Synergies between micronutrients and medicines

The globally rising need for and use of medicines continues unabated. In the context of an ever widening range of medicinal therapies and a constantly growing number of pharmaceutical substances, interactions between bioactive substances are very significant. In the past, interactions between drugs and micronutrients received little attention in pharmaceutical and medical practice, but now medication-induced disturbances of micronutrient status are leading to a number of undesirable pharmacological effects. More-over, concomitant food intake can reinforce or diminish the bioavailability and effect of a pharmaceutical substance. In some cases, synergistic effects can arise from interactions between pharmaceuticals and micronutrients: micronutrients may complement medicinal treatment and enhance its effectiveness or reduce potential side-effects.

Fat-soluble vitamins

An adjunctive effect of vitamin D has been described for a number of medications. One example is statins, which inhibit the enzymes that synthesize cholesterol (CSE inhibitors) and hence are used to lower cholesterol levels. Excessively high blood levels of cholesterol represent a significant risk factor for atherosclerotic thickening of the arterial walls, which can lead to cardiovascular diseases, heart attack, or stroke with the risk of fatal consequences. Studies have shown that concentrations of more than 30 ng/mL 25­OH­vitamin­D3 in the blood increase and broaden the cardioprotective effects of CSE inhibitors (3, 4). It has also been reported that undesirable effects of statins could be reduced by concurrent administration of vitamin D (5, 6). Vitamin D also appears to be able to prevent cardiovascular events like sudden heart failure, heart attack or stroke by lowering elevated levels of triglycerides and parathyroid hormone. High parathyroid hormone levels raise blood pressure and promote hardening of the arterial walls and heart valves, as well as cardiac arrhythmias (7–9).

In addition to lowering high blood lipid values, combating high blood pressure – hypertension, the cause of around 7 million deaths globally – is one of the challenges faced in preventing atherosclerotic cardiac and vascular complaints. One of the most important blood-pressure-regulating systems of the body is the renin-angiotensin-aldosterone system, a feedback loop of several hormones and enzymes which essentially con-trol the body’s salt and water balance. The enzyme renin activates the substance angiotensin I, which in turn is converted into angiotensin II by the mediation of the angiotensin-converting enzyme (ACE). Angiotensin II triggers a rise in blood pressure by narrowing arterioles (vasoconstriction) and increasing the retention of salt and water in the blood. The rate of angiotensin II synthesis is dependent on renin. Research with mice has shown that vitamin D3 lowers the strength of expression of the gene for renin through its interaction with the vitamin D receptor and hence could lower blood pressure by blocking the renin-angiotensin system (10, 11). Since over-activity of the renin-angiotensin system is considered to be an important factor in many forms of hypertension, a sufficiently high level of vitamin D may be important for the prevention of high blood pressure. A vitamin D status of 32–64 ng/mL 25­OH­D in plasma can optimize blood pressure regulation in hypertensive patients and reduce the need for blood-pressure-lowering medications – although it cannot replace them entirely (12, 13).

Glucocorticoids are widely used to treat patients with bronchial asthma, a complex inflammatory disease of the airways sometimes caused by an allergic reaction which is increasingly common around the world, especially among children. Glucocorticoids have, inter alia, anti-inflammatory and anti-allergic properties. However, they weaken the immune system and with long-term use can increase the risk of osteoporosis by disturbing vitamin D3 and bone metabolism. The anti-inflammatory effect of vitamin D3 appears to be able to reduce the organism’s burden of pro-inflammatory substances, such as histamine, and help regulate the balance of certain immune defense cells. Studies have shown that dietary supplementation with vitamin D3 as an adjunct to anti- asthmatic treatment can reduce the need for medication (14). Furthermore, adminis-tration of vitamin D3 can reduce the risk of corticoid-induced osteoporosis while improving the rate of response to the medication (15).

In addition, supplementary intake of vitamin D3 has been associated with an improved effect and reduction in side-effects of bisphosphonates used to treat osteoporosis. Nitrogen-containing bisphosphonates demon-strate a high affinity to the bone’s mineral substance and can effectively inhibit the demineralization of bone by osteoclasts. Vitamin D3 ensures the absorption of calcium into the bones, blocks the production of parathyroid hormone and hence osteoclastic bone demineralization, and promotes muscle strength and function, thus helping prevent falls and fractures. In addition to these activities, which support the effects of medication, adequate blood levels of vitamin D may reduce the occurrence of side-effects such as bisphosphonate-associated atypical fractures and osteonecrosis of the jaw (16–20).

Additionally, dietary supplementation with vitamin K can promote the effectiveness of bisphosphonates by aiding bone mineralization with calcium and inhibiting bone loss (21, 22).

The ability of vitamin D to improve immune defense also appears to be beneficial in tuberculosis therapy. Tuberculosis (TB) is an infectious disease caused by several species of mycobacterium which, in humans, primarily affect the lungs. The rapid development of resistance among these organisms to the substances used to treat the disease is making it harder to fight.  For 2008 the WHO reported 9.27 million cases of tuberculosis worldwide (around 1.8 million of which were fatal), with numbers rising in developed countries, too – especially among children (23). Vitamin D3-induced synthesis of antimicrobial peptides is crucial to unspecific immune defense in fighting the tuberculosis bacteria. Vitamin D improves anti-mycobacterial immunity and synergistically accelerates the cure of tuberculosis through anti-tubercular drugs (24, 25).

Rheumatoid arthritis is an inflammatory disease that affects various joints and can eventually destroy them. It affects around 1% of the general population – mainly women in developed countries. The disease can be controlled by anti-inflammatory and analgesic medication like diclofenac, ibuprofen, or indometacin. The anti-inflammatory action of these substances may be enhanced by adjunctive administration of vitamin E. Inflammation is associated with oxidative processes. Vitamin E seems to reduce the oxidative stress that is part of the inflammatory process in the joint and to help regulate metabolism of pro-inflammatory arachi-donic acid (26, 27). Hence vitamin E can allow for a reduction in the dose of medication (28). Moreover, it increases the gastric tolerance of diclofenac and may reduce a potential side-effect, the occurrence of stomach ulcers.

Water-soluble vitamins

According to WHO estimations, by 2020 various forms of depression will be the second most common diseases in modern industrial nations, after cardiovascular diseases (29). Patients with typical depression (major depression), which proceeds in phases, often have low plasma levels of folic acid and respond less well to antidepressants than patients with normal folic acid levels (30). Very low concentrations of folic acid, vitamin B6 or vitamin B12 in the cells of the body can have negative effects on the methylation cycle, an essential metabolic process in the synthesis of neurotransmitters like serotonin, the lack of which is thought to be a possible trigger for depression. Adjunctive treatment with folic acid accompanying therapy with selective serotonin reuptake inhibitors (SSRI) such as fluoxetine has been associated with improved efficacy of the medication (31). Moreover, combined administration of folic acid with vitamins B6 and B12 improved the response rate of SSRI, while folic acid deficiency impaired the efficacy of SSRI (32, 33).

Positive effects of vitamin B3 (niacin) on blood lipid values have been reported: Niacin can raise HDL-cholesterol in the blood and lower triglycerides. In this way, this B­vitamin strengthens and extends the lipid-lowering and cardioprotective properties of statins (CSE inhibitors) used to lower cholesterol levels and other blood lipids (34, 35). Further, the vasodilatory properties of niacin can be used to support the effect of beta-blockers in the treatment of hypertension (36).

Beta-blockers are used not only to lower blood pressure but also to prevent migraines. Their effect can be enhanced by adjunctive administration of vitamin B2, which increases energy metabolism in brain mitochon-dria (37,38).

Minerals and trace elements

Magnesium plays a crucial role in the body’s production of energy and ensures the healthy functioning of nerves and muscles. Because magnesium can have a positive influence on mitochondrial metabolism and the utilization of oxygen by the brain and nerve cells, like vitamin B2 it is used as an adjunct to the prophylactic treatment of migraine with beta-blockers (39).

Hyperactivity and attention deficit disorders (ADHD) are among the most common neurocognitive disorders of childhood in Western industrialized nations. The symptoms of ADHD (hyperactivity, impulsiveness, inat-tentiveness) are very similar to those of magnesium deficiency. Studies indicate that magnesium may play a role in ADHD or that magnesium deficiency may be one cause of it. Since a disturbance in neurotransmitter metabolism is suspected of being a cause of ADHD, the active substance methylphenidate, one of the amphetamines, is used to treat affected children. This psychostimulant influences the neurotransmitters norepinephrine and dopamine at the synapses of the nerve cells and lessens children’s restlessness. Magnesium improves the availability of neurotransmitters and can therefore enhance the activity of methylphenidate (40, 41).

Zinc, too, influences the availability of various neurotransmitters. It harmonizes signal transmission in neurotransmitter metabolism, supports neuronal energy metabolism and can ameliorate hyperkinetic behavioral disorders such as impulsiveness and hyperactivity in ADHD patients (42). Supplementary administration of zinc can therefore improve the efficacy of methylphenidate and in some cases make it possible to reduce the dose of medication (43).

Chronic inflammatory diseases like bronchial asthma, rheumatoid arthritis, Crohn’s Disease, chronic ob-structive pulmonary disease (COPD) or atopic dermatitis require long-term treatment with corticosteroids. Because of their potential side-effects (e.g. steroid osteoporosis) it is desirable to keep their dosage as low as possible. Administration of selenium in parallel can reduce the need for corticoids, since this trace element also has anti-inflammatory and immunomodulatory effects (44, 45). Adjunctive intake of selenium can also enhance the effect of the thyroid hormone levothyroxine (L-thyroxine), which is used to treat hypothyroidism, and may reduce the amount of the drug needed (46).

Essential fatty acids

The essential omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) possess anti-inflammatory and immunomodulatory properties which make it likely that they will have synergistic effects with various pharmaceuticals. Studies have shown that they can reduce the therapeutically required dose of anti-asthma drugs (47). This applies in particular to the corticosteroid class of substances which are used not only to treat asthma but also for rheumatoid arthritis and other chronic inflammatory diseases (48, 49).

DHA and especially EPA can also enhance the efficacy of antidepressants, since they modulate the metabo-lism of neurotransmitters in the central nervous system, increase the neuronal bioavailability of the chemical mediator serotonin, improve the physical properties of the nerve cell membranes and can improve mood (50–52).

Not least because of their function as regulators of neuronal glucose utilization, EPA and DHA may support the effects of psychostimulants (e.g. methylphenidate) in the treatment of hyperkinetic behavioral disorders (ADHD) and reduce their side-effects (53, 54).

Moreover, EPA and DHA are taken as an adjunct to anticoagulants such as warfarin or phenprocuomon (dicumarol-type anticoagulants). The anticoagulant properties of omega-3 fatty acids can reduce the need for medication to protect the blood vessels against thromboses and to thin the blood (55).

Furthermore, EPA and DHA can help lower blood cholesterol levels, enhance the effects of statins and hence help reduce the risk of heart attack (56, 57).

Coenzyme Q10

As a substrate of the mitochondrial respiratory chain, coenzyme Q10 can improve brain mitochondrial energy metabolism and hence optimize the efficacy of beta-blockers in prophylactic migraine therapy (58).

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