH.

As with drug absorption in the gut, passive reabsorption of drugs depends on the extent to which the
drug exists in the non-ionized lipid-soluble form. Only the non-ionized form is lipid soluble and able to diffuse
back through the tubular cell membrane. Thus, at alkaline pH, weakly acidic drugs (pKa 3.0–7.5) largely exist
as ionized lipid-insoluble molecules which are unable to diffuse into the tubule cells and will therefore be lost
in the urine. The renal clearance of these drugs is increased if the urine is made more alkaline. Conversely,
the clearance of weak bases (pKa 7.5–10) is higher in acid urine. Strong acids and bases are virtually completely
ionized over the physiological range of urinary pH, and their clearance is unaffected by pH changes. This
mechanism of interaction is of very minor clinical significance because most weak acids and bases are
inactivated by hepatic metabolism rather than renal excretion. Furthermore, drugs that produce large changes
in urine pH are rarely used clinically. Urine alkalization or acidification has been used as a means of increasing
drug elimination in poisoning with salicylates and amphetamines, respectively.

4.2 Changes in active renal tubule excretion.

Drugs that use the same active transport system in the kidney tubules can compete with one another
for excretion. Such competition between drugs can be used to therapeutic advantage. For example, probenecid
may be given to increase the plasma concentration of penicillins by delaying renal excretion. With the
increasing understanding of drug transporter proteins in the kidneys, it is now known that probenecid
inhibits the renal secretion of many other anionic drugs via organic anion transporters (Lee and Kim, 2004).
Increased methotrexate toxicity, sometimes life-threatening, has been seen in some patients concurrently
treated with salicylates and some other non-steroidal anti-inflammatory drugs (NSAIDs). The development
of toxicity is more likely in patients treated with high-dose methotrexate and those with impaired renal
function. The mechanism of this interaction may be multifactorial, but competitive inhibition of
methotrexate’s renal tubular secretion is likely to be involved. If patients who are taking methotrexate are
given salicylates or NSAIDs concomitantly, the dose of methotrexate should be closely monitored.

4.3 Changes in renal blood low.

Blood flow through the kidney is partially controlled by the production of renal vasodilatory
prostaglandins. If the synthesis of these prostaglandins is inhibited by drugs such as indomethacin, the renal
excretion of lithium is reduced with a subsequent rise in plasma levels. The mechanism underlying this
interaction is not entirely clear, because plasma lithium levels are unaffected by other potent prostaglandin
synthetase inhibitors, for example, aspirin. If an NSAID is prescribed for a patient who is taking lithium, then
the plasma levels should be closely monitored.

4.4 Biliary excretion and the enterohepatic shunt.

A number of drugs are excreted in the bile, either unchanged or conjugated, for example, as the
glucuronide, to make them more water soluble. Some of the conjugates are metabolized to the parent
compound by the gut lora and are then reabsorbed. This recycling process prolongs the stay of the drug within
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the body, but if the gut flora are diminished by the presence of an antibacterial, the drug is not recycled and
is lost more quickly. This mechanism has been postulated as the basis of an interaction between broad-
spectrum antibiotics and oral contraceptives. Antibiotics may reduce the enterohepatic circulation of
ethinylestradiol conjugates, leading to reduced circulating estrogen levels with the potential for therapeutic
failure. There is considerable debate about the nature of this interaction because the evidence from
pharmacokinetic studies is not convincing. Until a few years ago, due to the potential adverse consequences
of pill failure, most authorities recommended a conservative approach, including the use of additional
contraceptive precautions. This advice has now been changed to recommend that additional contraceptive
precautions are not required for short term use of antibiotics which do not induce liver enzymes (Joint
Formulary Commission, 2017).

4.5 Drug transporter proteins.

Drugs and endogenous substances are now known to cross biological membranes not just by passive
diffusion but by carrier-mediated processes, often known as transporters. Significant advances in the
identification of various transporters have been made and although their contribution to drug interactions is
not yet clear, they are now thought to play a role in many interactions formerly attributed to cytochrome 450
enzymes (DuBuske, 2005). P-glycoprotein is a large cell membrane protein that is responsible for the transport
of many substrates, including drugs. It is a product of the ABCB1 gene (previously known as the multidrug
resistance gene, MDR1) and a member of the adenosine triphosphate (ATP)–binding cassette family of
transport proteins (ABC transporters). P-glycoprotein is found in high levels in various tissues, including the
renal proximal tubule, hepatocytes, intestinal mucosa, the pancreas and the blood–brain barrier. P-
glycoprotein acts as an efflux pump, exporting substances into urine, bile and the intestinal lumen. Its activity
in the blood–brain barrier limits drug accumulation in the central nervous system (CNS). Examples of some
possible inhibitors and inducers of P-glycoprotein are listed in Table 4.4. The pumping actions of P-
glycoprotein can be induced or inhibited by some drugs. For example, concomitant administration of digoxin
and verapamil, a P-glycoprotein inhibitor, is associated with increased digoxin levels with the potential for
digoxin toxicity. An overlap exists between CYP3A4 and P-glycoprotein inhibitors, inducers and substrates.
Many drugs that are substrates for CYP3A4 are also substrates for P-glycoprotein. Therefore, both
mechanisms may be involved in many of the drug interactions initially thought to be due to changes in
CYP3A4. Digoxin is an example of the few drugs that are substrates for P-glycoprotein, but not CYP3A4.

II. PHARMACODYNAMIC INTERACTIONS

Pharmacodynamic interactions are those where the effects of one drug are changed by the presence of another
drug at its site of action. Sometimes these interactions involve competition for specific receptor sites, but often they
are indirect and involve interference with physiological systems. They are much more difficult to classify than
interactions with a pharmacokinetic basis.

1. Antagonistic interactions
It is to be expected that a drug with an agonist action at a particular receptor type will interact with antagonists
at that receptor. For example, the bronchodilator action of a selective β2-adrenoreceptor agonist such as salbutamol
will be antagonized by β-adrenoreceptor antagonists. There are numerous examples of interactions occurring at
receptor sites, many of which are used to therapeutic advantage. Specific antagonists may be used to reverse the effect
of another drug at receptor sites; examples include the opioid antagonist naloxone and the benzodiazepine antagonist
Flumazenil. α-Adrenergic agonists such as metaraminol may be used in the management of priapism induced by α-
adrenergic antagonists such as phentolamine. There are many other examples of drug classes that have opposing
pharmacological actions, such as anticoagulants and vitamin K and levodopa and dopamine antagonist
antipsychotics.
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2. Additive or synergistic interactions

If two drugs with similar pharmacological effects are given together, the effects can be additive (Table 4.5).
Although not strictly drug interactions, the mechanism frequently contributes to ADRs. For example, the concurrent
use of drugs with CNS depressant effects such as antidepressants, hypnotics, antiepileptics and antihistamines may
lead to excessive drowsiness, yet such combinations are frequently encountered. Combinations of drugs with
arrhythmogenic potential such as antiarrhythmics, neuroleptics, tricyclic antidepressants and those producing
electrolyte imbalance (e.g. diuretics) may lead to ventricular arrhythmias and should be avoided. Another example
which has assumed greater importance of late is the risk of ventricular tachycardia and torsade de pointes associated
with the concurrent use of more than one drug with the potential to prolong the QT interval on the electrocardiogram
(Roden, 2004).

Serotonin syndrome
Serotonin syndrome (SS) is associated with an excess of serotonin that results from therapeutic drug use, overdose or
inadvertent interactions between drugs. Although severe cases are uncommon, it is becoming increasingly well
recognized in patients receiving combinations of serotonergic drugs (Boyer and Shannon, 2005). It can occur when
two or more drugs affecting serotonin are given at the same time, or after one serotonergic drug is stopped and
another started. The syndrome is characterized by symptoms including confusion, disorientation, abnormal
movements, exaggerated reflexes, fever, sweating, diarrhea and hypotension or hypertension. Diagnosis is made
when three or more of these symptoms are present and no other cause can be found. Symptoms usually develop
within hours of starting the second drug, but occasionally they can occur later. Drug-induced SS is generally mild
and resolves when the offending drugs are stopped. Severe cases occur infrequently and fatalities have been reported.
SS is best prevented by avoiding the use of combinations of several serotonergic drugs. Special care is needed when
changing from a selective serotonin reuptake inhibitor (SSRI) to an MAOI and vice versa. The SSRIs, particularly
Fluoxetine, have long half-lives, and SS may occur if a sufficient washout period is not allowed before switching from
one to the other. When patients are being switched between these two groups of drugs, the guidance in
manufacturers’ Summaries of Product Characteristics should be followed. Many drugs have serotonergic activity as
their secondary pharmacology, and their potential for causing the SS may not be readily recognized. For example,
linezolid, an antibacterial with monoamine oxidase inhibitory activity, has been implicated in several case reports of
SS. Many recreational drugs such as amphetamines and cocaine have serotonin agonist activity, and SS may ensue
following the use of other serotonergic drugs.

Drug or neurotransmitter uptake interactions

Although seldom prescribed nowadays, the MAOIs have significant potential for interactions with other drugs and
foods. MAOIs reduce the breakdown of noradrenaline in the adrenergic nerve ending. Large stores of noradrenaline
can then be released into the synaptic cleft in response to either a neuronal discharge or an indirectly acting amine.
The action of the directly acting amines adrenaline, isoprenaline and noradrenaline appears to be only moderately
increased in patients who are taking MAOIs. In contrast, the concurrent use of MAOIs and indirectly acting
sympathomimetic amines such as amphetamines, tyramine, MDMA (ecstasy), phenylpropanolamine and
pseudoephedrine can result in a potentially fatal hypertensive crisis. Some of these compounds are contained in
proprietary cough and cold remedies. Tyramine, contained in some foods (e.g. cheese and red wine), is normally
metabolized in the gut wall by monoamine oxidase to inactive metabolites. In patients who are taking MAOI,
however, tyramine will be absorbed intact. If patients who are taking MAOIs also take these amines, there may be a
massive release of noradrenaline from adrenergic nerve endings, causing a sympathetic overactivity syndrome,
characterized by hypertension, headache, excitement, hyperpyrexia and cardiac arrhythmias. Fatal intracranial
haemorrhage and cardiac arrest may result. The risk of interactions continues for several weeks after the MAOI is
stopped because new monoamine oxidase enzyme must be synthesized. Patients who are taking irreversible MAOIs
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should not take any indirectly acting sympathomimetic amines. All patients must be strongly warned about the risks
of cough and cold remedies, illicit drug use and the necessary dietary restrictions.

III. DRUG–FOOD INTERACTIONS

It is well established that food can cause clinically important
changes in drug absorption through effects on gastro-intestinal absorption or motility, hence the advice that certain
drugs should not be taken with food, for example, iron tablets and antibiotics. Two other common examples already
outlined include the interaction between tyramine in some foods and MAOIs, and the interaction between grapefruit
juice and CCBs. With improved understanding of drug metabolism mechanisms, there is greater recognition of the
effects of some foods on drug metabolism. The interaction between grapefruit juice and felodipine was discovered
serendipitously when grapefruit juice was chosen to mask the taste of ethanol in a study of the effect of ethanol on
felodipine. Grapefruit juice mainly inhibits intestinal CYP3A4, with only minimal effects on hepatic CYP3A4. This is
demonstrated by the fact that intravenous preparations of drugs metabolized by CYP3A4 are not much affected,
whereas oral preparations of the same drugs are. Some drugs that are not metabolized by CYP3A4, such as
fexofenadine, show decreased levels with grapefruit juice. The probable reason for this is that grapefruit juice inhibits
some drug transporter proteins and possibly affects organic anion- transporting polypeptides, although inhibition of
P-glycoprotein has also been suggested. The active constituent of grapefruit juice is uncertain. Grapefruit contains
naringin, which degrades during processing to naringenin, a substance known to inhibit CYP3A4. Although this led
to the assumption that whole grapefruit will not interact, but that processed grapefruit juice will, some reports have
implicated the whole fruit. Other possible active constituents in the whole fruit include bergamottin and
dihydroxybergamottin. Initial reports of an interaction between cranberry juice and warfarin, prompting regulatory
advice that the international normalized ratio (INR) should be closely monitored in patients taking this combination,
have not been confirmed by subsequent controlled studies. Cruciferous vegetables, such as Brussels sprouts, cabbage
and broccoli, contain substances that are inducers of the CYP450 isoenzyme CYP1A2. Chemicals formed by burning
(e.g. barbecuing) meats additionally have these properties. These foods do not appear to cause any clinically
important drug interactions in their own right, but their consumption may add another variable to drug interaction
studies, thus complicating interpretation.

IV. DRUG–HERB INTERACTIONS

There has been a marked increase in the availability and use of herbal products in the UK, which include
Chinese herbal medicines and Ayurvedic medicines. Up to 24% of hospital patients report using herbal remedies
(Constable et al., 2007). Such products often contain pharmacologically active ingredients which can give rise to
clinically signiicant interactions when used inadvertently with other conventional drugs. Extracts of Glycyrrhizin
glabra (liquorice) used for treating digestive disorders may cause significant interactions in patients who are taking
digoxin or diuretics. It may exacerbate hypokalaemia induced by diuretic drugs and precipitate digoxin toxicity.
Herbal products such as Chinese ginseng (Panax ginseng), Chan Su (containing bufalin) and Danshen may also contain
digoxinlike compounds which can interfere with digoxin assays, leading to falsely elevated levels being detected. A
number of herbal products have antiplatelet and anticoagulant properties and may increase the risk of bleeding when
used with aspirin or warfarin. Herbal extracts containing coumarin-like constituents include alfalfa (Medicago sativa),
angelica (Angelica archangelica), dong quai (Angelica polymorpha, A. dahurica, A. atropurpurea), chamomile, horse
chestnut and red clover (Trifolium pratense), which can potentially lead to interactions with warfarin. Herbal products
with antiplatelet properties include borage (Borago oficinalis), bromelain (Ananas comosus), capsicum, feverfew, garlic,
ginkgo (Ginkgo biloba) and turmeric, amongst others. Other examples of drug–herb interactions include enhancement
of hypoglycaemic (e.g. Asian ginseng) and hypotensive (e.g. hawthorn) effects, and lowering of seizure threshold (e.g.
evening primrose oil and Shankhapushpi). The most widely discussed drug–herb interactions are those involving St
John’s wort (Hypericum extract), an unlicensed herbal medicine used for depression which has been implicated in
interactions, for example, with hormonal contraceptives including implants, ciclosporin and antiepileptic drugs. It is
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therefore imperative that patients are specifically asked about their use of herbal medicines because they may not
volunteer this information.

CONCLUSION
Whilst one should acknowledge the impossibility of memorizing all potential drug interactions, healthcare staff need
to be alert to the possibility of drug interactions and take appropriate steps to minimize their occurrence. Drug
formularies and the Summary of Product Characteristics provide useful information about interactions. Other
resources that may also be of use to prescribers include drug safety updates from regulators such as the Medicines
and Healthcare Products Regulatory Agency (available at https://www.gov.uk/drug-safety-update), interaction alerts
in prescribing software and the availability of websites which highlight interactions for specific drug classes, for
example, HIV drugs (http://www.hiv-druginteractions.org). Possible interventions to avoid or minimize the risk of a
drug interaction include:
1. switching one of the potential interacting drugs;
2. allowing an interval of 2–3 hours between administration of the interacting drugs;
3. altering the dose of one of the interacting drugs, for example, reducing the dose of the drug which is likely to have
an enhanced effect as a result of the interaction. In this case, the dose is generally reduced by one-third or half with
subsequent monitoring for toxic effects either clinically or by therapeutic drug monitoring. Conversely, if the drug is
likely to have reduced effects as a result of the interaction, the patient should be monitored similarly for therapeutic
failure and the dose increased if necessary;
4. advising patients to seek guidance about their medication if they plan to stop smoking or start a herbal medicine,
because they may need close monitoring during the transition.

Overall, it is important to anticipate when a potential drug interaction might have clinically significant
consequences for the patient. In these situations, advice should be given on how to minimize the risk of harm, for
example, by recommending an alternative treatment to avoid the combination of risk, by making a dose adjustment
or by monitoring the patient closely.

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