Download Interactions in Clinical Practice: Drug

Interactions in Clinical Practice:
Drug-Supplement, Drug-Nutrient
Leo Galland, M.D.
Applied Nutrition, Inc.
www.nutritionworkshop.com
Overview
Of almost 900 drugs and fixed-drug
combinations used in the U.S.:
• Almost 400 may deplete specific nutrients.
• Over 400 may interact with food or food
components.
• Over 300 have been shown to interact with
dietary supplements, with adverse and
beneficial interactions equally common.
Types of Interactions
• Pharmacodynamic: two substances exhibit
pharmacologic actions that reinforce or
interfere with each other’s actions.
• Pharmacokinetic: the absorption,
distribution, excretion or enzymatic
transformation of one substance is altered
by another. Most adverse interactions are of
this type.
Pharmacokinetic Mechanisms
• Alteration of gastrointestinal or urinary pH.
• Stimulation, induction or inhibition of
enzymes involved in biotransformation or
transport of drugs or nutrients .
• Displacement of a drug from binding to
plasma proteins.
• Alteration of solubility.
Effects of Interactions
• Nutrient depletion: Individual nutrients may have
their dietary requirement increased by specific
drugs (or supplements).
• Adverse: A specific supplement may undesirably
decrease or increase the effect of a drug or
supplement being taken.
• Beneficial: Drugs (or supplements) may have their
actions enhanced or side effects diminished by
specific supplements.
Drug-Induced Nutrient Depletion
• About half the drugs used in clinical
practice have documented nutrient depleting
effects.
• Co-enzyme Q10, folic acid, B2, B6, Mg, Zn
are nutrients most likely to be depleted.
• Mechanisms include impaired absorption or
bioactivation; increased excretion.
Co-enzyme Q10 Depletion
• Statin-induced co-Q depletion impairs
mitochondrial function, raising the serum
lactate/pyruvate ratio. Simvastatin but not
atorvastatin depletes myofibrillar co-Q.
• Supplemental co-Q, 100 mg/day, prevents the
decline in serum co-Q levels without impairment
of the lipid-lowering effect of statins and may
reverse symptoms of statin myopathy.
Co-enzyme Q10 Depletion
(cont’d)
• Statin-induced Co-Q depletion is increased by
vitamin E (700 IU/day).
• Co-Q is consumed in recycling tocopheryl
quinones back to tocopherols.
• Thiazides, some beta-blockers and many older
psychotropic drugs have been shown to interfere
with co-Q dependent enzymes, creating a possible
need for co-Q supplementation in patients
receiving them.
Are reported adverse
cardiovascular effects of vitamin
E supplements related to co-Q
depletion in patients taking drugs
that interfere with co-Q
synthesis or co-Q dependent
enzymes?
Vitamin E and Statins
• a-Tocopherol prevents statin benefits in
people with low HDL-C and normal TC.
• Related to tocopherol inhibition of statininduced elevation of HDL2-C.
• Selenium (100 mcg/day) and fish oil have
the opposite effect.
• a-Tocopherol depletes gamma-tocopherol
by competitive binding to transport protein.
Clinically Significant Depletions-1
• Adriamycin depletes co-enzyme Q10.
Cardiotoxicity is reduced by co-Q and
proprionyl-L-carnitine.
• Cisplatin depletes Mg. Nephtrotoxicity is
reduced by i.v. and oral Mg (160 mg tid).
• Thiazides and 5-ASA derivatives deplete
folate, raising homocysteine concentration.
Clinically Significant Depletions-2
• Loop diuretics increase excretion of K, Ca,
Mg, Zn, B1, B6, C. Correcting B1 deficit
improves cardiac function of CHF patients.
• Cephalosporins (parenteral) can deplete
vitamin K2, causing hemorrhage.
• Steroids deplete Ca and Mg, causing bone
loss. Reversible with calcium and vit D3.
Antiretroviral Nutrient Depletion
• AZT depletes muscle carnitine and
increases lymphocyte apoptosis. Reversed
with carnitine supplementation.
• AZT is associated with decreased serum
zinc and copper; zinc 200 mg/day reduced
Candida and Pneumocystis infections in
patients taking AZT.
Phenytoin-induced Depletions
• Phenytoin may deplete biotin, folate,
thiamine, vitamin D (causing hypocalcemia
and osteomalacia and vitamin K.
• Memory impairment is associated with
reduced RBC folate. Folic acid, 1 mg/day,
prevents deficiency without adversely
affecting phenytoin metabolism.
Valproic Acid Depletions
• Valproate depletes carnitine, raising
ammonia; reversed with carnitine 2 g/day.
• Valproate acid lowers serum folate and P5P,
raising homocysteine; reversed with 400
mcg folate, 120 mg B6 and 75 mg B2.
• Valproate inhibits biotinidase. Biotin 10
mg/day reverses valproate-associated hair
loss and dermatitis in children.
Chelation and Drug Absorption
• Chelation by minerals impairs absorption of
quinolone or tetracycline antibiotics,
thyroid, bisphosphonates, L-DOPA, some
ACE inhibitors.
• Even some herbs like dandelion and fennel,
can be so rich in minerals that they inhibit
absorption of these same drugs.
.
The Cytochrome P450 System and
Drug-Supplement Interactions
• Expressed chiefly in liver, intestines, lungs
and kidneys (“Phase 1 detoxication”).
• 20 different human CYPs, grouped by
amino acid homology, not by function.
• CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1 and CYP3A4 most important for
oxidation of drugs, xenobiotics.
CYP1A2
• Liver only. Inactivates caffeine and
bioactivates aromatic and heterocyclic
amines; large inter-individual differences
(up to 100-fold). Induced by char-broiled
meat, cigarettes, pollutants, dioxins and
cruciferous vegetables.
CYP2: Drug-Drug Interactions
• CYP2C9 accounts for 30% of CYP activity in
human liver. May be modified by Ginkgo biloba.
• CYP2C19 is primarily hepatic. Phenotype reflects
the interaction of 8 gene alleles.
• CYP2D6 is extra-hepatic. Bioactivates
codeine/codones. 55 alleles.
• CYP2E1 in liver, lung, brain metabolizes organic
solvents like ethanol. Induced with chronic
ethanol use, fasting, obesity. Inhibited by acute
alcohol intake, tea, broccoli, garlic, onion,
watercress.
CYP3A4
• Liver and small intestine.
• Transforms about 50% of common drugs.
• Induced by St. John’s wort (liver, intestine)
and Echinacea (liver only).
• Inhibited by peppermint oil and piperine.
• Intestinal but not liver CYP3A4 is inhibited
by grapefruit juice, Seville orange juice and
Echinacea.
CYP3A4 and St. John’s Wort
• CYP3A4 stimulation by St. John’s wort
reduces blood levels of benzodiazepines,
calcium channel blockers, anti-retrovirals,
estrogens (including OCPs), amitriptyline,
cyclosporine, methadone, tacrolimus and
possibly warfarin.
Intestinal CYP3A4 Inhibition
• Increases blood levels of amiodarone,
artemisinin, atorvastatin, buspirone,
carbemazepine, cyclosporine, diazepam,
diltiazem, erythromycin, estradiol,
felodipine, fentanyl, fluoxetine, lovastatin,
methyl-prednisolone, nifedipine,
nimodipine, praziquantel, saquinavir,
sertraline, sildenafil, simvastatin, verapamil
P-glycoprotein Transporter (P-gp)
• Ejects xenobiotics from cells and causes
backflow of some drugs from intestinal
mucosa into the lumen.
• Produces multi-drug resistance to cancer
chemotherapy.
• Inhibited by piperine, milk thistle and
acutely by St. John’s wort.
• Stimulated by continued St. John’s wort.
Alteration of Intestinal CYP3A4
and/or P-glycoprotein
• Often involves the same substrates.
• Primarily effects drugs that pass slowly
through intestinal mucosa.
• Interactions in vivo may not be predicted by
interactions in vitro.
Adverse Pharmacodynamic
Interactions
•
•
•
•
•
•
5-HTP and SSRI’s
Licorice and horsetail, diuretics or laxatives
Phenylalanine or kava and neuroleptics
Bee venom and ACE inhibitors
Brewer’s yeast and MAO inhibitors
Interferon-alpha and bupleurum
Antithrombotic Interactions
• 35 natural products inhibit platelet function
in vivo following oral use. They may
reinforce each other or interact with
antithrombotic medication.
• Aspirin-vitamin E interaction: aspirin
inhibits platelet aggregation; vitamin E
inhibits platelet adhesion to endothelium.
Aspirin-Vitamin E Interactions
• a-Tocopherol (50 IU/day) raised risk of gingival
bleeding 25% among ASA users.
• 400 IU/day a-tocopherol added to 325 mg
ASA/day reduced incidence of TIAs compared to
aspirin alone.
• Vit E 50 IU/day, decreased ischemic stroke by
30% but increased hemorrhagic stroke by 145% in
hypertensive, non-diabetic male smokers. In
diabetics, there was no increase in hemorrhagic
stroke and ischemic stroke decreased by 70%.
Warfarin Interactions
• 49 natural products may interfere with
warfarin; 21 confirmed, 28 possible.
• Herbal coumarins might compete for
binding to plasma protein, increasing
plasma free warfarin concentration.
• Controlled studies found no effect on
vitamin E or coenzyme Q10 on INR of
patients taking warfarin.
Beneficial Drug-Supplement
Interactions
• Reflect additive/complementary effects of
supplements and drugs, or amelioration of
toxic drug effects by supplements.
• Fish oils enhance anti-inflammatory,
antiarrhythmic, anti-lipemic, antidepressant,
and neuroleptic drugs, beta-blockers,
lithium and insulin. EPA and DHA may
have differential effects.
Acetaminophen Toxicity
• Protective supplements:
N-acetyl cysteine (clinical use)
L-methionine and SAMe
Milk thistle
Andrographis
Schisandra
ASA/NSAID Gastropathy
• Protective supplements (human trials):
Vit C (500-1000 mg bid)
SAMe 500 mg/day
Cayenne 20 grams
Deglycyrrhizinated licorice 350 mg tid
Colostrum 125 mg tid
Neuroleptic Side Effects
• Protective supplements:
Vitamin E 1200-1600 IU/day (T.D.)
Branched chain amino acids (T.D.)
Ginkgo biloba 350 mg/day
Sarcosine (N-CH3-glycine) 2 gm/day
Eicosapentaenoate (EPA) 2 gm/day
Glycine 0.4-0.8 mg/kg/day
Cisplatin Toxicity
• Protective supplements:
Bismuth 150 mg/kg/day X 10days
Ginkgo bilomba 100 mg/kg single dose
Glutathione 5 gm i.v.
MgSO4 3 gm i.v./ Mg 160 mg tid
Silibinin 200 mg/kg i.v. single dose
N-acetyl cysteine 8 gm/day
Selenium 4000 mcg/day X 8 days
Vitamin C 50-200 mg/kg i.v. single dose
Vitamin E 300 IU/day till 3 months post-chemotherapy
More Antineoplastic Toxicity
• Protective supplements
Vitamin B6 50 mg tid
Glutamine 30 gm/day
Melatonin 20 mg HS
Coriolus versicolor 1 gm tid
Theanine (in vitro)
Inositol hexaphosphate (IP6) (in vitro)
Calcium D-glucarate (in vitro)
Fish oils, NSAIDs, ASA
• 2600 mg of EPA + DHA for 3 months allow
NSAID reduction in rheumatoid arthritis.
Plasma phospholipid EPA must reach 5%.
• Fish oil 30 ml/day reversed ASA’s increase
of LTB4 synthesis; no hemorrhage.
• ASA increases synthesis of antiinflammatory resolvins and protectins from
DHA in vitro by acetylating COX-2.
Conclusion
• Almost half the drugs commonly used in the
US may deplete specific nutrients, creating
a need for nutritional supplementation.
• Adverse interactions have received
extensive press coverage.
• Beneficial drug-supplement interactions are
at least as important and permit creative
nutritional therapies.