Drug nutrient interactions have been recognized for decades Drug-nutrient interaction is defined as an alteration of kinetics or dynamics of a drug

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1 Dr Lesley Braun PhD, BPharm, DipAppSciNat Senior Research Fellow Department of Surgery Monash University Honorary Senior Research Fellow Monash/Alfred Psychiatric Research Centre Research Pharmacist Alfred Hospital

2 Drug nutrient interactions have been recognized for decades Drug-nutrient interaction is defined as an alteration of kinetics or dynamics of a drug or a nutritional element, or a compromise in nutritional status as a result of the addition of a drug most of the known drug nutrient interactions involve changes in oral bioavailability but other mechanisms also exist.

3 Calcium + Tetracycline L- thyroxine Zinc + Tetracycline Iron + ACE inhibitors dec drug bioavailability dec drug bioavailability dec drug bioavailability dec drug bioavailability

4 1. Ex vivo inactivation E.g. Complexation upon physical contact Calcium and tetracyclines 2. Reduced absorption resulting in decreased bioavailability E.g PPI drugs and magnesium 3. Altered systemic disposition E.g. Changing tissue distribution or concentration at target site Vitamin K and warfarin 4. Altered elimination E.g. Impaired renal or enterohepatic elimination ACE inhibitors increasing urinary zinc elimination

5 1. Ex vivo inactivation E.g. Complexation upon physical contact Calcium and tetracyclines 2. Altered absorption resulting in decreased bioavailability E.g PPI drugs and magnesium 3. Altered systemic disposition E.g. Changing tissue distribution or concentration at target site Vitamin K and warfarin 4. Altered elimination E.g. Impaired renal or enterohepatic elimination ACE inhibitors increasing urinary zinc elimination

6 Drug-induced hypomagnesaemia related to proton pump inhibitor (PPI) therapy, recognised since 2006 Series of cases reported to TGA and FDA of serious hypomagnaesemia -> arrhythmias Mechanistic studies show omeprazole impedes Mg(2+) transport across the intestinal wall so less is absorbed Last year, the US FDA stated that information about the potential risk of low serum magnesium levels from PPIs will be added to the WARNINGS AND PRECAUTIONS sections of the labels for all the prescription PPIs FDA Internet site:

7 hypomagnesemia has been reported in adult patients taking PPIs for at least 3 months, but most cases occurred after a 1 year of treatment Of these, 75% found additional magnesium was sufficient to correct deficiency 25% also required discontinuation of PPI treatment + magnesium supplementation Rechallenge with PPIs induces hypomagnesaemia again within 2 wks. True class effect because substitution with different PPI drugs caused the same depletion effect

8 PPIs are among the most widely used classes of drugs in Australia, with more than 130 million prescriptions dispensed since The Medicines Safety Update volume 2 no. 3 on the TGA website ( omeprazole = Losec (R) esomeprazole = Nexium (R) pantoprazole = Somac (R) lansoprazole = Zoton (R)

9 1. Ex vivo inactivation E.g. Complexation upon physical contact Calcium and tetracyclines 2. Altered absorption resulting in decreased bioavailability E.g PPI drugs and magnesium 3. Altered systemic disposition E.g. Changing tissue distribution or concentration at target site Vitamin K and warfarin 4. Altered elimination E.g. Impaired renal or enterohepatic elimination ACE inhibitors increasing urinary zinc elimination

10 Over the last 3 decades clinical studies have been conducted with thiazide diuretics, frusemide, angiotensin converting enzyme (ACE) inhibitors (mainly captopril) and losartan evaluating their effects on zinc status as measured by plasma levels, red cell zinc, urinary zinc excretion and urinary zinc:creatine ratios.

11 Majority of clinical studies indicate Significantly increased urinary zinc losses with longterm captopril (Golick et al 1998; Abu-Hamdan et al 1998) and losartan (Loren-Michowitz et al 2005) Not seen with the enalapril sulphydryl groups present in the captopril molecule (but absent from enalapril) might be partly responsible for the observed hyperzincuria (Golick et al 1990) Lower plasma zinc with captopril (Abu-Hamdan et al 1988) Intracellular zinc levels decrease with captopril (Golick et al 1998) Impaired zinc absorption with perindopril (Tubek et al)

12 5. Reduced endogenous synthesis of nutrients E.g. Impaired Vitamin K synthesis by gastrointestinal flora due to antibiotic use E.g. CoQ10 and statin drugs

13 Coenzyme Q10 (CoQ10) is naturally occurring, fat-soluble quinone found in the lipophilic portions of all cellular membranes making it ubiquitous in the human body. Has an essential role in intracellular energy production within the mitochondria & ATP production. CoQ10 is also involved in cell signalling & gene expression the stabilization, fluidity and permeability of the cell membrane. protects the cell membrane from lipid peroxidation acts as an antioxidant, recycles and regenerates vitamins C and E

14 The main source of CoQ10 in humans is biosynthesis a complex process requiring at least seven vitamins (mostly B grp and C) and several trace elements. Most CoQ10 in human plasma is produced in the liver. Hepatocytes can efficiently synthesize CoQ10 via the mevalonate pathway Dietary CoQ10 is poorly absorbed in the small intestine The average Danish diet contains 3-5mg of CoQ10 daily

15 The distribution of CoQ10 in tissues is related to the lipid content & metabolic activity, with relatively higher concentrations found in the heart (~70 mg/kg wet weight), liver (~60 mg/kg) and skeletal muscle (~40 mg/kg) and low concentration in the blood (~1 mg/l).

16 Since 1990, statins were shown to reduce circulating blood CoQ10 levels in animal models. Statins block the production of mevalonate, which is the essential precursor to both cholesterol and CoQ10 With few exceptions, this observation has been confirmed in multiple observational studies and RCTs which demonstrate that statins reduce plasma/serum levels of CoQ10 by 16% to 54%

17 Deichmann et al. The Oschner Journal; 2010, 10(1), 16-21

18 it has been suggested that statin-induced decreases in blood CoQ10 levels are mainly due to decreased low-density lipoproteins (LDLs), as CoQ10 is transported by LDL cholesterol however... a decrease is also found in platelets & lymphocytes of statin treated patients, therefore it could truly depend on inhibition of CoQ 10 synthesis

19 Animal studies confirm that statins can reduce CoQ10 levels in cardiac muscle and liver however inconsistent results have been obtained in relation to skeletal muscle CoQ10 levels. In humans, the effect of statins on skeletal muscle CoQ10 appears to be drug and dose dependant E.g. high dose simvastatin (80mg/day), atorvastatin (40mg/day) or placebo over 8 weeks produced a 34% reduction in skeletal muscle CoQ10 after simvastatin use only

20 Alterations to skeletal muscle CoQ10 and associated mitochondrial dysfunction may be part of the aetiology behind statin-associated myalgia unlikely that decreased CoQ10 levels alone are sufficient to induce myalgia CoQ10 supplements inconsistent in reversing the effect more likely that CoQ10 concentrations become significant when other aetiological factors are also present E.g. pre-existing CoQ 10 deficiency as seen in the elderly and in those with pre-existing heart failure

21 Another concern is the effect of long-term statin use on CoQ10 concentrations within major body organs such as the brain and the potential consequences of depleted organ levels. E.g. Cognitive problems are also identified amongst patients reporting statin adverse events.

22 Brain tissue shares with muscle tissue a high mitochondrial vulnerability and both are the dominant organs clinically affected in CoQ10 deficiency mitochondrial syndromes. The brain has a high metabolic demand, accounting for approximately 20% of oxygen and 50% of glucose utilisation and high demand for cellular energy production. CoQ10 deficiency results in decreased mitochondrial activity & degradation, increased reactive oxygen species (ROS) and inflammation which can affect cognitive function

23 12 beagles to 13.2 years old Atorvastatin 80mg/d vs placebo for 14.5 mths Cognitive tests used to assess learning & memory After being euthanized, CoQ10 was extracted from both serum and parietal cortex Results: total serum CoQ10 was significantly reduced in statin treated dogs compared with controls lower levels of CoQ10 in the parietal cortex, but not serum, were associated with deficits in reversal learning ability no correlation between serum and parietal cortex CoQ10 levels Martin et al; Neuroscience Letters, Vol 501, Issue 2, 26 Aug 2011, Pgs 92-95

24 Need to establish Prevalence & severity of cognitive impairment due to high dose &/or long term statin use? What dose/time frame? Does oral dosing of CoQ10 increase CoQ10 levels in the brain? Optimal dose/time frame? Does oral CoQ10 attenuate cognitive impairments caused by statin use? Optimal dose/time frame?

25 Could drug induced nutrient depletion lead to Some drug side effects? E.g. Muscle soreness New symptoms? E.g. Impaired wound healing New risk factors? E.g impaired recovery after cardiac surgery? increased risk of arrhythmias? impaired QOL? E.g. memory People at greater risk Elderly - Less homeostatic reserve, compromised gastrointesinal/hepatic/renal function? Polypharmacy Inadequate diets - Poor starting nutritional status Co-morbidities e.g. Diabetes

26 Much focus in pharmacology rests on mechanisms of action responsible for wanted therapeutic effects Less attention on mechanisms behind unwanted side effects Drugs can compromise nutrient levels via multiple mechanisms Can this be easily and safely identified & rectified? Greater awareness of possible nutrient depletion could improve drug tolerance, prevent new problems Further investigation is required to work out optimal clinical approaches to prevent drug-nutrient interactions

27 ACE-Inhibitors and zinc status Antibiotics and probiotics Statins and CoQ10 PPIs and magnesium

28 1.Magnesium Magnesium (Mg) is the fourth most abundant cation in the body, with 50 60% sequestered in the bone, the remainder distributed equally between muscle and non-muscular soft tissue. Only about 1% of total body Mg is found in the extracellular fluid. Dietary intake, renal and intestinal function finely balance and maintain plasma Mg concentrations

29 salts of high solubility having the most complete absorption (e.g. magnesium citrate) Magnesium absorption requires selenium, parathyroid hormone and vitamins B6 and D and is hindered by phytate, fibre, alcohol, excess saturated fat and the presence of unabsorbed fatty acids, high phosphorous

30 Good dietary sources of Mg include legumes, wholegrain cereals, nuts, dark green leafy vegetables, cocoa, soy flour, seeds, nuts, mineral water and hard water. Healthy people absorb 30 40% of ingested Mg; increasing to 70% bioavailability in cases of low intake or deficiency While serum testing is still frequently performed, it is only indicative of severe depletion, as evidenced by values <0.75 mmol/l and while some studies demonstrate a correlation between these values and the Mg content of other tissues, many do not

31 Deficiency signs and symptoms: many deficiency symptoms are also due to alterations in potassium and/or phosphorus status and manifest as neurological or neuromuscular symptoms.

32 anorexia and weight loss, nausea and vomiting, muscular weakness and spasms, numbness, tingling, cramps Lethargy, difficulty remembering things, apathy and melancholy, confusion, depression, mental confusion, decreased attention span and poor concentration, personality changes, hyper-irritability and excitability dysregulation of biorhythms (some sleep and mental health disorders including insomnia). vertigo cardiac arrhythmia, tetany and ultimately convulsions can develop if deficiency is prolonged.

33 RDIs Men: years: 400 mg/d. >30 years: 420 mg/d. Women: years: 310 mg/d. >30 years: 320 mg/d Therapeutic doses vary from mg/daily Safety: Adverse effects: most common adverse effects of oral supplements are diarrhoea (18.6%) and gastric irritation (4.7%). Dividing total daily supplemental amounts over 2 3 separate doses may help to reduce this risk and maximise bioavailbility. Caution: Magnesium supplementation is contraindicated in renal failure and heart block (unless a pacemaker is present).

34 Intestinal absorption of CoQ10 is enhanced when taken with food and in divided doses Serum level tests by ARL approx $70 ea Does not necessarily correlate with tissue levels but gives an indication of compliance and bioavailability Dose range : mg/day Safety : no significant interactions or side effects

35 The human body contains approximately 2 g zinc in total, distributed across all body tissues and fluids, with 60% found in skeletal muscle and 30% in bone mass Dietary intake of zinc by healthy adults is 6 15 mg/d, however, less than half of this is absorbed

36 Foods with high phytate content significantly reduce zinc absorption due to the formation of strong and insoluble complexes e.g. whole grains, seeds and nuts, is reported to render the zinc virtually unobtainable calcium in large amounts constitutes the main antagonistic mineral interaction and therefore, calcium-rich diets may also precipitate zinc deficiency. Alternatively, the amount of animal protein in a meal positively correlates to zinc absorption and the amino acids histidine and methionine, and various organic acids present in foods, such as citric, malic and lactic acids, can also increase absorption. As such, zinc, similarly to iron, is best absorbed from animal food sources

37 Food sources: Meat, liver, eggs and seafood (especially oysters and shellfish) are the best sources. Also miso, tofu, mushrooms, brewers yeast While zinc is also found in nuts, legumes, whole grains and seeds, the high phytate content of these foods render them an inferior source Supplemental forms: Zinc sulfate and gluconate are the most commonly used

38 According to a large national survey of over 29,000 people conducted in the USA, only 55.6% had adequate zinc intakes (based on total intakes of >77% of the 1989 US RDI levels). The clinical picture of mild zinc deficiency is subtle, ambiguous, idiosyncratic and notoriously difficult to diagnose

39 Most consistently reported: Anorexia, impaired sense of taste and smell. Slowed growth and development. Delayed sexual maturation, hypogonadism, hypospermia and menstrual problems. Dermatitis, particularly around the body's orifices Alopecia Chronic and severe diarrhoea. Immune system deficiencies and increased susceptibility to infection, including bacterial, viral and fungal. Impaired wound healing due to decreased collagen synthesis. Night blindness; swelling and clouding of the corneas. Behavioural disturbances such as mental fatigue and depression

40 RDI for Adults Males >19 years: 14 mg/d. Females >19 years: 8 mg/d. Therapeutic doses ~ 30mg elemental Zn daily Safety Adverse effects: Mild gastrointestinal distress has been reported at doses of mg/d of supplemental zinc Toxicity: Signs of toxicity are nausea, vomiting, diarrhoea, fever and lethargy and have been observed after ingestion of 4 8 g zinc according to a 2002 WHO report. Single doses of mg of zinc usually induce vomiting Doses of zinc ranging from 100 to 150 mg/d interfere with copper metabolism and cause hypocuprinaemia, red blood cell microcytosis and neutropenia if used long term.

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