01 - Nutritional Pharmacology (1).pdf

Naturopathic Nutrition Year 2 Nutritional Pharmacology © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 1  Learning Outcomes In this lecture you will learn: Drug restrictions, administration and metabolism. Side effects of drugs. Drug-nutrient interactions....

Naturopathic Nutrition Year 2 Nutritional Pharmacology © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 1  Learning Outcomes In this lecture you will learn: Drug restrictions, administration and metabolism. Side effects of drugs. Drug-nutrient interactions. Drug-induced nutrient depletions. Major groups and actions of pharmaceutical drugs. Pharmaceuticals and the nutrition consultation. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 2  Nutritional Pharmacology Nutritional therapists need to know about a drug’s side effects and interactions: Clients often use a range of complex prescription and over-the-counter drugs. Every drug produces side effects e.g., gastric ulceration when taking ibuprofen. Food or supplements may interact with a drug producing unwanted effects e.g., increased bleeding risk with warfarin and vitamin E. Drugs can lead to important nutrient depletions e.g., metformin and vitamin B12. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 3  MHRA = Medicines & What is a Medicine? Healthcare Products Regulatory Agency A medicine is normally defined by a country’s regulatory body and the following is an example from the UK MHRA body: “Any substance or combination of substances presented as having properties for treating or preventing disease in human beings.” “Any substance or combination of substances which may be used in, or administered to, human beings, either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.” (MHRA, 2020) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 4  Drug Restrictions Drugs are governed by a number of regulatory restrictions: Intended mode of action — all drugs must have a regulatory licence. How they are supplied — supply route. ‒ Prescription only (POM) — supplied only under direction of qualified healthcare professional e.g., doctor’s prescription. ‒ Controlled medicines — special group of medicines that require extra controls e.g., codeine, morphine. ‒ Pharmacy only (PO) — sold by a registered pharmacy ‒ General sales list (GSL) — can be sold via a number of outlets including supermarkets. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 5  OTC = over OTC Drugs the counter OTC drugs are products that are used to self-medicate a range of common illnesses: They are generally classified by the legal distinction: ‒ PO — sold and supplied under pharmacist supervision. ‒ GSL — general sales list supplied by a pharmacy and many non-pharmacy outlets e.g., grocery store. Clients may choose to self-medicate in order: ‒ To treat a minor ailment e.g., a cough mixture. ‒ To support a chronic illness when not fully controlled by prescribed medicines e.g., ibuprofen for osteoarthritis. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 6  OTC Drugs It is important to recognise common OTC drugs as they can contribute to significant side effects and drug-nutrient interactions. The availability of OTC drugs will vary by country: Analgesics (codeine, paracetamol, aspirin, ibuprofen). Laxatives (bisacodyl, senna). Proton pump inhibitors (omeprazole). Cough mixtures (diphenhydramine). Anti-histamines (chlorphenamine, cetirizine). Decongestants (pseudoephedrine). © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 7  What do Drugs Contain? A drug contains both active and inactive ingredients: Active ingredient: This is the part of the drug that is intended to deliver its mode of action and is responsible for side effects e.g., ibuprofen to reduce inflammation. Inactive ingredients: These alter the physical properties of the drug e.g., fillers, colouring agents, preservatives, lactose, gluten, aspartame, other E numbers. Studies increasingly show that inactive ingredients can trigger allergic reactions and food intolerances. (Reker et al. 2019) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 8  Drug Naming A number of terms are used to describe the presentation of a drug: Generic name: This is the actual active ingredient within the drug e.g., paracetamol (Europe), acetaminophen (US). Paracetamol and acetaminophen are, in fact, the same active ingredient. Brand name: Paracetamol can be provided under a number of branded names e.g., Panadol (UK), Tylenol (US). Always check: A nutritional therapist must always look for the generic name. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 9  Drug Resources Each country normally provides a comprehensive drug resource outlining all necessary information about drugs: Nutritional therapists should make themselves aware of such reference resources. Most drug resources are now online and often free. UK-BNF — The British National Formulary www.bnf.org Ireland — Medicine Database www.medicines.ie USA — Drugs.com www.drugs.com Check what resources are available in your country! © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 10  Drug Terminology It is important to understand terms that are used in drug resources: Drug class: Penicillin is an antibiotic. Indication: What the drug is intended for, e.g., hypertension (high blood pressure). Contraindication: When the drug must not be used e.g., in pregnancy, renal failure. Side effects: Ibuprofen can produce gastric ulcers. Interactions: A drug’s activity is affected by another substance causing an increase, decrease or a new effect. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. (Russell, 2001) 11  Drug vs Nutrient? Drugs suppress and manage symptoms: They do not target the actual underlying cause! Nutrients encourage the body to restore homeostasis and heal. Consider the following scenarios: ‒ Paracetamol to manage ongoing tension headache when the client is clearly stressed. ‒ Topical corticosteroid for atopic eczema that flares in a child with intestinal dysbiosis. ‒ Laxatives to manage constipation in a client with low stomach acid and digestive enzymes. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 12  Drug vs Nutrient? Drugs suppress symptoms and can cause side effects. Nutrients aim to restore balance and heal the body! Many drugs are derived from plant sources e.g., aspirin, but research and pharmaceutical companies extract what is considered important and then process to a marketable potent drug. This completely ignores the plant’s overall benefit as a ‘whole unit’ which relies upon all of its constituent parts. It also gives rise to significant side effects! © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 13  Drug vs Nutrient? Aspirin is derived from willow bark (Salix alba) an ancient herb. Let’s consider the difference! Willow bark contains salicin, which does not convert to salicylic acid (a gastric irritant) until it reaches the bloodstream and body tissues. It naturally reduces fever, inflammation and pain without GI side effects. Through research, aspirin was synthetically developed from salicylic acid. Aspirin can cause gastrointestinal bleeding, peptic ulceration and hypersensitivity! Willow bark contains numerous active components which influence each other and in totality contribute to its overall healing potential. (Chen et al. 2014; Cryer & Mahaffey, © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 2014; Lemmon & Roseen, 2018) 14  Important Drug Concepts As nutritional therapists, we must appreciate a number of important concepts in relation to drugs: Movement of drugs within the body — pharmacokinetics. How drugs interact with the body to exert their effect — pharmacodynamics. Recognising and understanding side effects. The importance of drug-nutrient interactions. Common drug-induced nutrient depletions. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 15  What is Pharmacokinetics? Pharmacokinetics is the study of the movement of drugs within the body: An easy way to remember this concept is to think of the word ‘kinetics’ meaning movement. This movement can be timed. Pharmacokinetics is, therefore, the timed movement of any drug going into, through and out of the body. It involves four key processes: Absorption, distribution, metabolism and elimination (ADME). © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 16  ADME — A Basic Overview ADME refers to the absorption, distribution, metabolism and excretion of a drug: A. To exert its action (or toxicity) internally, a drug must first enter the body and be absorbed into the bloodstream. D. In the bloodstream, the drug can now be distributed to its target site (normally a receptor) to exert its action. M. Once the drug and receptor have interacted, the drug returns to the bloodstream and progresses to the liver to be metabolised and then eliminated from the body. E. Once metabolised, excretion normally takes place via urine or bile. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 17  hepatic First Pass Hepatic Metabolism = liver First pass metabolism ― the process by which drugs taken orally are absorbed from the GIT and taken via the portal vein into the liver to be metabolised. The effects of this mean that drug concentrations can be reduced by the time they enter systemic circulation: When a drug is extensively metabolised, the amount of drug reaching the bloodstream is greatly reduced and cannot exert its effect. This type of medicine should be administered by a different route e.g., nitro glycerine (GTN) spray for angina. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 18  Drug Administration Two main factors determine whether a drug reaches its target site of action in the body: Bioavailability — this simply refers to the ‘proportion’ of drug that can reach the bloodstream and is, therefore, available for distribution to its intended site of action. Route of administration — how a drug is administered e.g., oral tablets, sublingual B12, suppository, injectables, topical creams, patches, all directly influence the medicine’s bioavailability. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 19  Drug Administration Drugs can be administered via a number of routes: Oral: Tablets, capsules, liquids: ‒ Absorption is mainly via the small intestine. Sublingual / buccal: ‒ Sublingual / buccal: e.g., glyceryl trinitrate spray. ‒ Bypasses liver metabolism. Topical: ‒ Local effect: Creams, patches, ear and eye drops. ‒ Systemic effect: Inhalation (rapid effects). Parenteral: ‒ Injections: Intravenous, sub-cutaneous, intra-muscular. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 20  Factors Affecting Absorption Related to the body: Gastro-intestinal motility: Diarrhoea increases motility and reduces absorption. Malabsorption states reduce absorption e.g., Coeliac disease. Presence of other substances: E.g., absorption of iron is reduced when given with milk. Related to the medicine: Absorption is greatest for lipid soluble and small molecule drugs. Acidic drugs absorb quicker in an acidic environment e.g., stomach. A liquid medicine will absorb quicker than a solid tablet. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 21  Drug Distribution After a drug enters the systemic circulation, it is distributed to the body’s tissues. The distribution of a drug is affected by a number of factors: – Binding to plasma proteins which affects the active concentration of the drug. – Binding to other tissues e.g., tetracycline (antibiotic) binds to calcium in bones and teeth. – Accumulation in lipids e.g., general anaesthetics. – Natural barriers to distribution e.g., blood brain barrier, placental barrier. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 22  Drug Metabolism Drug metabolism ― the process by which drugs are chemically changed from a lipid soluble to a more water-soluble form suitable for excretion: Phase I: Drug / toxin is altered chemically to make it suitable for Phase II reactions or for excretion. Involves the cytochrome P450 enzyme family. Phase II: Molecules from Phase I (or in some cases unchanged drugs) are conjugated to a more water-soluble product and aid excretion. The rate of metabolism varies widely between individuals, influenced by genetic and environmental factors. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 23  Drug Excretion Drug excretion ― the process by which drugs and their metabolites are removed from the body: Main excretion routes: Urine, faeces. Minor excretion routes: Exhaled air, sweat, saliva, tears. Renal excretion is the normal route for elimination of small water-soluble molecules. Renal dysfunction can, therefore, affect the rate at which a drug / metabolite is cleared from the body. Some drugs (very lipid soluble) may be re-absorbed and re-enter the portal vein. This is known as ‘entero-hepatic circulation’ and prolongs excretion times. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 24  What Affects Pharmacodynamics? Pharmacodynamics is the study of how drugs interact with the body to exert their effects: Factors affecting a drug’s mode of action include advancing age, genetic mutations, malnutrition, medical conditions e.g., Parkinson’s disease, Alzheimer’s disease. Together pharmacokinetics and pharmacodynamics provide information about a drug’s: ‒ Mode of action and administration route. ‒ Dosage (incl. knowledge of toxic doses). ‒ Side effects and drug interactions. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 25  Drug Side Effects All drugs can produce unwanted side effects: Side effects are unpleasant, unwanted effects of a drug. They range from mild to severe and in some cases life-threatening. Categorised by occurrence e.g., very common, common, uncommon or rare. Side effects often affect a patient’s quality of life. It is important to consider that a client’s presenting signs and / or symptoms could be due to a drug’s side effects. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 26  Drug Side Effects The most commonly experienced short-term side effects are: Nausea and vomiting. Headache. Dizziness. Constipation. Diarrhoea. Indigestion. Skin rashes. Dry mouth. Insomnia. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 27  Drug Side Effects The longer a drug is prescribed, the higher the risk of long-term side effects. These include: Nutrient deficiencies e.g., metformin and B12 deficiency. Metabolic effects e.g., omeprazole and hypomagnesaemia. Dependence e.g., diazepam, opiate analgesics (codeine). Osteoporosis e.g., corticosteroids. Gout e.g., thiazide diuretics. Cardiovascular disease e.g., diclofenac (NSAID). Peptic ulceration e.g., NSAID. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 28  The Proton Pump Inhibitor (PPI) Prescribed for over 30 years and heralded globally as a safe drug, studies now clearly demonstrate that this is not the case! PPIs are associated with a number of long-term worrying and serious side effects: Bone fractures. Hypomagnesaemia (low blood magnesium). Vitamin B12 deficiency. Bacterial enteric infections e.g., serious Clostridium difficile. Rebound acid hypersecretion (when PPI is stopped). Kidney disease. Dementia. (Eusebi et al. 2017; Naito et al. 2018; Savarino, 2018) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 29  Diclofenac — Why? NSAIDs are commonly used to manage pain and reduce inflammation: It was widely accepted that diclofenac (NSAID) increased the risk of cardiovascular events yet the product was commonly prescribed by medical doctors. Following clinical trials, guidance advice eventually changed in 2013 to contraindicate the use of diclofenac in patients with established ischaemic heart disease, peripheral artery disease, cerebrovascular disease. OTC sales via pharmacies are still permitted (with restrictions)! © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. (BMJ, 2018; Schmidt et al. 2018) 30  Drug Side Effects As a nutritional therapist, if you suspect that a client is experiencing side effects: Check the presenting sign / symptom against the drug in your selected resource e.g., the BNF. Advise the client to consult his / her GP or medical specialist. Ensure that the food or supplement that you recommend does not interact with the client’s drug which could then cause side effects. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 31  Summary Quiz 1. Why do nutritional therapists need to know about pharmacology? 2. What do drugs contain? 3. Compare the use of willow bark and aspirin. 4. Briefly outline what is meant by ADME. 5. Explain how the cytochrome P450 system affects drugs (HINT: Phase 1 drug metabolism). 6. Name TWO factors that can affect the absorption of a drug. 7. Give ONE long-term side effect of taking corticosteroids. 8. List FOUR side effects of taking PPIs. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 32  Drug Interactions An interaction occurs when the effects of one drug are altered by the co-administration of another substance. Other substances can include: St John’s wort Drugs. Herbal medicines. Food and drinks. Nutritional supplements. See the ANP interactions checker: Environmental chemical agents. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 33  Drug Interactions Nutritional therapists should exercise caution for certain groups of drugs to minimise interactions: Narrow Therapeutic Index (NTI) drugs: ‒ Drugs that may become dangerously toxic or ineffective with only relatively small changes in their blood concentrations. ‒ Examples: Digoxin, phenytoin, theophylline, warfarin, lithium. ‒ During a consultation it is essential that these medicines are clearly highlighted on case notes. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 34  Drug Interactions The risk of drug interactions increases with the number of drugs used (polypharmacy) and this can place certain patient populations at increased risk of serious side effects: Patients experiencing renal and liver dysfunction (metabolism and excretion of drugs!). Elderly patients who take more medicines and whose renal and liver function is declining. Patients taking drugs for chronic long-term illnesses e.g., same patient has epilepsy, diabetes and cardiovascular disease (think of the number of drugs administered!) Critically-ill patients. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 35  Drug — Nutrient Interactions A comprehensive resource for checking herb and nutrient interactions with pharmaceutical drugs is available through The ANP (Association of Naturopathic Practitioners): Access to this database is FREE to ANP members. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 36  Drug — Nutrient Interactions Garlic: Interactions have been reported with cholesterol and blood pressure drugs, such as atorvastatin, propranolol, hydrochlorothiazide or captopril. Garlic could theoretically interact with anticoagulant or antiplatelet drugs, but current evidence has shown that at 4g / day it has little effect on warfarin-stabilised patients. Garlic interspersed throughout the diet is okay, but regular, high dietary intake and / or supplements could allow for interactions. (Asdaq & Inamdar, 2011; © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. Reddy et al. 2012) 37  Drug — Nutrient Interactions Ginkgo: Should be avoided with any antiplatelet and anti-coagulant medication, as it has a small potential to increase bleeding risk. It should be stopped one week before surgery. Due to possible CYP induction, it is best to monitor with the following drugs: Benzodiazepines (sedatives), anti-epileptic medication, anti- psychotic drugs, diabetic drugs, HIV medications, omeprazole (for gastrointestinal reflux), nifedipine and talinolol (blood pressure drugs). (Sierpina et al. 2003) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 38  Drug — Nutrient Interactions Grapefruit: Selectively inhibits CYP3A4 in the intestinal wall for up to 24 hours, but NOT in the liver. Caution is advised with the many drugs that are metabolised via this pathway ― e.g., digoxin, statins. CYP 3A4 is involved in the metabolism of over 50% of all drugs. Pomegranate: Similar interactions to grapefruit. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 39  Drug — Nutrient Interactions Green vegetables: Large amounts of green vegetables such as broccoli, spinach, cabbage, Brussels sprouts, seem to reduce the effect of anticoagulants such as warfarin. They contain indoles which increase the metabolism of warfarin, and also contain vitamin K, which reduces the anti-clotting effects of warfarin. Vitamin K is a coagulant, whilst warfarin is an anti-coagulant. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 40  Drug — Nutrient Interactions Soy: Soy decreases absorption of levothyroxine: Separate ingestion by three hours. Soy may also interfere with oestrogen-blocking drugs such as Tamoxifen, due to its isoflavone (phytoestrogen) content (both positive and negative effects observed). Soy may reduce the effectiveness of warfarin. Dairy produce / calcium: Calcium can bind to antibiotics like the quinolones and tetracycline, and also bisphosphonates reducing their absorption; reduces levothyroxine absorption (take four hours apart). (Dixon, 2014; Georgetown University Medical Center, 2017) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 41  Effects of Different Diets Dramatic changes in diet can also affect medication. Examples: High protein diets may reduce the effects of theophylline (appears to increase renal clearance) and L-Dopa (decreases intestinal absorption and interferes with transport from the bloodstream to the brain). High-fibre diets can reduce serum levels of tricyclic antidepressants e.g., amitriptyline (decreases intestinal absorption ― take medication away from high-fibre meals). Salt restriction can increase serum lithium to toxic levels (sodium is involved in active transport of lithium, low levels can cause lithium to accumulate in cells). (Juan et al. 1986; Stewart, 1992; Timmer & Sands, 1999; Gonzalez Canga et al. 2010; Wang et al. 2017) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 42  Drug — Nutrient Depletions Nutrient depletion by drugs: Some medications can affect levels of nutrients in the body. Here are some of the most notable interactions: Drug: Nutrients affected: Mechanism: Proton Pump Beta-carotene, calcium Reduced gastric Inhibitors chromium, iron, magnesium, acid levels inhibit (Omeprazole): folate, vit. B12, vit. C, zinc. absorption. Steroids Calcium, vit. D, chromium, Increase urinary (Prednisolone): folic acid, magnesium, excretion, losses potassium, strontium, zinc. from bone tissue. (Caniggia, 1981; Heidelbaugh, 2013) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 43  Drug — Nutrient Depletions Drug: Nutrients affected: Mechanism: Statins: CoQ10 Block synthesis of mevalonic acid, which is a precursor of cholesterol and coenzyme Q10. Antibiotics: Biotin, pantothenic acid Destruction of normal (B5), pyridoxine (B6) intestinal microflora may lead riboflavin (B2), to decreased production of thiamine (B1), vit. B12, various B vitamins and vit. K. vitamin K. Metformin: Vitamin B12, folate. Malabsorption of B12 and B9. (Nawarskas, 2005; Deichmann et al. 2010; De Jager et al. 2010; Aroda et al. 2016; Langdon © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. et al. 2016; Kim et al. 2019) 44  Drug — Nutrient Depletions Drug: Nutrients affected: Mechanism: Diuretics: Calcium, magnesium Increased urinary loss. potassium, folate, vits. B1, B6, C. Antacids: Calcium, Increased gastric pH may reduce iron, solubility and absorption. Aluminium- chromium, containing antacids can bind to folate. calcium preventing absorption. Thyroxine: Calcium. Increased bone turnover may lead to increased urinary calcium losses. (Suter & Vetter, 2000; Sica, 2007; © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. Ross, 2021) 45  Drug — Nutrient Depletions Drug: Nutrients Mechanism: affected: Oral Folate Reduced absorption, increased contraceptive Magnesium excretion, increased protein binding pill: Vitamin B6 and induction of liver enzymes. Shift from plasma to tissues. Reduced Vitamin B2 absorption or interference with Vitamin B1 conversion to active form. Vitamin A Reduction in activity of the thiamine- Vitamin B12 dependent enzyme. Reduced liver Vitamin C storage of vit. A. Reduced B12 protein binding. Increased requirement. Zinc © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. (Palmery et al. 2013; Wakeman, 2019) 46  Alcohol and Drugs Alcohol can inhibit a drug's metabolism by competing with the drug for the same set of metabolising enzymes: Long-term alcohol ingestion may activate drug-metabolising enzymes, thus decreasing the drug's availability and diminishing its effects. Enzymes activated by chronic alcohol consumption transform some drugs into toxic chemicals that can damage the liver or other organs. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 47  Alcohol and Drugs Alcohol can magnify the inhibitory effects of sedative and narcotic drugs at their sites of action in the brain (codeine, morphine, fentanyl): Some drugs affect the metabolism of alcohol, thus altering its potential for intoxication and adverse effects: e.g., cimetidine (reduces stomach acid) appears to inhibit the enzyme needed to break down alcohol (alcohol dehydrogenase). Alcohol can also force certain drugs (slow-release ‘depot’ injections) out of their depot (storage in muscle) resulting in overdose; this can happen with some antipsychotic drugs. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 48  Exercise: Case Questions Case scenarios: 1. Mark is 58 and taking metformin for Type 2 diabetes. How might this medication contribute to him feeling fatigued? 2. Carol is taking a statin for hypercholesterolaemia. She read online that grapefruit juice should be avoided with statins. Explain the reason for this. 3. Derek is taking warfarin after suffering from a DVT 4 years ago. What should Derek pay attention to in his diet, to avoid possible drug interactions? © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 49  Pharmaceutical Drugs Here we discuss commonly-used drugs. This list is not exhaustive and it is important to have access to an up-to-date drug resource: ACE inhibitors. SSRIs. Statins. Antihistamines. Diuretics. NSAIDs. Digoxin. Corticosteroids. Thyroid PPIs / antacids. replacement Anti-coagulants hormones. e.g., warfarin. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 50  ACE Inhibitors / Angiotensin II Antagonists Prescribed for: Heart failure, hypertension: ACE inhibitor examples: Ramipril, lisinopril, captopril. Angiotensin II antagonist examples: Losartan, candesartan. Contraindications: Pregnancy / breastfeeding, previous allergic reaction to ACE inhibitor. Common side effects: Hyperkalaemia, postural hypotension, constipation, diarrhoea, nausea, vomiting. Specific side effects: ACE inhibitors cause a persistent dry cough (due to rise in bradykinin) and angioedema. Avoid potassium-rich diets if not taking a drug which lowers potassium alongside (e.g., a thiazide or loop diuretic). © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 51  Statins Prescribed for: Hypercholesterolaemia (incl. familial), hypertriglyceridemia, prevention of cardiovascular events in those with atherosclerotic disease or diabetes: Examples: Simvastatin, Atorvastatin, Pravastatin, Rosuvastatin. Mode of action: Competitively inhibits HMG CoA reductase — an enzyme involved in cholesterol (and COQ10) synthesis. Contraindications: Pregnancy, breastfeeding, liver disease. Caution: High alcohol intake, liver disease history. Side effects: GIT disturbance, headaches, fatigue, insomnia, myositis (inflammation of muscles), statin-induced myopathy. (Nawarskas, 2005; © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. Deichmann et al. 2010) 52  Statins Statins (cont.): Statin use can lead to rhabdomyolysis — the breakdown of muscle cells. This can result in kidney disease and even failure. Extra care needed with foods / supplements that may interfere with metabolism. Interactions: Important interactions with other drugs, so do check your medicine resources! Grapefruit juice / pomegranate juice: Significantly increases GI absorption of CYP3A4 substrates and increases peak levels of statins. This combination should be completely avoided. (Harper & Jacobson, 2011; Hanley et al. 2011) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 53  Statins Statins (cont.): Nutrient depletion: CoQ10 (watch for muscle pain / fatigue). Co-administration: Often prescribed alongside other drugs for the prevention of cardiovascular events. Important to check if your client is taking any other medication. Red yeast rice: A combination of mevinic acids and derivatives e.g., monacolin K (identical to the active in Lovastatin), and other constituents that exhibit cholesterol lowering activity. Combining with statins may increase overall side effects. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 54  Diuretics Prescribed for: Oedema due to heart failure, hypertension: Examples: Furosemide (loop diuretic), bendroflumethiazide (thiazide diuretic). Spironolactone (potassium-sparing diuretic). Mode of action: Inhibit reabsorption of filtrate from various sections of the nephron (i.e., increased urine output), decreasing blood volume and pressure. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 55  Diuretics Diuretics (cont.): Contraindications: Metabolic imbalances (hypokalaemia, hyponatraemia, hypercalcaemia), Addison’s disease. Caution: Exacerbates diabetes, gout and SLE. Elderly are susceptible to side effects! Taraxacum officinalis Side effects: Hypokalaemia (can be — (dandelion) dangerous), hypotension, GIT disturbance, Acts as a diuretic but impotence. Milk-alkali syndrome may occur also supplies potassium when thiazides are combined with large (the leaf), unlike most pharmaceutical diuretics. quantities of calcium carbonate! © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 56  Digoxin Prescribed for: Atrial fibrillation, heart failure: Mode of action: Increases force of myocardial contraction and reduces conductivity within the atrio-ventricular node. Contraindications: Heart block, ventricular tachycardia. Caution: Hypokalaemia and low blood magnesium can increase the risk of toxicity from digoxin! Side effects (usually in overdose): Nausea, vomiting, diarrhoea, loss of appetite, abdominal pain, visual disturbance, arrhythmias. The elderly are especially susceptible to side effects. Interactions: Hawthorn can increase myocardial contraction. Concomitant use may require digoxin’s dose to be reduced. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. (Dahmer & Scott, 2010) 57  Antacids Prescribed for: Gastro-oesophageal reflux Do you think disease (GORD), indigestion: aluminium intake is safe? Examples: Calcium carbonate, magnesium, aluminium. Mode of action: Neutralisation: acid + base = water + salt. Cautions: Low gastric HCl. Overuse can result in a rebound effect if the drug is discontinued (the acid comes back more strongly). Side effects: Impaired nutrient absorption; magnesium versions can be laxative, aluminium versions can be constipating. (Reinke et al. 2003) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 58  Antacids Antacid medication (cont.): Marshmallow Interactions: Vit. D may ↑ aluminium absorption if taken at the same time. Alternatives: Diet and lifestyle changes: Chew food well, fluids away from meals; demulcent / anti-inflammatory herbs ― aloe vera juice, slippery elm, liquorice, marshmallow root; avoid caffeine, lose weight if needed, stop smoking; manage stress e.g., breathing exercises to support a shift into a parasympathetic state. Nutritional therapists can provide immense support in GORD! © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 59  Proton Pump Inhibitors (PPIs) Prescribed for: Gastro-oesophageal reflux disease (GORD), prevention of NSAID-associated ulcers, triple therapy with antibiotics for gastric / duodenal ulceration: Examples: Omeprazole, lansoprazole, esomeprazole. Mode of action: Blocks gastric cells proton (hydrogen) pump. Cautions: Liver disease, pregnancy, breast-feeding, gastric cancer (masks symptoms). Side effects: Headache, GI disturbances, rebound gastric hypersecretion and heartburn after discontinuation of drug. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 60  Proton Pump Inhibitors (PPIs) Key long-term side effects: Increased risk of GI infections (e.g., Clostridium difficile) and SIBO. Alkaline gastric pH allows bacterial survival. Increased fracture risk: Reduced calcium absorption leads to decreased bone mineral density, possible inhibition of osteoclast activity. Vitamin B12 deficiency: Gastric acid is needed for release of vit. B12 from proteins to help intestinal absorption. Low blood magnesium due to decreased intestinal absorption. Also reduced iron absorption (= possible iron deficiency anaemia). © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. (Nehra et al. 2018; Savarino, 2018) 61  PPI Withdrawal for GORD PPI withdrawal depends upon several factors including the dose and duration of treatment. Sudden withdrawal may cause rebound reflux. The 5R approach supports clients to reduce and withdraw from PPIs over a period: Remove: ‒ Remove trigger foods (acidic — tomatoes, alcohol, caffeine, spicy food, fatty foods, dairy, chocolate). Identify and manage any food intolerances e.g., gluten. Stop smoking. ‒ Avoid overeating, avoid fluid intake with meals — also to reduce stomach distension. Eat last meal at least 4 hours before bed. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 62  PPI Withdrawal for GORD PPI withdrawal (cont.): Remove (cont.): – Prone position ― elevate head of bed by 4‒6 inches. – Reduce intra-abdominal pressure — weight loss / avoid tight-fitting clothes. Replace (introduce): ‒ Increase nutritious foods to replace deficiencies e.g., magnesium rich. Clients may also need supplementation B12, magnesium, Vitamin A (introduce a general multivitamin and mineral). ‒ Digestive enzymes / betaine HCl / digestive bitters. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 63  PPI Withdrawal for GORD PPI withdrawal (cont.): Slippery elm contains mucilage, Repopulate: which can reduce the absorption ‒ Introduce probiotics — some of oral drugs and decrease their clients may suffer from SIBO effectiveness. Therefore, you after long-term acid suppression. should take slippery elm at least one hour after taking an oral drug. Repair: – To protect and repair the gut lining ― use slippery elm, marshmallow, chamomile, glutamine. Rebalance: – Reduce and manage stress — acupuncture, aerobic exercise (not following meals). Stress is a key trigger. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 64  Anti-coagulants: Warfarin Prescribed for: DVT, pulmonary embolism, transient ischaemic attacks: Examples: Warfarin is the most common anti-coagulant prescribed. Mode of action: Antagonises the effects of vitamin K — a co-factor for the production of four clotting factors. Contraindications: Haemophilia, cerebral thrombosis, peptic ulcers, hypertension, pregnancy. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 65  Anti-coagulants: Warfarin Warfarin (cont.): INR = International Normalised Ratio – a Cautions: Surgery, Liver / Kidney measure of how long impairment, breastfeeding. it takes the blood to clot. Side effects: Haemorrhage is the worrying side effect! Interactions: Major changes in diet (salads / green vegetables) and alcohol consumption can affect anticoagulant control. Pomegranate juice increases the INR by inhibiting the CYP450 enzyme that metabolises warfarin. High doses of vitamin E inhibit platelet aggregation and should be avoided with warfarin. (Jarvis et al. 2010; Pastori et al. 2013) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 66  Thyroid Hormones: Levothyroxine Prescribed for: Hypothyroidism: Examples: Levothyroxine. Mode of action: Lifelong replacement. Contra-indications: Thyrotoxicosis. Cautions: Elderly, cardiovascular disorders. Side effects: Headache, insomnia, tremor, anxiety, flushing. Dosing: The dose should be taken 30–60 minutes pre-breakfast or caffeine-containing liquids to avoid reduced absorption. Interactions: Oral iron and calcium supplements (and cow’s dairy) reduce the absorption of levothyroxine. It is important that doses are separated by at least four hours. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 67  Exercise: Antihistamines 1. Using a drug resource identify: ONE sedating anti-histamine. ONE non-sedating anti-histamine. 2. Identify TWO side effects (not drowsiness) of a sedating anti-histamine. 3. Anti-histamines are used to treat allergies e.g., hayfever. List ONE alternative approach to managing hayfever. 4. Name ONE phytonutrient that also has anti-histamine properties. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 68  Antidepressants — SSRIs Prescribed for: Depressive illness, post-traumatic SSRIs = Selective Serotonin Re- stress, obsessive compulsive disorder: uptake Inhibitors Examples: Sertraline, citalopram, fluoxetine. Mode of action: Selectively inhibit the re-uptake of serotonin (5-hydroxytryptamine, 5-HT). Contraindications: Poorly-controlled epilepsy. Side effects: GIT disturbance, constipation, diarrhoea, insomnia, anxiety, agitation, sexual dysfunction, reduced appetite. SSRIs should never be stopped abruptly! They should be tapered over a few weeks or longer under medical supervision to prevent withdrawal syndrome. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 69  Serotonin Syndrome The serotonin syndrome is associated with an excess of serotonin due to therapeutic drug use, overdose or interactions between drugs: Although rare, it can be fatal. It can occur when two or more drugs affecting serotonin are given at the same time or after one serotonergic drug is stopped and another started. Special care is needed when switching from an SSRI to an MAOI (mono amine oxidase inhibitor) or vice versa. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 70  Serotonin Syndrome The serotonin syndrome (cont.): Symptoms include confusion, disorientation, exaggerated reflexes, abnormal movements, fever, sweating, hypo / hypertension. Two important supplements: 5-HTP and St. John’s wort must not be combined with SSRIs as the additive effect significantly increases the risk of serotonin syndrome. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 71  NSAIDs Prescribed for: Pain relief, inflammation, temperature reduction: Examples: Ibuprofen, diclofenac, naproxen. Mode of action: Inhibits the activity of cyclooxygenases (COX-1 and COX-2), thereby inhibiting prostaglandin synthesis. Contra-indications: Peptic ulceration, history of gastrointestinal bleeding or hypersensitivity to aspirin, IBD. Cautions: Asthma, cardiac impairment, impaired renal function. Important: Coadministration with warfarin increases bleeding risk. Concomitant use of NSAIDs with high doses of nutrients and herbs with antiplatelet activity e.g., vitamin E, garlic and turmeric, may increase the risk of bleeding. (Daily et al. 2016; Linus Pauling Institute, 2021) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 72  NSAIDs Side effects: Inhibit prostaglandins that play a vital role in gastric mucosal defence, increasing the risk of gastric bleeding and ulceration. Block renal prostaglandins that normally dilate vessels in the kidneys. This can lead to reduced blood flow and oxygen supply causing acute kidney damage. Selective COX-2 Inhibitors: NSAIDS that selectively inhibit COX-2 allow COX-1-induced production of prostaglandins that have important gastro-protective effects. However, they are associated with an increased risk of cardio-vascular events in those with heart disease. (Perry et al. 2014; Solomon, 2021) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 73  NSAIDs Alternative options: Willow bark (Salix alba) reduces inflammation and fever and has analgesic properties. Willow bark does not have antiplatelet activity and can be safely used alongside NSAIDs where pain is more severe. Turmeric (curcumin), ginger and boswellia are also COX inhibitors. Ensure an anti-inflammatory / alkalising diet incorporating a range of fruit and vegetables rich in flavonoids and chlorophyll. Quercetin inhibits LOX and COX pathways and down-regulates NF-kB. Food sources include onions, asparagus, apples, berries. (Maroon et al. 2010; Shara & Stohs, © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 2015; Lemmon & Roseen, 2018) 74  Corticosteroids Prescribed for: Asthma, eczema, IBD, hypersensitivity reactions, autoimmune conditions: Examples: Prednisolone, hydrocortisone. Mode of action: Modulates protein synthesis by binding to DNA. It stimulates the production of a glycoprotein called lipocortin, which inhibits the activity of phospholipase A2 and hence inflammatory mediators. Contraindications: Active infection, live virus vaccination. Side effects: Long-term systemic use increases risk of Cushing’s syndrome, diabetes mellitus, osteoporosis and infections. Delivery: Available as inhalers, enemas, topical creams, tablets. (Kragballe, 1989; Ramamoorthy © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. & Cidlowski, 2016) 75  Corticosteroids Corticosteroids (cont.): Important: Abrupt withdrawal after a prolonged period can lead to acute adrenal insufficiency, hypotension or death Alternative approach: Anti-inflammatory diet; nutrients and herbs that inhibit inflammatory mediators e.g., EFAs, quercetin, turmeric, ginger. Liquorice root has been shown to modify or even increase the body’s levels of cortisol. Liquorice, if given in large quantities with corticosteroids, may cause additive hypokalaemia. Pharmacodynamic interactions are possible with liquorice and fludrocortisone due to mineralocorticoid effects, and with liquorice and medicines that deplete potassium levels such as diuretics. (Yang et al. 2015; Sabbadin et al. 2019) © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 76  Exercise: Laxatives 1. Laxatives are a popular OTC drug for self medication. Using a drug resource identify: – ONE bulk laxative. – ONE stimulant laxative (HINT: Bisacodyl). 2. Identify TWO side effects of laxatives. 3. Consider TWO natural approaches to addressing constipation. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 77  Nutritional Consultation Most people regard pharmaceuticals as primary medications, and patients may be using them but forget to tell you: It is essential that we ensure to ask about use of pharmaceutical medication in the case-taking process. Specifically ask about OTC as well as prescribed medications. Ask women of reproductive age about the oral contraceptive. It may not be perceived by the client as a medication! In the rare event that there is a problem with a supplement / food- drug interaction, the supplement may well get the blame! It is therefore essential that you can demonstrate responsible practice in this regard, by keeping full and detailed records. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 78  Nutritional Consultation As a nutritional therapist, it is important to retrieve the following information to provide an overall drug picture: 1. Ensure that a full list of drugs is identified (prescribed and OTC drugs). 2. Understand why they are using the drug even if it is obvious e.g., levothyroxine for underactive thyroid. 3. The duration of treatment — how long has the client taken / used the medication? 4. Establish how often they take / use the medication e.g., once daily, twice daily. 5. Ensure the dosage is recorded e.g., levothyroxine 100 mcg. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 79  Nutritional Consultation Clients will often ask if they can stop a prescribed medication: A nutritional therapist should NOT suddenly stop a client’s prescribed drug. You should educate the client about the drug and its side effects as it could be causing their presenting signs / symptoms. However, if there is an opportunity to reduce a drug, you can work with the client’s healthcare professional. We must always be open to this! Example: Client with Type 2 diabetes achieving better glucose control with a recommended nutritional protocol will need their metformin (anti-diabetic drug) dosage reduced. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 80  Nutritional Consultation Clients are often surprised by the negative impact of self medicating with OTC drugs: A nutritional therapist has a major role to play in removing OTC drugs that provide no benefit or indeed do more harm. Explaining to clients that OTC drugs are causing their signs / symptoms often comes as a surprise! – Example: Using OTC ibuprofen for tension headaches is increasing the risk of gastric irritation. – Example: Consuming copious quantities of antacids is simply feeding acid reflux (a vicious circle). © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 81  Exercise: Stopping Drugs! 1. During a consultation, you identify that a prescribed drug is contributing to severe side effects. How would you manage this scenario? 2. Think of TWO prescribed drugs that must never be abruptly stopped. 3. Explain how you might withdraw a client off a PPI, after taking it for GORD. What are the side effects of long-term PPI use? © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 82  Case Study 1 John, 45-year-old male: Presents with: Acid reflux and fatigue. He was diagnosed with borderline high cholesterol and prescribed simvastatin 10 mg six months ago. He has been advised to self medicate with omeprazole (a PPI) to manage his acid reflux but has not yet taken it. Diet: His diet is high in refined sugar, alcohol, salt, saturated fats and low in fibre, omega-3 and general micronutrients. 1. What is your assessment of John’s medication? 2. Are there any specific dietary interactions? 3. What would you advise John about self-medicating a PPI? © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 83  Case Study 1: Solution Medication assessment / dietary interactions: Simvastatin — depletion of CoQ10 causing fatigue. Supplement it? Simvastatin and alcohol interact and can increase liver toxicity so alcohol should be avoided. Self medication advice — omeprazole: Explain nutrient depletions e.g., vitamin B12, vitamin C, zinc. Discuss short-term side effects e.g., headache, constipation, diarrhoea, rebound heartburn causing long-term use. Explain long-term adverse effects e.g., fractures, hypomagnesaemia, gastro-intestinal infections. Offer nutritional and lifestyle support. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 84  Case Study 2 Annie, 32-year-old female: Presents with: Generalised anxiety following a car accident. Her GP has prescribed sertraline (an SSRI). She would like to adopt a more natural approach to managing her anxiety. She has been experiencing severe constipation and self medicating with bisacodyl (a laxative). A friend has recommended she take St. John’s wort to manage her anxiety. 1. What is your assessment of Annie’s medication? 2. Are there any specific drug-nutrient interactions to cause concern? 3. Can you advise Annie to stop sertraline? © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 85  Case Study 2: Solution Medication assessment: Sertraline (SSRI)-constipation is a common side effect. Bisacodyl, a stimulant laxative, can contribute to a lazy bowel and should be avoided. Recommend natural approaches e.g., increased fibre, water intake, digestive enzymes. Specific drug-nutrient interactions: Concomitant use of sertraline and St. John’s wort can place the client at risk of developing serotonin syndrome: AVOID! It is important that sertraline is not stopped. A joint approach with the client’s GP could be considered. Manage anxiety naturally with B vitamins, magnesium, increased exercise etc. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 86  Case Study 3 Sue, 65-year-old female: Presents with: Recently diagnosed atrial fibrillation. Her doctor has prescribed warfarin. Recently she has noticed some bruising. She occasionally uses ibuprofen (over the counter) to manage osteoarthritis. She would like to enhance her overall cardiovascular health. 1. What is your assessment of Sue’s medication? 2. Are there any specific supplements to avoid? 3. Identify specific dietary advice for Sue given her medications and explain why? © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 87  Case Study 3: Solution Medication assessment: Warfarin is often the first choice of medication in atrial fibrillation to prevent stroke. Ibuprofen (NSAID) can increase the risk of bleeding and should, therefore, be avoided. Bruising may indicate bleeding so referral to the client’s doctor is necessary. Specific supplements to avoid: High dose vit. E can interfere with vit. K-dependent clotting factors. Gingko biloba and garlic can increase bleeding risk. Specific dietary advice Avoid excessive intake of vitamin K-rich green vegetables (broccoli, spinach, cabbage). Vit. K opposes the effects of warfarin. Can eat in moderation with GP supervision and regular INR level monitoring. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 88  Further Activities Research the following as a further activity: 1. Research and identify useful drug resources that you can use this year, especially for client consultations. 2. Identify TWO drugs that could cause gastrointestinal irritation. 3. Consider how you might manage a client who would like to reduce / cease their use of OTC paracetamol to treat a tension headache. 4. Research how antibiotic medicines affect your gut microbiome. © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 89  Non-examinable Extra Resource: CYP Interactions Supplement: Enzyme interaction: Berberine Inhibits CYP3A4 Chamomile Inhibits CYP1A2 and 3A4 Cranberry Inhibits CYP1A2, 2D6, 2C9 and 3A4 Curcumin Inhibits CYP2C19, 2B6, 2C9 and 3A4 Echinacea Inhibits CYP1A2 and 3A4 Garlic Inhibits CYP2E1, 2C9, 2C19 and induces 3A4 Ginger Inhibits CYP1A2, 2D6 and 3A4 Ginseng (Panax) Induces CYP3A4 and inhibits 2D6 Ginseng (Siberian) Inhibits CYP1A2, 2C9, 2D6, 3A4 Ginseng (Siberian) Inhibits CYP1A2, 2C9, 2D6, 3A4 © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 90  Non-examinable Extra Resource: CYP Interactions Supplement: Enzyme interaction: Gingko Induces CYP1A2, 2C9, 2C19, 2D6 and may induce or inhibit 3A4 Grape seed extract Inhibits CYP2C9 and 3A4 Grapefruit Inhibits CYP3A4 Liquorice Inhibits CYP1A2, 2C9, 2C19, 2D6 and 3A4 Milk thistle Inhibits CYP2C9 Pomegranate Inhibits CYP2D6 and 3A4 Quercetin Inhibits CYP2C8, 2C9, 2D6 and 3A4 Resveratrol Inhibits CYP2C9, 2D6 and 3A4 St John’s wort Induces CYP1A2, 2C9 and 3A4 © CNM: Nutrition Year 2: Nutritional Pharmacology. JD. 91  References Aroda, VR. Edelstein, SL. Goldberg, RB. Knowler, WC. et al. (2016). ‘Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study’. J Clin Endocrinol Metab. 101(4). 1754-1761. Asdaq, SMB. & Inamdar, MN. (2011). ‘Pharmacodynamic and Pharmacokinetic Interactions of Propranolol with Garlic (Allium sativum) in Rats’. Evidence Based Complement Alternat Med. 2011:824042. ANP, The. (2020). 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