Drug–Nutrient Interactions

Overview

Definition and Clinical Significance

• A drug-nutrient interaction ( DNI DNI Advance Directives) is defined as a physical, chemical, physiological, or pathophysiological relationship between a drug and a nutrient. These interactions can alter the therapeutic efficacy of a drug or compromise the nutritional status of a patient.  
• Clinical Significance: Failure to identify and manage DNIs can lead to serious consequences, including therapeutic failure, nutritional deficiencies, or drug toxicity Toxicity Dosage Calculation. The risk is particularly high in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with chronic diseases, the elderly, and those on polypharmacy.

Classification of Interactions

• Drug-nutrient interactions are broadly classified based on their underlying mechanism into two main categories: pharmacokinetic and pharmacodynamic interactions.  
• Pharmacokinetic Interactions: These occur when a nutrient alters the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption, distribution, metabolism, or excretion (ADME) of a drug. In essence, the nutrient changes what the body does to the drug, affecting the concentration of the drug that reaches its target site.  
• Pharmacodynamic Interactions: These occur when a nutrient alters the action of a drug at its target site. The nutrient changes what the drug does to the body, either by enhancing (synergism) or opposing (antagonism) the drug’s effects.  

Pharmacokinetic Interactions: The Effect of Nutrients on Drugs

Effects on Drug Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

• The presence of food in the GI tract can significantly alter the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of orally administered drugs. 
• Binding and Chelation: Nutrients, particularly divalent and trivalent cations Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes like calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes, iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements, and magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes, can bind BIND Hyperbilirubinemia of the Newborn to certain drugs, forming insoluble complexes (chelates) that are poorly absorbed. This reduces the drug’s bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics.  
• Alteration of Gastric pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance: Food changes gastric pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance, delays gastric emptying Gastric emptying The evacuation of food from the stomach into the duodenum. Gastrointestinal Motility, and increases intestinal time, which can either enhance or reduce a drug’s properties. Drugs that require an acidic environment for dissolution and absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption may have reduced efficacy when taken with food, which temporarily increases gastric pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance. Conversely, drugs that are unstable in acid may benefit from the buffering effect of food.  
• Stimulation of bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy secretion Secretion Coagulation Studies: High-fat meals increase bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy secretion Secretion Coagulation Studies, enhancing the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of lipophilic drugs by improving their solubility.  

Effects on Drug Metabolism

• Drug metabolism, primarily occurring in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and intestinal wall, is the most common site of pharmacokinetic DNIs. This process is mediated by a family of enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, most notably the Cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury (CYP) system.  
• Enzyme Inhibition Enzyme inhibition Enzyme inhibitors bind to enzymes and decrease their activity. Enzyme activators bind to enzymes and increase their activity. Molecules that decrease the catalytic activity of enzymes can come in various forms, including reversible or irreversible inhibition. Enzyme Inhibition: Some food components can inhibit the activity of specific CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. This slows down the metabolism of drugs that are substrates for that enzyme, leading to higher-than-expected drug concentrations in the blood and an increased risk of toxicity Toxicity Dosage Calculation. The most well-known inhibitor is grapefruit juice, which inhibits CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers).  
• Enzyme Induction: Other food components can induce, or increase, the activity of CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. This accelerates drug metabolism, leading to lower-than-expected drug concentrations and potential therapeutic failure. 
• Nutritional Status and Weight: Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries and protein deficiency generally decreases the activity of drug-metabolizing enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, reducing drug clearance and potentially increasing toxicity Toxicity Dosage Calculation. Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity may decrease activity of CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that can lead to decreased clearance and possible toxicity Toxicity Dosage Calculation, while weight loss Weight loss Decrease in existing body weight. Bariatric Surgery does the opposite.

Pharmacodynamic Interactions: The Effect of Nutrients on Drug Action

• Pharmacodynamic interactions occur at the drug’s site of action and involve a direct modification of the drug’s effect by a nutrient.
• Antagonistic Effects: This occurs when a nutrient directly opposes the mechanism of a drug. The classic example is the interaction between vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies and the anticoagulant warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants.  
• Synergistic/Additive Effects: This occurs when a nutrient enhances the effect of a drug. For example, the central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification depressant effects of sedative medications can be potentiated by alcohol.  

The Effect of Drugs on Nutrient Status

• Pharmacotherapy can also negatively impact a patient’s nutritional status by altering nutrient absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption, metabolism, or excretion.
• Effects on Nutrient Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
  • Drugs that alter GI motility GI Motility The primary functions of the GI tract are digestion and absorption, which require coordinated contractions of the smooth muscles present in the GI tract. Peristaltic waves, segmentation contractions, and the migrating motor complex are all important contraction patterns that help to mix contents, get them in contact with the intestinal walls, and propel material down the tract at appropriate times and in appropriate amounts. Gastrointestinal Motility, such as laxatives Laxatives Laxatives are medications used to promote defecation. Most often, laxatives are used to treat constipation or for bowel preparation for certain procedures. There are 4 main classes of laxatives: bulk-forming, stimulant, osmotic, and emollient. Laxatives, can reduce the transit time for nutrient absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption. Drugs can cause gastrointestinal side effects such as nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, that can decrease food intake and contribute to malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries.
  • Drugs that increase gastric pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance, such as proton pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitors and H2-receptor antagonists, can impair the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 and non-heme iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements, which require an acidic environment.  
• Effects on Nutrient Metabolism and Excretion:
  • Some drugs can increase the metabolic breakdown or urinary excretion of specific vitamins and minerals Minerals Electrolytes, leading to depletion over time. For example, loop and thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Chronic Coronary Syndrome Medication are known to increase the urinary loss of potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia and magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes.  

Clinically Significant Examples and Management

Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants and Vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies

• Mechanism: Pharmacodynamic. Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants exerts its anticoagulant effect by inhibiting the enzyme Vitamin K Epoxide Reductase Vitamin K Epoxide Reductase Anticoagulants (VKORC1), which is necessary to activate vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies. Activated vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies is a required cofactor for the synthesis Synthesis Polymerase Chain Reaction (PCR) of clotting factors II, VII, IX, and X. A high intake of dietary vitamin K Vitamin K A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: vitamin K 1 (phytomenadione) derived from plants, vitamin K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, vitamin K 3 (menadione). Vitamin k 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin k. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin k. Fat-soluble Vitamins and their Deficiencies can overcome this blockade, leading to the synthesis Synthesis Polymerase Chain Reaction (PCR) of clotting factors and a reduction in warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants‘s efficacy.  
• Clinical Relevance: Inconsistent intake of vitamin K-rich foods (e.g., leafy green vegetables like spinach and kale) can lead to fluctuations in the International Normalized Ratio International normalized ratio System established by the world health organization and the international committee on thrombosis and hemostasis for monitoring and reporting blood coagulation tests. Under this system, results are standardized using the international sensitivity index for the particular test reagent/instrument combination used. Hemostasis (INR) and increase the risk of either thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus or bleeding.
• Management: Patient counseling should focus on maintaining a consistent, rather than a low, intake of vitamin K-rich foods to allow for stable warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants dosing.  

Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins and Grapefruit Juice

• Mechanism: Pharmacokinetic. Grapefruit contains compounds called furanocoumarins that irreversibly inhibit the CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) enzyme in the intestinal wall. This significantly reduces the first-pass metabolism of statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins that are substrates for CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers), leading to a dramatic increase in their bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics and plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products concentrations.  
• Clinical Relevance: Elevated statin levels increase the risk of adverse effects, most notably myopathy Myopathy Dermatomyositis and, in rare cases, life-threatening rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis.  
• Management: This interaction is specific to statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins metabolized by CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers), including atorvastatin Atorvastatin A pyrrole and heptanoic acid derivative, hydroxymethylglutaryl-CoA reductase inhibitor (statin), and anticholesteremic agent that is used to reduce serum levels of ldl-cholesterol; apolipoprotein b; and triglycerides. It is used to increase serum levels of hdl-cholesterol in the treatment of hyperlipidemias, and for the prevention of cardiovascular diseases in patients with multiple risk factors. Statins, simvastatin Simvastatin A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic ldl receptors, it increases breakdown of ldl cholesterol. Statins, and lovastatin Lovastatin A fungal metabolite isolated from cultures of aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Statins. Other statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins, such as rosuvastatin Rosuvastatin A hydroxymethylglutaryl-coa-reductase inhibitor, or statin, that reduces the plasma concentrations of ldl-cholesterol; apolipoprotein b, and triglycerides while increasing hdl-cholesterol levels in patients with hypercholesterolemia and those at risk for cardiovascular diseases. Statins and pravastatin Pravastatin An antilipemic fungal metabolite isolated from cultures of nocardia autotrophica. It acts as a competitive inhibitor of hmg CoA reductase. Statins, are not metabolized by this enzyme and are therefore safe to take with grapefruit. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship on affected statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins should be advised to avoid grapefruit and grapefruit juice.  

Monoamine Oxidase Oxidase Neisseria Inhibitors ( MAOIs MAOIs Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors) and Tyramine

• Mechanism: Pharmacokinetic/Pharmacodynamic. MAOIs MAOIs Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors block the enzyme monoamine oxidase-A (MAO-A) in the gut and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, which is responsible for metabolizing dietary amines like tyramine. When tyramine is ingested, it is absorbed systemically and acts as a sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs, causing a massive release of norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS from nerve terminals.  
• Clinical Relevance: The surge in norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS can precipitate a hypertensive crisis Hypertensive Crisis Oxazolidinones, a medical emergency characterized by a rapid, severe increase in blood pressure, severe headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, and risk of stroke.  
• Management: Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship taking irreversible MAOIs MAOIs Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors must adhere to a strict low-tyramine diet, avoiding foods such as aged cheeses, cured meats, fermented soy products, and draft beer.  

Metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs and Vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12

• Mechanism: Pharmacokinetic. Long-term use of metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs can interfere with the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 in the terminal ileum Ileum The distal and narrowest portion of the small intestine, between the jejunum and the ileocecal valve of the large intestine. Small Intestine: Anatomy. The prevailing mechanism suggests that metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs interferes with the calcium-dependent binding of the vitamin B12-intrinsic factor complex to its receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( cubilin Cubilin Tubular System) on ileal cells.  
• Clinical Relevance: This malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion can lead to a clinically significant vitamin B12 deficiency Vitamin B12 deficiency A nutritional condition produced by a deficiency of vitamin B12 in the diet, characterized by megaloblastic anemia. Since vitamin B12 is not present in plants, humans have obtained their supply from animal products, from multivitamin supplements in the form of pills, and as additives to food preparations. A wide variety of neuropsychiatric abnormalities is also seen in vitamin B12 deficiency and appears to be due to an undefined defect involving myelin synthesis. Folate and Vitamin B12 over time, which can manifest as megaloblastic anemia Megaloblastic anemia Megaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies. Megaloblastic Anemia or irreversible peripheral neuropathy Neuropathy Leprosy.
• Management: Periodic monitoring of vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 levels is recommended for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship on long-term metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs therapy, particularly if they develop anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types or neuropathy Neuropathy Leprosy.

Tetracyclines Tetracyclines Tetracyclines are a class of broad-spectrum antibiotics indicated for a wide variety of bacterial infections. These medications bind the 30S ribosomal subunit to inhibit protein synthesis of bacteria. Tetracyclines cover gram-positive and gram-negative organisms, as well as atypical bacteria such as chlamydia, mycoplasma, spirochetes, and even protozoa. Tetracyclines and Divalent Cations Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes

• Mechanism: Pharmacokinetic. Tetracycline Tetracycline A naphthacene antibiotic that inhibits amino Acyl tRNA binding during protein synthesis. Drug-Induced Liver Injury and fluoroquinolone antibiotics form insoluble chelate complexes with divalent and trivalent cations Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes, such as calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes (in dairy products, antacids), iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements, and magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes.  
• Clinical Relevance: Co-administration of these antibiotics with cation-containing products can significantly reduce the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption and bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics of the antibiotic, leading to therapeutic failure.  
• Management: Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be counseled to separate the administration of the antibiotic from dairy products, antacids, or mineral supplements by at least 2 to 4 hours.