W11 Food Drug Interactions (GP)

Question 1

Food->drug interaction
What are the possible effects? (3)(pharmacokinetic parameters)

Answer 1

• Decrease Action of Drug(s)
• Increase Action of Drug(s)
• Cause Adverse effects

Question 2

What is a Food->drug interaction Vs Drug-> food/nutrient intake?

Answer 2

1. Food can prevent the drug from working the way it should due to alterations of pharmacokinetic parameters
2. Effects of drug treatment on nutritional status/appetite of the patient

Question 3

Food-drug interactions can be broadly classified as occurring at what levels? (3)

Answer 3

I. pharmaceutical level: regarding food-drug compatibility, solubility, stability;
II. pharmacokinetic level: interactions
concerning absorption, distribution,
metabolism, excretion;
III. pharmacodynamic level: regarding the clinical effect and/or mode of action of the drug.

Question 4

When do Pharmacokinetic food-drug interactions occur?

Answer 4

When food alters the absorption, distribution, metabolism, or excretion of a drug, thus increasing or decreasing the amount of drug available to produce its pharmacological effects.

Question 5

Food -> drug interactions: Absorption
The presence of food in GI tract can alter
drug absorption by:

Answer 5

• changing the gastric motility (gastric emptying rate)
• changing intestinal transit
• changing the gastrointestinal pH
  (effecting drug dissolution)
• food-drug complexation/chelation/adsorption effects
• causing drug degradation
• modulation of transporters

Question 6

Absorption of most oral drugs is… by the presence of food.
Example?

Answer 6

Delayed.
Aspirin:
* Taken with food, the aspirin is adsorbed onto the food -> slow absorption ->
delayed onset time of the therapeutic effect
* However, the food delays gastric emptying -> no alteration of amount of
drug being absorbed (no changes in bioavailability).

Most drugs should not be taken with food.
* Few exceptions are known instead…

Question 7

Absorption:
Drugs that are given with food?
Why? (3)

Answer 7

• Cimetidine (heart burn)
  According EMC, this is taken with breakfast/meals. First fraction of drug is
  absorbed while food is present, allowing the remaining drug to be dissolved
  once the gut is cleared -> Maintenance of therapeutic levels
• A small amount of food or milk may be desirable when a drug is likely to
  cause gastric upset -> Ibuprofen, ketoprofen, naproxen -> protection from
  side effects
• Lipophilic drugs are best absorbed in the presence of a high-fat meal -> The
  increased residency in the gut improves drug dissolution
• **metronidazole - antibiotic
• spironolactone - potassium-sparing diuretic
• griseofulvin – antifungal drug**

Question 8

Absorption:
Dairy products effect on abx? (e.g., ciprofloxacin and tetracycline)

Answer 8

Decrease the absorption of antibiotics-> COMPLEXATION
ACTION: Avoid eating meals one to two hours before or six hours after

Question 9

• If walnuts are eaten close to a levothyroxine dose (thyroid hormone)…?

Answer 9

The medication can bind to the walnuts (Iodine-rich foods) which decrease the medication’s absorption

ACTION: Avoid eating meals one to two hours before or six hours after

Question 10

For info: Tannins

Answer 10

• Tannins (component of strong tea, coffee, and some wines) form complexes with iron (in iron supplements), which are then not absorbed -> CHELATION

Question 11

Grapefruit juice:
MOA- what does it cause?
Effect on statins?
Effect on Cyclosporine?

Answer 11

Reduces the activity of the enterocyte efflux transporter P glycoprotein (P-gp) which is an ABC-transporter that actively pumps lipophilic molecules back into the intestinal lumen (opposite direction of the
absorption).
* This causes an increase in the absorption of statins (cholesterol-lowering drugs) in the blood -> TRANSPORTER MODULATION
* Grapefruit juice increase the bioavailability of cyclosporine (post organ transplants treatment) with a dual effect

➔Decrease the organ rejection potential
➔Increase the potential of cyclosporine toxicity

Question 12

Distribution

Answer 12

• Most of medications bind to blood proteins within the blood plasma.
• A chemical equilibrium will exist between the bound and unbound states
• It is the unbound fraction which exhibits
  pharmacologic effects, that may be metabolized and/or excreted.
• The less bound a drug is, the more efficiently it can traverse or diffuse through cell membranes

Question 13

Distribution

Answer 13

• Most of medications bind to blood proteins within the blood plasma.
• A chemical equilibrium will exist between the bound and unbound states
• It is the unbound fraction which exhibits
  pharmacologic effects, that may be metabolized and/or excreted.
• The less bound a drug is, the more efficiently it can traverse or diffuse through cell membranes.
• More common is the drug-drug interactions involving the blood transport
• One substance can displace the other bound substance from the binding site
  -> transient effect as the increased effect of the free drug may be countered by
  increased metabolism/excretion of the free drug.
• Some significance is possible if the second agent is taken on an intermittent
  basis
• Less common food-drug interactions involved in the distribution (different
  albumin binding sites and affinities for food components)
• Mostly studied interaction is correlated to anticonvulsants that can be displaced from albumin-binding by fat emulsions of co-administered parenteral nutrition formula
• Salvianolic acid B and rosmarinic acid (Salvia miltiorrhiza B.) were reported to
  bind to human serum albumin, interfering with warfarin binding

Question 14

Drug metabolism definition?

Answer 14

the term used to describe the biotransformation of drugs
into metabolites within the body so that they can be eliminated more easily.
2 phases

Question 15

drug metabolism
2 phases?

Answer 15

Phase I - oxidative reactions. The major enzymes belong to the family of cytochrome P-450 (e.g., CYP3A4, CYP2D6, CYP1A2, and the CYP2C).
Phase II - conjugating reactions. Drugs are primarily converted to glucoronides, ester sulfates, or glutathione conjugates to make them more hydrophilic to be excreted.
-Phase I and II reactions occur in the liver as well as in the intestinal mucosa

Question 16

Metabolism
Grapefruit juice cause?
which medicines affected? (4)

Answer 16

• Grapefruit juice cause inhibition of CYP450-mediated metabolism (isoenzymes 1A2 and 3A4).
• This induces high level of drug in the blood, raising the risk of side effects.
• Class of medicines affected:
• Calcium channel blockers (prescribed for high blood pressure)
• Statins (prescribed to lower cholesterol levels)
• Immunosuppressants (Cyclosporine)
  -decrease the potential for organ rejection following transplants, but may also increase the potential for cyclosporine toxicity
• Anti-anxiety and anti-depressants
  -Avoid drinking grapefruit juice when taking the following drugs

Question 17

Tyramine Rich Foods + Non selective MAOIs or MAO-B inhibitors

Answer 17

• Monoamine oxidase inhibitors (MAOIs) block the activity of the enzyme
  monoamine oxidase, which normally breaks down neurotransmitters like
  serotonin, norepinephrine, and dopamine.
• They are used to treat depressive disorders, tuberculosis and high blood
  pressure.
• MAO (particularly type B) is also an enzyme that metabolises tyramine contained in ages cheese, beer,
  food and cured meat.
• Patients under treatment with selective MAO-A inhibitors (meclobemide and toloxatone) have no concerns
• MAO-B still available for the tyramine metabolism.
• Patients taking any of the non-selective MAOIs should not eat foods reported to contain substantial amount of tyramine.
• High levels of tyramine can cause a sudden, dangerous increase in your blood pressure, headache, palpitations -
  Tyramine syndrome/Cheese reaction
• Linezolid (oxazolidone antibiotic) and isoniazid (antitubercular drug) has some MAO inhibition properties.
  Action: Avoid foods and drinks with tyramine and foods with histamine with antidepressant drugs

Question 18

Food-drug interactions: Warfarin – vitamin K (green leaves)

Answer 18

• Vitamin K is vital for the formation of the clotting factors II,
  VII, IX and X, as well as the anticoagulant proteins C and S.
• Warfarin blocks the re-use of Vitamin K so the clotting
  pathway will be interrupted, leading to a reduction in blood
  coagulation (Vitamin K antagonist).
• Foods like beef liver, cabbage, kale, soybean oil, broccoli,
  collard greens, spinach, turnip greens, brussel sprouts,
  green tea, green leafy vegetables are high in vitamin K.
• They can reduce the effectiveness of warfarin
  (pharmacodynamic antagonism)
• Actions: increase the dosage requirement for warfarin or keep green vegetables intake under control, avoid sudden increase.

Question 19

Effect of drugs on appetite
Which drugs affect appetite?

Answer 19

• Non steroidal anti-inflammatory agents cause irritation of the upper GI
  mucosa and ulcers -> depression of appetite and weight loss.
• Chemotherapeutic anti-cancer agents can affect rapidly growing tissues
  (the lining of the GI) can cause nausea which interfere with eating.
• Antibiotic treatment can suppress commensal bacteria -> overgrowth of
  other organisms (Candida albicans) -> malabsorption and diarrhea in GI and
  candidiasis and oral thrush reducing oral intake.

Question 20

Some drugs may cause malabsorption of nutrients and induce nutrient
deficiencies in the long term

Answer 20

❖ Single or multivitamin deficiencies (e.g., vitamin D, B12)
❖ Mineral imbalances secondary to increased urinary excretion
❖ Complex nutrient deficiencies (e.g., folate)
❖ Slow and gradual storage deficiencies
It’s important to be aware of this problem especially in a long-term treatment

Question 21

Drug-induced nutrient deficiencies
Example: Folate malabsorption

Answer 21

• Dulcolax® (laxative)- decrease gastrointestinal transient time and cause pH alteration -> decrease absorption of dietary folate
• Sulfasalazine (for ulcerative colitis, Crohn’s disease and rheumatoid arthritis) interferes with folate absorption (interaction with intestinal proton-coupled high-affinity folate transporter) – not to take with meals!
• Antiprotozoals treatments (e.g., pentamidine - Pentam 300®) may require folate supplementation

Question 22

Drug-induced vitamin deficiencies:
Example: Vitamin B12

Answer 22

• Vitamin B12 (present in foods of animal origins) must be bound to intrinsic factor (IF) that is produced in the stomach and acid environment is required for the binding. H2 antagonists or proton pump inhibitors present the IF binding thus lowering B12 absorption.

Question 23

Drug-induced vitamin deficiencies:
Example: Vitamin D

Answer 23

• Rifampin (Rifamate®) used as antitubercular drug may induce a vitamin D deficiency.
• The drug induces CYP3A4, thereby increasing the catabolism of 25-
  hydroxyvitamin D and 1,25-dihydroxyvitamin D, lowering levels of available vitamin D.

Question 24

Drug-induced mineral imbalances:

Answer 24

Mineral imbalances can be caused by unbalanced urinary excretion
* Hypokalemia – reduced amount of potassium
* Loop diuretics (furosemide/Lasix®, bumetanide/Bumex®)
* Potassium wasting diuretics (e.g., Hydrodiuril®)
* ACTION: potassium supplements (potatoes, citrus fruits, and coffee)

• Hyperkalemia – high level of potassium
• Patients taking potassium-sparing diuretics should be monitored for high
  intakes of dietary potassium or use of potassium supplements.
• ACTION: avoid potassium supplements and potassium salt substitutes or
  potassium rich food

Question 25

Role of Pharmacist in prevention of Drug-Food Interactions?

Answer 25

• Be vigilant in monitoring for potential drug-food interactions
• Counselling patients on medicines
• Discussing with them food-drug interactions
• making recommendations
• medications need to be taken at different times relative to meals.
• consult a physician when health problems persist.
• Rapidly evolving field, some unknown mechanism, keep up-to-date on
  potential drug-food interactions of medications, especially today’s new
  drugs.

Question 26

1. Should I be concerned about chocolate and MAO inhibitors?
2. What type of food-drug interaction is this?
   Pharmaceutical interaction
   Pharmacodynamic interaction
   Pharmacokinetic interaction

Answer 26

1. Yes- possible interaction
2. Pharmacodynamic interaction