dr lesley braun - imer group

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

Drugndashnutrient 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 drugndashnutrient interactions involve changes in oral bioavailability but other mechanisms also exist

Calcium +

Tetracycline dec drug bioavailability

L- thyroxine dec drug bioavailability

Zinc +


Iron +

ACE inhibitors dec drug bioavailability

1 Ex vivo inactivation Eg Complexation upon physical contact Calcium and tetracyclines

2 Reduced absorption resulting in decreased bioavailability Eg PPI drugs and magnesium

3 Altered systemic disposition Eg Changing tissue distribution or concentration at

target site Vitamin K and warfarin

4 Altered elimination Eg Impaired renal or enterohepatic elimination

ACE inhibitors increasing urinary zinc elimination

1 Ex vivo inactivation Eg Complexation upon physical contact

Calcium and tetracyclines 2 Altered absorption resulting in decreased

bioavailability Eg PPI drugs and magnesium





Drug-induced hypomagnesaemia related to proton pump inhibitor (PPI) therapy recognised since 2006 Series of cases reported to TGA and FDA of serious

hypomagnaesemia -gt 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 httpwwwfdagovDrugsDrugSafetyucm245011htmData_Summary

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

PPIs are among the most widely used classes of

drugs in Australia with more than 130 million prescriptions dispensed since 1992

The Medicines Safety Update volume 2 no 3 on the TGA website ( httpwwwtgagovauhpmsu-2011-03htmrisk)

omeprazole = Losec (R) esomeprazole = Nexium (R) pantoprazole = Somac (R) lansoprazole = Zoton (R)








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 zinccreatine ratios

Majority of clinical studies indicate Significantly increased urinary zinc losses with long-

term 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)

5 Reduced endogenous synthesis of nutrients

Eg Impaired Vitamin K synthesis by gastrointestinal flora due to antibiotic use

Eg CoQ10 and statin drugs

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 amp ATP production

CoQ10 is also involved in cell signalling amp 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

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

The distribution of CoQ10 in tissues is related to

the lipid content amp metabolic activity with relatively higher concentrations found in

the heart (~70 mgkg wet weight) liver (~60 mgkg) and skeletal muscle (~40 mgkg) and low concentration in the blood (~1 mgL)

Since 1990 statins were shown to reduce circulating blood CoQ10 levels in animal models

Statins block the production of lsquomevalonatersquo 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 plasmaserum levels of CoQ10 by 16 to 54

Deichmann et al The Oschner Journal 2010 10(1) 16-21

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 amp lymphocytes of statin treated patients therefore it could truly depend on inhibition of CoQ10 synthesis

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 Eg high dose simvastatin (80mgday) atorvastatin

(40mgday) or placebo over 8 weeks produced a 34 reduction in skeletal muscle CoQ10 after simvastatin use only

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 Eg pre-existing CoQ10 deficiency as seen in the elderly and in

those with pre-existing heart failure

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

Eg Cognitive problems are also identified amongst patients reporting statin adverse events

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 amp degradation increased reactive oxygen species (ROS) and inflammation which can affect cognitive function

12 beagles - 89 to 132 years old Atorvastatin 80mgd vs placebo for 145 mths Cognitive tests used to assess learning amp 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

Need to establish Prevalence amp severity of cognitive impairment

due to high dose ampor long term statin use What dosetime frame

Does oral dosing of CoQ10 increase CoQ10 levels in the brain Optimal dosetime frame

Does oral CoQ10 attenuate cognitive impairments caused by statin use Optimal dosetime frame

Could drug induced nutrient depletion lead to Some drug side effects Eg Muscle soreness New symptoms Eg Impaired wound healing New risk factors Eg impaired recovery after cardiac

surgery increased risk of arrhythmias impaired QOL Eg memory

People at greater risk Elderly - Less homeostatic reserve compromised

gastrointesinalhepaticrenal function Polypharmacy Inadequate diets - Poor starting nutritional status Co-morbidities eg Diabetes

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 amp 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

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

1Magnesium Magnesium (Mg) is the fourth most abundant

cation in the body with 50ndash60 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

salts of high solubility having the most complete absorption (eg 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

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 30ndash40 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 lt075 mmolL and while some studies demonstrate a correlation between these values and the Mg content of other tissues many do not

Deficiency signs and symptoms

many deficiency symptoms are also due to alterations in potassium andor phosphorus status and manifest as neurological or neuromuscular symptoms

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

RDIs Men 19ndash30 years 400 mgd gt30 years 420 mgd Women 19ndash30 years 310 mgd gt30 years 320 mgd Therapeutic doses vary from 200-600mgdaily Safety Adverse effects most common adverse effects of oral supplements are

diarrhoea (186) and gastric irritation (47) Dividing total daily supplemental amounts over 2ndash3 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)

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 100-300mgday Safety no significant interactions or side effects

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 6ndash15 mgd however less than half of this is absorbed

Foods with high phytate content significantly reduce zinc absorption due to the formation of strong and insoluble complexes eg 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

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

According to a large national survey of over 29000 people conducted in the USA only 556 had adequate zinc intakes (based on total intakes of gt77 of the 1989 US RDI levels)

The clinical picture of mild zinc deficiency is subtle ambiguous idiosyncratic and notoriously difficult to diagnose

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 bodys 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

RDI for Adults Males gt19 years 14 mgd Females gt19 years 8 mgd

Therapeutic doses ~ 30mg elemental Zn daily

Safety Adverse effects Mild gastrointestinal distress has been reported at doses of 50ndash

150 mgd of supplemental zinc Toxicity Signs of toxicity are nausea vomiting diarrhoea fever and lethargy

and have been observed after ingestion of 4ndash8 g zinc according to a 2002 WHO report Single doses of 225ndash450 mg of zinc usually induce vomiting

Doses of zinc ranging from 100 to 150 mgd interfere with copper

metabolism and cause hypocuprinaemia red blood cell microcytosis and neutropenia if used long term

Drugndashnutrient 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 drugndashnutrient interactions involve changes in oral bioavailability but other mechanisms also exist

Calcium +



Zinc +


Iron +






















































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dr lesley braun - imer group

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