Levodopa + carbidopa and iron interactions

Levodopa + carbidopa and iron interactions are both complex and extensive. The theories for many of these interactions are speculative, and sustained with reasoned argument, however supporting evidence is very limited.

Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder that includes slow movements, rigidity and freezing, and sustained tremor. Dopamine deficiency is considered the main cause of PD however the causes of dopamine deficiency remain elusive.

The evidence that iron metabolism is dysregulated in PD is steadily increasing. Iron is an essential metal with multiple biological functions and is tightly regulated to minimise potential harm. Both inadequate and excessive intakes of iron cause profound negative impacts. Increased iron deposition in the brain’s substantia nigra is considered a likely cause of damage to critical dopaminergic neurons.

The mechanisms of action for levodopa + carbidopa and iron interactions include both direct and indirect interactions.

1. Direct interactions

Levodopa can chelate (bind) with metal ions such as iron to form very stable ring compounds. The chelated compound is ultimately excreted in the urine. As a chelated compound neither levodopa nor iron are available for therapeutic or biological functions.

Administer iron and levodopa interventions separately, including a 2-hour minimum gap, to minimise a potential drug-nutrient interaction.

2. Indirect interactions

a. Tyrosine hydroxylase (TH)

Dopamine production requires the rate limiting enzyme TH to facilitate the conversion of tyrosine to dopamine. TH requires iron (Fe 2+) as a cofactor and is regulated by a zinc-iron. Increasing zinc intake decreases iron availability which causes decreased TH activity and consequent decreased dopamine production.

Seemingly cobalt and nickel could also bind with TH and inhibit its activity.

Zinc depletion and iron enhancement achieve the same end result ie increased dopamine production. Consequently, dopamine production can be changed by altering availability of either iron or zinc. Some authors propose preferentially manipulating zinc status rather than manipulating iron levels as they acknowledge both iron’s -

   - short term benefit in raising dopamine levels, and

   - longterm risk of harm to dopaminergic neurons due to iron increasing reactive oxygen species (ROS) production.

Levodopa chelates both zinc and iron, however whether both metals are chelated equally does not appear to have been established.

b. Thiamine (B1)

Vitamin B1 deficiency disrupts the integrity of the blood-brain barrier (BBB), enabling iron to enter the brain in an uncontrolled manner.

Thiamine is also an ROS scavenger. Increased iron levels due to thiamine depletion further stimulate ROS production due to both –

   - increased iron availability, and

   - decreased thiamine availability.

Levodopa’s mechanisms of action on thiamine availability remain opaque.

c. Hyperglycaemia (excessive glucose availability)

Levodopa + carbidopa’s side effects include hyperglycaemia however the mechanism of action remains unclear.

1/. Ferritin

Hyperglycaemia is associated with –

• high serum ferritin concentrations,
• low soluble transferrin receptor-to-ferritin ratios.

Ferritin can be a marker of -

• tissue iron status,
• systemic inflammation.

Combining Diet History and presence/absence of inflammatory response markers will identify whether the recorded iron status reflects tissue status or inflammation.

2/. Pancreatic beta cells

High iron levels both enhance iron uptake and cause oxidative stress - beta cells are particularly sensitive to oxidative stress. Increased oxidative stress is associated with decreased insulin production and secretion.

Iron deficiency in beta cells results in decreased synthesis and processing of proinsulin and therefore reduced insulin is available.

Ultimately both high and low iron levels in beta cells result in decreased insulin production and secretion.

Iron status also impacts the coupling of insulin secretion to hyperglycaemia.

Clinical considerations

Both inadequate and excessive intakes of iron have profound direct and indirect negative impacts on a range of factors. Consequently, increased caution is essential when iron supplements are being considered.

Clinical questions

What actions will you initiate as you a review a person whose prescribed medications include levodopa + carbidopa, will you -

• recommend regular monitoring of a range of iron status markers?
• consider the negative impacts of other prescribed medications on iron and zinc levels, and ultimate impacts on dopamine status?
• factor in the effects of iron and hyperglycaemia when considering iron supplements?
• recommend the Medications Advisory Committee develop guidelines for iron supplement administration when levodopa + carbidopa is prescribed?

Conclusions

The levodopa + carbidopa and iron interactions are extensive and profound, and indicate caution is essential when considering iron supplements.

Case study

The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.

Data summary

Medical History with Nutritional Aspect

Biochemistry with Nutritional Aspect

Medications That May Adversely Affect Nutritional Status

Transporter-mediated interactions and nutrients

Biochemistry

Recent relevant available biochemistry indicates -

   - low albumin – primary carrier for 3 prescribed medications therefore advisable to monitor status and ensure improving;

   - adequate vit D - current intervention 50,000 IU/month. Increasingly the evidence is indicating vitamin D levels should be > 100 nmol/L to minimise non-bone health impacts. Advisable to monitor vitamin D management strategy on a regular basis;

   - low magnesium - there is now a recommendation that 0.80 mmol/L be the lower acceptable limit for magnesium therefore intervention recommended. Adequate magnesium status is essential for the activation of thiamine, vitamin C, vitamin D, iodide, and for carnitine production. Currently prescribed metformin which negatively impacts magnesium status on a ongoing basis. Advisable to consider a magnesium intervention and to monitor status on a regular basis;

Glycaemia

BSLs

   - before breakfast - 5.2-8.8; recommended range 4-6;

   - daily range - 5.2-10.8; recommended range 4-10;

   - tested daily bd;

   - reportable limits: < 4 and > 20 (Care Plan) and < 3 and > 28 (drug chart);

   - last HbA1c indicates good glycaemic control.

Diabetes drugs

   - glargine has a time to onset of one hour, minimal peak, and duration of 20-26 hours;

   - metformin has a duration of 12 hours.

Diabetes drugs coverage

   - before breakfast BSLs - minimal, if any, coverage from previous morning's glargine or metformin; minimal, if any, coverage from previous evening's metformin; covered by previous evening's glargine;

   - before evening meal BSLs - minimal, if any, coverage from previous evening's metformin; covered by previous evening's glargine and current morning's metformin.

Currently prescribed 3 medications that include hyperglycaemia as a side effect – olanzapine, metformin and rosuvastatin.

Pharmaconutrition

Currently prescribed medications side effects include -

   - 5 medications include constipation and nausea;

   - 4 medications include diarrhoea;

   - 3 medications altered taste side, and altered weight status effects;

   - 2 medications include hypercholesterolaemia, hypokalaemia, altered iron status, vomiting, and altered appetite status.

Calcium carbonate may impair iron absorption.

Clopidogrel and paracetamol are CYP1A2 substrates (can be carried by the transporter). CYP1A2 substrates include caffeine, retinol, melatonin, phosphatidylcholine, inhibitors include grapefruit juice and inducers include coffee; drug’s metabolism inhibited by caffeine therefore drug will remain active in the body for longer.

Coloxyl + senna may promote excessive loss of water and electrolytes, especially potassium and their regular monitoring recommended.

Coffee inhibits vitamin D uptake by osteoblasts (bone builders) by inhibiting their vitamin D receptors. As a consequence of inhibited vitamin D receptors calcium and zinc absorption is also impaired.

Metformin decreases B12, thiamine absorption, pyridoxine, folate, magnesium and zinc - there is now a recommendation that B12 status be monitored on a regular basis ie at least annually.

Dietary levels of caffeine intake in conjunction with paracetamol inhibit antinocieception.

Concurrent ingestion of paracetamol and iron resulted in increased rate of iron absorption and decreased extent of drug absorption; the authors advise drug and iron to be administered at different times from each other.

Currently prescribed rosuvastatin therefore advisable to monitor lipid levels. There is variability between pathology laboratories with regard to appropriate lower acceptable cholesterol level - some pathology ranges have set the lower acceptable limit at 3.5, others 3.0, and some do not set a lower limit. Cholesterol is important in brain structure and function amongst many other roles.

Statins interfere early in the cholesterol metabolic pathway and consequently decrease -

   - conversion of sun to vitamin D - vitamin D intervention recommended;

   - production of CoQ10 - important in cellular energy production; CoQ10 intervention recommended;

   - DHEA production - low DHEA associated with increased risk of metabolic syndrome; intervention recommended.

Bowel management

   Regular aperient prescribed.

   Oral + anal PRN interventions prescribed.

   No Nurse Initiated interventions administered.

Staff comments

Staff advise Mr ACZ is fully assisted with his meals, that he eats most of his meals most of the time, and that he really enjoys desserts; staff agree Mr ACZ could manage double desserts.

Observations

Mr ACZ is a pale frail man with a lovely smile and who was sitting in the Dining Room when I went to speak to him - he told me the food does not have much taste, that he sometimes feels upset in the tummy, and that he really likes ice cream.

Mr ACZ has been losing weight in the last 3 months which has been exacerbated by a hospital admission 3 months ago.

Pharmaconutrition comments

Since Mr ACZ has commented the food has minimal taste, advisable to -

   - review rosuvastatin prescription. Rosuvastatin's side effects include altered sense of taste and given there is an interrelationship between glycaemic control and lipid control, and since Mr ACZ has well-controlled glycaemia, advisable to consider a statin "holiday" until his appetite improves and he weighs at least 60 kg;

   - review metformin prescription. Metformin’s side effects include decreased appetite which can be a significant negative impact;

   - check zinc levels. Zinc is important in a range of body functions, including sense of taste and release of the hunger hormone Neuropeptide Y. Since Mr ACZ has lost weight, and is prescribed metformin, advisable to check zinc levels and if inadequate then consider a short term (90-120 days) intervention and recheck status prior to cessation of the intervention.

Since Mr ACZ has been prescribed metformin for at least 2 years, and likely before then, and given metformin is associated with depletion of B12 status, advisable to monitor B12 levels on a regular basis.

Chronic pain

Mr ACZ’s diagnoses include chronic pain - nutritional factors that may be useful to consider in pain management include

   - vitamin D - current intervention may not be adequate to attain adequate range. Evidence indicates increasingly brittle pain control with decreasing vitamin D levels.

   - vitamin C - pain increases the reactive substances (formerly Reactive Oxygen Species) within cells. Vitamin C is important in quenching reactive substances and if there is insufficient vitamin C then cell status becomes compromised and the cells typically die which also causes pain. Currently prescribed metformin therefore advisable to consider a vitamin C intervention. Vitamin C is not considered part of the pain management armament however it won't cause harm and evidence suggests it may confer benefit.

   - low B12 exacerbates elevated TNF- α which is an inflammatory response marker; elevation of the inflammatory response can include a pain response and currently prescribed metformin therefore advisable to check B12 status.

   - magnesium – proposed mechanism magnesium blocks the NMDA receptor channels in the spinal cord and thus limits the influx of calcium ie reduces the risk of excitotoxicity and consequent exacerbation of pain. Currently prescribed metformin and current status low therefore advisable to review current magnesium management strategies.

Strategies to improve insulin sensitivity

There are a number of nutritional interventions to improve insulin sensitivity or reduce insulin resistance including

   - magnesium – is important in glycaemic control and inadequate intake may impair insulin synthesis, secretion and signalling pathways; in fact there is evidence of an inverse correlation between magnesium status and diabetes incidence. Currently prescribed metformin which negatively impacts magnesium availability, and currently no intervention. Advisable to review status;

   - thiamine - people with diabetes have a significantly increased urinary excretion of thiamine; thiamine is important in glycaemic control; currently also prescribed metformin which further increases thiamine excretion;

   - TNF-α – evidence indicates TNF- α has systemic effects that result in insulin resistance and NIDDM; low B12 status exacerbates elevated TNF- α  and currently prescribed metformin therefore advisable to check B12 status;

   - zinc – is integral to insulin formation, and enhances insulin sensitivity through stimulation of insulin receptors; inadequate intake may impair insulin synthesis, secretion and signalling pathways. It is important in the glucose metabolism, protects the mitochondria from oxidative stress and glycation, and altered glomerular function, as well as modifying the inflammatory response pathway and activation of the polyol pathway (a part of intracellular signalling and metabolism) and currently prescribed metformin therefore advisable to check status.

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The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.