Food-drug interactions Do they really matter by cgz40019

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									                                                                                                     Foods – general
                                                                                                          The first occasion for a food-drug
                                                                                                     interaction to occur is during the absorption
                                                                                                     phase of the drug. Most drugs are optimally
                                                                                                     absorbed in the small intestine and food
                                                                                                     ingestion can either reduce or increase the
                                                                                                     rate or extent of absorption.3,4
                                                                                                          With some drugs the presence of
                                                                                                     increased amounts of stomach acid results
                                                                                                     in the destruction of acid-labile drugs.3,5. In
                                                                                                     other cases food components such as calcium
                                                                                                     or iron may chelate some drugs reducing

Food-drug interactions:                                                                              their absorption. Delayed absorption does
                                                                                                     not necessarily reduce the total overall
                                                                                                     exposure to the drugs and the area under the

Do they really matter?                                                                               curve (AUC) may be equivalent regardless of
                                                                                                     how the drug is taken.5 On the other hand
                                                                                                     some medicines should be taken after meals
                                                                                                     since their bioavailability is enhanced by
                                                                                                     food.1 Table 1 summarizes some of these
Valerie Vella BPharm(Hons), MSc (Aberdeen), MpharmS                                                  interactions.


Senior Clinical Pharmacist, Mater Dei Hospital, Tal-Qroqq, Malta                                     Alcohol
Email: valerie.vella@gov.mt                                                                               The two main types of interactions,
                                                                                                     which can occur following concurrent
                                                                                                     alcohol and medicine ingestion, are (i)
Educational aims
                                                                                                     CNS depression and (ii) the flushing
 •		To	have	a	better	understanding	of	the	types	of	interaction	occur	between	food	and	               reaction.6 The effects of drugs that have
     medicines                                                                                       CNS depressant activity are enhanced by
 •		To	be	better	informed	on	the	advice	that	patients	should	be	given	on	drug-food	                  consumption of alcohol, thus impairing
     interactions                                                                                    driving ability and other skills. This
                                                                                                     interaction involves drugs such as
                                                                                                     amphetamines, analgesics, antiepileptics,
Keywords: food, medicines, interactions, alcohol, grapefruit, cranberry juice, dairy products,       antihistamines, antipsychotics, appetite
caffeine, tyramine                                                                                   suppressants, benzodiazepines, isoniazid,
                                                                                                     lithium, maproteline, metoclopramide,
                                                                                                     mianserin, selective serotonin reuptake
                                                                                                     inhibitors (SSRIs) and tricyclic
In pharmacists’ daily practice, particularly when advising patients
                                                                                                     antidepressants.6
regarding their dosage regimen, they are often faced with the                                             The flushing reaction also known as a
recurring question “do I need to take this after a meal?” Sometimes it                               disulfiram reaction occurs between alcohol
makes one wonder whether this is a true concern or whether it is just                                and some drugs, chemicals and certain
an excuse to eat! The truth, however, is that interactions between food                              fungi, and although unpleasant and possibly
                                                                                                     frightening it is rarely dangerous.5,6 This
and medicines can have a significant influence on the adverse effect
                                                                                                     reaction is expected with disulfiram since
profiles of many drugs and on the therapeutic success of the drug                                    it blocks the metabolism of alcohol and
being administered.                                                                                  leads to an accumulation of acetaldehyde
                                                                                                     in the blood stream resulting in flushing,
    A food-drug interaction may be defined            necessary tools at hand? Do they have the      fullness of the face and neck, tachycardias,
as the alteration of absorption, metabolism,          time?                                          breathlessness, giddiness, hypotension,
elimination or effect of a drug by a food                  Regardless of the response to these       nausea and vomiting.5,6,7 The reaction can
component.1                                           questions healthcare professionals are duty    occur with 10 minutes of alcohol ingestion
    Now, a number of questions follow – how           bound to provide this information in a         and may last several hours.7 Drugs reported
knowledgeable are healthcare professionals            correct manner to the patient and in failing   to provoke a similar reaction include azole
about this subject? How willing are they              to do so they might compromise patient         antifungals, cephalosporins, furazolidone,
to provide the correct information to the             care. Severe adverse reactions, therapeutic    griseofulvin, metronidazole and topical
patient by looking it up on a reference book          failures and fatalities have been reported     tacrolimus and pimecrolimus.6
or on the patient’s insert? Do they have the          following food-drug interactions.2                  Alcohol should also be avoided in

16      Journal of the Malta College of Pharmacy Practice                                                                    Issue 15 Summer 2009
Table 1. Before food, with food or after food?                                                       recommendation of the CSM (Committee on
                                                                                                     Safety of Medicines)/MHRA (Medicines and
                                                                                                     Healthcare products Regulatory Agency)
  Recommendation                   Drugs                          Reason                             in the UK is that patients taking warfarin
                                                                                                     should limit or avoid completely drinking
  Take	with	a	high	fat	meals	      •	Griseofulvin	                Increased	absorption               cranberry juice.2. This measure was taken
  	                                •	Albendazole                                                     following reports that the anticoagulant
  With food		                      •	Acitretin	                   Food enhances bioavailability      effects of warfarin were increased in patients
  	                                •	Carbamazepine                                                   drinking cranberry juice. One patient had
  	                                •	Fenofirate                                                      a very marked increase and died from a
  	                                •	Isotretinoin                                                    haemorrhage while a further patient had
  	                                •	Itraconazole	capsules                                           a reduction in his INR (International
  	                                •	Ketoconazole                                                    Normalized Ratio).2,11
  	                                •	Labetalol
  	                                •	Lopinavir                                                       Milk and dairy products
  	                                •	Mebendazole                                                         The absorption of most tetracyclines is
  	                                •	Tamsulosin                                                      markedly reduced by milk and other dairy
  	                                •	Tenofovir                                                       products. Reduction is reported at up to
                                                                                                     65%.5 Doxycyline and minocycline are less
  	                                •	NSAIDs	+	Aspirin	            To	minimise	gastrointestinal       affected by this food group although a
  	                                •	Co-amoxiclav	                adverse	effects                    reduced absorption of 25-30% is reported.2
  1	hour	before	food	              •	Azithromycin capsules        Food reduces bioavailability       Dairy products also reduce the bioavailability
  or	2	hours	after	                •	Indinavir	                   either	because	drugs	are           of ciprofloxacin and norfloxacin.5 As a
  	                                •	Itraconazole	solution	       acid-labile	or	via	the             consequence, it is usual to recommend that
  	                                •	Lansoprazole	                formation	of	complexes	      	     tetracyclines and quinolones are taken one
  	                                •	Penicillins	                 with	the	drug                      hour before food or 2 hours after food to
  	                                •	Quinolones                                                      avoid an interaction with all forms of dairy
  	                                •	Saquinavir                                                      calcium.2
  	                                •	Tetracyclines                                                       In the case of strontium, the
                                                                                                     manufacturer remarks that food, milk and
  30 minutes before food	          •	Didanosine
                                                                                                     dairy products reduce the bioavailability
  	                                •	Perindopril
                                                                                                     of strontium by 60 to 70% when compared
  	                                •	Rifampicin
                                                                                                     to bioavailability following administration
                                                                                                     3 hours after a meal. For this reason
  	                                •	Alendronate	                 Specifically	30	minutes
                                                                                                     recommendations state that strontium
  	                                •	Risedronate	                 before	the	first	food
                                                                                                     should be taken at bedtime at least 2 hours
                                                                  of the day
                                                                                                     after eating.2,12
  2	hours	after	eating	            •	Strontium	                   Reduced	bioavailability
                                                                                                     Caffeine
                                                                                                          Caffeine is a methylxanthine derivative
patients on concurrent hepatotoxic                   circulating in the body.2,5,9 The concern
                                                                                                     that is contained in tea, coffee, chocolate,
medications such as paracetamol,                     is that concomitant administration of a
                                                                                                     and beverages and in compound analgesic
methotrexate, leflunamide, and phenytoin.6,8         single serving of grapefruit or its products
                                                                                                     preparations. Caffeine is a proven ergogenic
                                                     with certain drugs may cause toxic effects
                                                                                                     aid, increasing athletic performance,
Grapefruit and grapefruit juice                      based on increased exposure.9 For those
                                                                                                     endurance, and mental chronometry even at
    Grapefruit and grapefruit juice alter            patients who are unwilling to terminate their
                                                                                                     very low doses.13 As a consequence of this
the pharmacokinetics of several drugs                consumption of this product, alternative
                                                                                                     it is likely that caffeine-containing products
such as statins, calcium channel blockers,           drugs within the same class that exhibit a
                                                                                                     will reduce the efficacy of hypnotics and
antibiotics and others. This was, as often           weak or no interaction should be prescribed.
                                                                                                     increase the risk of insomnia. Patients on
is the case, discovered accidentally in a            Table 2 summarizes the most significant
                                                                                                     antiarrythmics should also avoid excessive
study investigating alcohol-drug interactions        drug-grapefruit interactions.
                                                                                                     caffeine because of the risk of tachycardias.
where grapefruit juice was utilised to mask                                                               Theophylline, which is chemically related
the taste of the alcohol being studied.9             Cranberry juice                                 to caffeine and licensed for the prophylaxis
The major mechanism in the induction of                  Cranberry juice has gained a lot of         and treatment of reversible bronchospasm
grapefruit-drug interactions seems to be             popularity in recent years because of           associated with asthma and chronic
the ability of grapefruit to inhibit intestinal      claims that it reduces the risk of urinary      obstructive pulmonary disease, is a xanthine-
CYP3A4, thus reducing ‘first-pass’ metabolism        tract infections10 and because of its           derivative. Thus the concurrent consumption
leaving a higher concentration of drug               antioxidant potential. However, the current     of other xanthine-containing products is
                                                                                                     contraindicated.14

18       Journal of the Malta College of Pharmacy Practice                                                                   Issue 15 Summer 2009
    With high doses caffeine also reduced the    Table 2. Interactions with grapefruit and grapefruit products2,9
seizure threshold and produced a significant
reduction in the anticonvulsant effects of
carbamazepine, phenobarbitone, phenytoin,        Interacting drug Expected effect of interaction                    Patient advice
and valproate in mice.15 This interaction was    (oral form only)
pharmacodynamic in nature since caffeine
did not affect the plasma concentrations         Amiodarone          Increased peak serum level by 84%              It is prudent to suggest
of these anti-epileptics. In case of newer                           and increased AUC of amiodarone                to patients that they avoid
antiepileptics, both acute and chronic                               by 50%.                                        grapefruit juice.
caffeine decreased the protective potential                          Reduced effect of amiodarone on
of gabapentin and topiramate but not that                            the PR and QTc intervals.
of lamotrigine and tiagabine.17 Regardless       Calcium Channel     The significant increase in the                The manufacturers of these
of this however none of the manufacturing        blockers            bioavailability of felodipine may              products contraindicate the
companies advise against the consumption                             alter their haemodynamic effects.              intake of grapefruit and
of such products.16,17,18,19,20,21,22                                The bioavailability of nifedipine              its products, although this
    It is advisable to avoid caffeine-                               and nimodipine is also increased               interaction is most
containing products with other stimulant                             without altering the haemodynamic              significant in patients
products such as ginseng, guarana,                                   effect. The bioavailability of amlodipine,     receiving felodipine.
pseudoephedrine and ephedra (available in                            diltiazem and verapamil is only
some slimming preparations). Fatalities have                         minimally affected although with
been reported with concomitant ephedra and                           verapamil some ECG changes were seen.
caffeine use.23                                  Carbamazepine       Possible carbamazepine toxicity                Grapefruit or grapefruit
                                                                                                                    juice should be avoided
Protein                                                                                                             but if its consumption is
    Protein content in the diet may cause                                                                           desirable, carbamazepine
fluctuations in the response of parkinsonian                                                                        levels should be monitored.
patients being treated with levodopa. This
is thought to be due to a reduction in           Cyclosporin         Trough and peak serum levels and
the efficacy of levodopa secondary to the                            bioavailability of cyclosporin is increased.   Concurrent use should be
action of the amino acid methionine and a                                                                           avoided.
reduction in the blood levels of levodopa        Pimozide            Raised pimozide levels may lead to             Concurrent use is
as a result of the amino acid tryptophan.                            potentially fatal torsades de pointes          contraindicated.
Spreading out the intake of proteins and                             arrhythmias.
restricting daily allowance of protein to        Sildenafil,         Grapefruit juice can increase the area         Avoid concurrent use of
800mg/kg body weight is reported to reduce       Tadalafil and       under curve (AUC) of sildenafil by 23%.        grapefruit and grapefruit
this interaction.2                               Vardenafil          Although this is unlikely to be clinically     juice.
                                                                     significant this combination is best
Tyramine – rich foods                                                avoided because concurrent use results
     Perhaps the most feared food-drug                               in an increased variability in sildenafil
interaction is that between monoamine                                pharmacokinetics. Products within the
oxidase inhibitors (MAOIs) and the amino                             same class are likely to interact similarly.
acid tyramine.2,5 Tyramine is indirectly
sympathomimetic and when its metabolism          Simvastatin and     Plasma levels of lovastatin and simvastatin    Even small quantities of
is suppressed, as it is by MAOIs, it can cause   Lovastatin          can increase by upto 12-fold and 9-fold        grapefruit and its products
a significant release of norepinephrine,                             respectively if given with grapefruit juice,   can cause a signification
resulting in markedly increased blood                                increasing the risk of muscle damage and       interaction and thus
pressure, cardiac arrhythmias, hyperthermia                          possible development of rhabdomyolysis.        concomitant use should
and cerebral hemorrhage. Fatalities have                                                                            be avoided.
been reported5. As little as 6mg of tyramine     Sirolimus           Grapefruit juice may raise sirolimus           Although the extent of this
can raise the blood pressure and 10 to 25mg                          serum levels.                                  interaction is unknown the
of tyramine would be expected to cause                                                                              manufacturer suggest
a serious hypertensive reaction. Tyramine                                                                           avoidance of this product.
is found in foods such as cheeses, salami,       Tacrolimus          Grapefruit juice can markedly                  Combination should be
sausages, smoked meats, yeast extracts,                              increase serum levels of tacrolimus by         avoided if consumption is
pickled foods, chocolate and drinks such as                          up to 400%                                     desirable close monitoring
beers and wine. Since the tyramine levels                                                                           is recommended.
vary so much it is impossible to guess the
amount of tyramine present in any food and
drinks.2


Issue 15 Summer 2009                                                                  Journal of the Malta College of Pharmacy Practice         19
    A milder form of this reaction has also      supplements.2 Other foods such as garlic,        there are suitable reference publications
been observed with moclobemide, selegiline       mango, avocado, soybean products and             to refer to such as the British National
and large quantities of tyramine rich foods      herbs are know to interact with warfarin         Formulary, Stockley’s Drug Interactions and
(e.g. 300g Gorgonzola® cheese).2                 and patients should be referred to their         specific product characteristics available on
                                                 anticoagulant book for more information.2,4,23   www.medicines.org.uk.
Others                                                                                                Pharmacists should not fear opening a
    The effects of warfarin can be               Conclusion                                       book or a package insert in front of a patient
antagonized by vitamin K, which is found             This review has highlighted the outcome      in order to guide them accordingly. Priority
in large amounts in green vegetables such        of some common food-drug interactions.           should be given to patients on drugs, which
as spinach, broccoli, cabbage and green          Needless to say it is quite impossible for       have a narrow therapeutic index, such as
tea. Patients should be advised to avoid         a pharmacist to remember all the known           warfarin, and to elderly patients who are
dramatic dietary alterations. Care should also   clinically important reactions, which is why     most at risk due to polypharmacy, renal and
be given to patients starting new vitamin                                                         hepatic impairment.



  Multiple choice questions

  A correct response of 80% and over will entitle MCPP members to 1 credit towards their annual continuous education requirement.
  Answers may be sent by email to: president@mcppnet.org by 30 September 2009.


  1. Patients on oral hypoglycaemics should avoid excessive                 6. Excessive consumptions of alcohol may increase the risk
     amounts of:                                                               of gastrointestinal haemorrhage in patients taking:
       a. Protein rich foods                                                     a. NSAIDs
       b. Alcohol                                                                b. Opioid analgesics
       c. Vegetables                                                             c. Benzodiazepines
       d. Black coffee with artificial sweeteners                                d. Ginseng

  2. Drugs which are acid-labile like penicillin have their                 7. Alcohol may cause facial flushing or skin erythema in
     efficacy reduced by:                                                      patients using:
       a. Water                                                                  a. Topical corticosteroids
       b. Orange juice                                                           b. Topical NSAIDs
       c. Black Coffee                                                           c. Topical antihistamines
       d. Alcohol                                                                d. Topical tacrolimus

  3. Iron supplements has its absorption reduced by:                        8. When taken with grapefruit juice the following drug can
       a. Tea                                                                  cause severe rhabdomyolysis:
       b. Water                                                                  a. Simvastatin
       c. Orange Juice                                                           b. Fluvastatin
       d. Black coffee                                                           c. Atorvastatin
                                                                                 d. Rosuvastatin
  4. Patients on ACE inhibitors should avoid large amounts of
     salt-substitutes avoid the risk of:                                    9. High doses of omega-3 marine triglycerides
       a. Constipation                                                         (4 capsules) increase bleeding time in patients on:
       b. Hypotension                                                            a. Aspirin
       c. Hypertensive Crisis                                                    b. Warfarin
       d. Hyperkalaemia                                                          c. Ticlopidine
                                                                                 d. Clopidogrel
  5. How long after finishing a course of metronidazole
     should a person wait before he or she can drink alcohol?               10. Food reduces the absorption of:
       a. 12 hours                                                               a. Isotretinoin
       b. 24 hours                                                               b. Azithromycin suspension
       c. 48 hours                                                               c. Azithromycin capsules
       d. 1 week                                                                 d. Ketoconazole




Issue 15 Summer 2009                                                                  Journal of the Malta College of Pharmacy Practice       21
 Practice points
 •	 It	is	the	duty	of	healthcare	professionals	to	educate	patients	on	the	possibility	of	
    interactions between their medications and their diet.
 •	 Patients	require	correct	administration	instructions	so	as	to	get	the	maximum	benefit	
    from their medicinal treatment and to avoid adverse reactions.
 •	 Patients	should	be	given	clear	information	on	the	consequences	of	an	alcohol-drug	
    interaction as this can prevent severe outcomes.
 •	 Patients	buying	vitamins	and	herbal	medicines	should	always	be	asked	for	a	medication	
    history.
 •	 If	one	knows	that	a	patient	is	unlikely	to	stick	to	the	dietary	advice	recommended	
    with his/her medication than it would be advisable for the pharmacist to suggest an
    alternative.



References

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    Nutrition & Metabolism 2008; 52:29-32                       Health-System Pharmacy 2007; 64(5) 490-494              Epanutin. 2009. http://medicines.org.uk (Last
2. Stockley Ivan. Food. In Baxter Karen, editor.            12. Electronic Medicines Compendium for the                 accessed on 01 May 2009)
    Stockley’s Drug Interactions Pocket Companion.              Professional. Specific Product Characteristics.     19. Electronic Medicines Compendium for the
    London: Pharmaceutical Press; 2008.                         Protelos. 2009. http://medicines.org.uk (Last           Professional. Specific Product Characteristics.
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22         Journal of the Malta College of Pharmacy Practice                                                                                      Issue 15 Summer 2009

								
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