Important drug nutrient

interactions
Pamela Mason
 Outline
n What is a drug nutrient interaction?
n Types and mechanisms of interaction
n Influence of drugs on nutrition
n Interactions between supplements and drugs
n Interactions involving St John’s wort and
grapefruit juice
n Risk and implications of interactions
n Patient care
What is a drug nutrient interaction?

That which results from a physical, chemical, physiological or

pathophysiological relationship between a drug and a nutrient.
The interaction is considered significant from a clinical
perspective if therapeutic response is altered (reduced or
enhanced)
 Context
n Potential for interactions appear infinite, but
n What proportion of these have been identified?
n What number of the identified subset are
clinically relevant?
 Diagnosis
n Any outcome should be consistent
n A reasonable temporal relationship between
the intake of the drug, the nutrient and the
observed effect
n The association should be plausible
 Clinical effects
n Failure of drug therapy
n Nutritional deficiencies
n Adverse drug events
n Discontinuation of the drug
 Types of interactions
n Pharmacokinetic (e.g., tetracyclines and calcium, iron;
levothyroxine and calcium)
n Pharmacodynamic (e.g., vitamin B6 and levodopa, St John’s
wort and anticoagulants, antiepileptics, cytotoxics)
n Drug and nutrient/supplement have similar action (e.g., fish
oils and anticoagulants; St John’s wort and antidepressants)
n Supplement counteracts drug (e.g., echinacea and
immunosuppressants)
n Beneficial interactions
n probiotics and antibiotics
 Drugs influence:
n Ingestion
n Appetite
n Taste
n Secretion
n Oral secretion
n Gastric acid secretion

n Absorption
n Gastrointestinal drug metabolising enzymes
n Gastrointestinal transporters

n Gastrointestinal motility
n Gastrointestinal flora (immunity)
n Nutrient metabolism
n Nutrient excretion
 Drugs and appetite
Reduce appetite Increase appetite
n Amantadine n Cyproheptadine
n Digoxin n MAOIs
n Fluoxetine n Tricyclics
n Levodopa n Valproate
n Lithium
n Metformin
n Penicillamine
 Drugs and taste
n ACE inhibitors
n Allopurinol
n Amiodarone
n Baclofen
n Griseofulvin
n Lithium
n Metformin
n Metronidazole
n Penicillamine
n Terbinafine
 Drugs and oral secretion
n Suppression of saliva production – dry mouth
(xerostomia)
n Anticholinergics (eg, antihistamines, tricyclics,
orphenadrine, oxybutinin, procyclidine,
propantheline, trihexyphenidyl hydrochloride)
n Selegeline
 Gastric acid secretion
n Influence on intrinsic factor- vitamin B12
absorption
n Proton pump inhibitors1-3
n H2 receptor antagonists1-3

1. J Clin Gastroenterol 2000;30:29-33

2. Ann Pharmacother 2002;36:812-6
3. Aliment Pharmacol Ther 1999;13:453-8
 Drugs and intrinsic factor
n Allopurinol
n Colestyramine
n Colchicine
n Metformin
n Methyldopa
n Neomycin
 Drugs and absorption
n Modulation of mucosal enzymes
n Modulation of intestinal transporters
n Formation of insoluble complexes (eg,
tetracyclines, quinolones, doxycycline,
lymecycline, minocycline, penicillamine)
n Binding of bile acids (eg, colestyramine,
colestipol)
 Gastrointestinal drug metabolising
enzymes and transporters
n Cytochrome P450 (CYP)3A4 – regulates oral bioavailability
of drugs and nutrients
n Grapefruit juice
n St John’s wort
n P-glycoprotein
n Inhibition (eg, water soluble vitamin E)
n Increased bioavailability or ciclosporin1 and digoxin2
n Induction (eg, St John’s wort3)
n Reduced bioavailability of ciclosporin, digoxin and indinavir
JPEN 2001;25:132-41
1. Clin Pharmacol Ther 2004;75:P95
2. Br J Clin Pharmacol 2002;53:75-82.
 Gastrointestinal motility
n Benzhexol
n Benztropine
n Dicyclomine
n Oxybutinin
n Procyclidine
n Propantheline
n Tricyclic antidepressants
 Gastrointestinal flora
n Antibiotics
n Destruction of gut flora
n Antibiotic associated diarrhoea
n Reduction in production of B vitamins and vitamin K
 Probiotics
n Lactobacillus GG and Saccharomyces
boulardii – trials indicate benefit of both in
prevention of antibiotic-associated diarrhoea
n S boulardii – trials indicate benefit in
Clostridium difficile disease (less convincing
evidence for Lactobacillus GG)
 Probiotics in antibiotic-associated
diarrhoea – meta-analyses
Number of trials Relative risk (RR) 95% CI
9 0.37 0.26-0.53;P<0.001
BMJ 2002;324:1361
22 0.39 0.27-0.57
Aliment Pharmacol Ther
2002;16:1461-7

5 0.43 0.23-0.78
Aliment Pharmacol Ther NNT =10 (S boulardii)
2005;22:365-72

25 0.43 0.31-0.58, p<0.001

Am J Gastroenterol (S Boulardii,
2006;101:812-22 Lactobacillus GG,
probiotic mixture)
Drugs and nutrient metabolism
Frusemide Thiamine

Isoniazid, Pyridoxine
hydralazine,
penicillamine,
OCs, theophylline

Anticonvulsants Folic acid

Methotrexate
Sulphasalazine
Trimethoprim

Anticoagulants Vitamin K
 Grapefruit juice interactions
(BNF 57, Appendix 1)

n Buspirone
n Calcium channel blockers (felodipine, isradipine, lacidipine, lercanidipine,
nicardipine, nifedipine, nimodipine, nislodipine, verapamil)
n Carbamazepine
n Ciclosporin
n Ethinyloestradiol
n Saquinavir
n Sildenafil
n Sirolimus and tacrolimus
n Simvastatin
 Mechanisms of grapefruit juice
interactions
n Grapefruit juice inhibits 2 of the 6 major P450 enzymes: 3A4 and 1A2
n 3A4 is located in the liver (30%) and gut wall (70%)
n Grapefruit juice selectively inhibits gut wall 3A4 with little effect on
hepatic 3A4
n Effects on oral drugs (eg oral midazolam vs IV midazolam)
n Grapefruit juice components responsible:
n Flavonoids: naringenin, naringin
n Furanocoumarins: bergamottin, 6’,7’-dihydroxybergamottin
n Whole grapefruit
n Confectionery made from grapefruit peel?

Inhibition is fully developed after 1 glass of juice and lasts up to 24 hours

 St John’s wort interactions
BNF 57, Appendix 1

n Anticoagulants
n Antidepressants
n Antiepileptics – carbamazepine, phenytoin, primidone
n Antimalarials
n Antipsychotics
n Antivirals
n 5-HT antagonists
n Oral contraceptives
n Ciclosporin
n Digoxin
n Phenobarbitone
n Tacrolimus
n Theophylline
 Mechanisms of SJW interactions
n Induction of intestinal transporter (e.g. P-gp)
activity
n Increased activity of CYP3A4 (liver and
intestine) and CYP2B6
n Additive serotonergic effects with SSRIs (e.g.,
paroxetine, sertraline, trazodone, nefazodone)
 Pharmacokinetic interactions with
SJW
CYP3A4
P-gp substrates
substrates
n Antiarrhythmics (digoxin,
(amiodarone,
quinidine,
quinidine)
amiodarone)
n Calcium channel blockers (diltiazem, verapamil)
verapamil, nifedipine)
n Immunosuppressants (ciclosporin, tacrolimus)
n Protease inhibitors (amprenavir,
(ritonavir, indinavir,
indinavir,
saquinavir,
nelfinavir,
nelfinavir)
n saquinavir)
Antiepileptics (carbamazepine)
 Interactions with vitamin and
mineral supplements
Supplement (precipitant) Drug (object) Outcome

Folic acid Phenytoin ↓ drug effect

Pyridoxine Levodopa ↓ drug effect

Vitamin E Ciclosporin ↑ drug effect

Vitamin K Anticoagulants ↓ drug effect

Calcium Thyroid hormone May reduce drug absorption

Iron ACE inhibitors May interfere with drug absorption

Levodopa/carbidopa
Potassium ACE inhibitors ↑ risk of hyperkalaemia

Divalent minerals Pencillamine ↓ drug availability

4-quinolones ↓ drug availability
Tetracyclines ↓ drug availability
 Some proposed interactions between non-nutrient
supplements and drugs
Supplement (precipitant) Drug (object) Outcome

S-adenosyl-methionine SSRIs Risk for serotonin syndrome

Chitosan Warfarin May potentiate drug effect
Co-enzyme Q Warfarin May antagonise drug effect
Dong quai Warfarin May potentiate drug effect
Echinacea Immnosuppressants Potential for altered drug effectiveness

Feverfew NSAIDs Additive inhibition of prostaglandin

production
Fish oils Anticoagulants May have additive effects (by different
mechanisms)
Garlic Saquinavir May reduce blood levels of the drug

Genistein Paclitaxel May improve availability of drug

Ginseng Oral hypoglycaemics Additive hypoglycaemic effects

Ginkgo biloba Anticoagulants Possibly increased bleeding

Glucosamine Warfarin May potentiate drug effect

Valerian Sedative drugs May potentiate sedative effects

 Prevalence of supplement and
medicine use
n US study in 1539 adults - 44% on prescribed medicines; 20%
of these using herbal or high dose vitamins
n UK study on 164 herbal medicine users - 59% had taken
conventional medicines
n Canada study in 195 older patients - 97% on prescription
medicines and 17% using natural health products
n Studies in cancer and HIV patients 50-65% using
supplements/CAM
n US study in 979 pre-operative patients undergoing anaesthesia
– 17.4% reported current use of herbal or dietary supplements
 Risk of interaction
n Survey of 458 US patients taking prescription
medicines
n 197 (43%) taking supplements
n Vitamins, minerals, ginkgo biloba, garlic, saw
palmetto, ginseng
n 89 (45%) had potential for interaction
n 6% were potentially serious
Arch Intern Med 2004;164:630-6
 Study in cancer patients
n Supplements used by 61% of cancer patients (121
patients)
n 65 patients (54%) reported taking >1 supplement
n Risk for interaction identified in 12% of patients
n Documentation on medical record in only 28% of
patients taking supplements

Am J Clin Oncol 2006;29:178-82

 Mayo Clinic Study
n 1795 patients in 6 specialty clinics
n 39.6% reported use of supplements
n 107 potentially clinically significant interactions
n Supplements: 68% of interactions accounted for with
garlic, valerian, gingko, St John’s wort
n Drugs: 94% accounted for with antithrombotic
medicines, sedatives, antidepressants and antidiabetic
agents
n No patient seriously harmed
Am J Med 2008;121:207-11
 Patients at risk
n Multiple or long-term drug regimens
n Diseases that prejudice nutritional status
n Enteral or parenteral nutrition
n Poor diet
n Medication taken at mealtimes
n Drugs with narrow therapeutic margins
n Drugs that alter taste, appetite or cause GI
disturbances
 Patient care
n Use only essential drugs for as short a time as
possible
n Take diet-supplement- herbal-drug histories
n Consider timing of medication in relation to
food
n Clinical monitoring
n Changing drug therapy where necessary
 Conclusion
n Interactions a concern in the context of
increased use of medication and supplements
n Much more data and evidence to generate
n Clinical significance of some interactions not
well understood
n Patients should be routinely screened for
supplement and herbal use
 Finally…

Thank you for listening!

pamelamason@apotek.org.uk