Chapter 3: Impact of Drug Interactions and Adverse Events on Therapeutics Copyright © 2017 Wolters Kluwer · All Rights Reserved Four Major Categories of Drug Interactions • Drug–drug interactions • Drug–food interactions • Drug–herb interactions • Drug–disease interactions Copyright © 2017 Wolters Kluwer · All Rights Reserved Pharmacokinetic Factors Affecting Drug Therapy • Absorption • Distribution • Metabolism • Excretion Copyright © 2017 Wolters Kluwer · All Rights Reserved Pharmacokinetic Drug–Drug Interactions Involving Absorption • Acidity (pH): one drug may alter the acidity of the GI tract • Adsorption: occurs when one agent binds the other to its surface to form a complex • Gastrointestinal motility and rate of absorption: drugs that affect the GI tract can affect the rate of absorption instead of amount of drug absorbed • GI flora: bacteria present in the GI tract are responsible for a portion of the metabolism of some agents Copyright © 2017 Wolters Kluwer · All Rights Reserved Distribution of Drugs in Bloodstream • Most are bound to plasma proteins such as albumin or α1-acid glycoprotein. • Only an unbound drug is free to interact with its target receptor site and is therefore active. • The percentage of drug that binds to plasma proteins depends on the affinity of that drug for the proteinbinding site. • Clinically significant drug displacement interactions normally occur only when drugs are more than 90% protein bound and have a narrow therapeutic index. Copyright © 2017 Wolters Kluwer · All Rights Reserved Metabolism • Main sites of metabolism – Liver (hepatocytes) – Small intestine (enterocytes) – Kidneys, lungs, brain play minor role • Classification of cytochrome P-450 isoenzymes – Family (>36% homology in amino acid sequence) – Subfamily (77% homology) – Individual gene Copyright © 2017 Wolters Kluwer · All Rights Reserved Inhibition of Drug Metabolism: Competitive and Noncompetitive • Affinity: the greater the affinity of an inhibiting drug for an enzyme, the more it blocks binding of other drug molecules • Half-life: determines duration of the interaction • Concentration: threshold concentration must be reached or exceeded to inhibit an enzyme • Toxic potential of the object drug • Efficacy: effectiveness of the object drug Copyright © 2017 Wolters Kluwer · All Rights Reserved Question • A practitioner is prescribing amiodarone for a patient with cardiac arrhythmia. Which factor affecting the duration of the drug must a practitioner consider if an adverse interaction occurs? A. Efficacy B. Half-life C. Concentration D. Toxic potential Copyright © 2017 Wolters Kluwer · All Rights Reserved Answer • B. Half-life • Rationale: Along with affinity, the half-life (t½) of the inhibiting drug determines the duration of the interaction. The longer the half-life of the inhibiting drug, the longer the drug interaction lasts. Efficacy refers to the effectiveness of the drug. Concentration is a factor contributing to a drug’s ability to inhibit hepatic enzymes. A threshold concentration must be reached or exceeded to inhibit an enzyme. Serious toxic potential may cause a drug to be removed from the market. Copyright © 2017 Wolters Kluwer · All Rights Reserved Drug–Drug Interactions Caused by Induction • Result of the action of one drug (inducer) stimulating the metabolism of an object drug (substrate) • Enhanced metabolism produced by an increase in hepatic blood flow or an increase in the formation of hepatic enzymes • Increases the amount of enzymes available to metabolize drug molecules, thereby decreasing the concentration and pharmacodynamic effect of the object drug Copyright © 2017 Wolters Kluwer · All Rights Reserved Competitive and Noncompetitive Inhibition Copyright © 2017 Wolters Kluwer · All Rights Reserved Renal Excretion of Drugs • Drugs are removed from the bloodstream by the kidneys by filtration or urinary secretion. • Reabsorption from the urine into the bloodstream may also occur. • Absorption may be affected by acidification or alkalinization of the urine and alteration of secretory or active transport pathways. • Although most drugs cross the membrane of the renal tubule by simple diffusion, some drugs are also secreted into the urine through active transport pathways. Copyright © 2017 Wolters Kluwer · All Rights Reserved Biliary Excretion of Drugs • Biliary excretion allows for the elimination of drugs and their metabolites into the feces. • This route is involved in interactions with drugs that undergo enterohepatic recirculation. • Drugs are excreted into the GI tract through the biliary ducts and have the potential to be reabsorbed through the intestinal wall into the bloodstream. • Some of these drugs depend on enterohepatic recirculation to achieve therapeutic concentrations. Copyright © 2017 Wolters Kluwer · All Rights Reserved Question • A practitioner prescribes a bicarbonate for a patient with severe heartburn. The practitioner knows that what factor caused by the drugs plays a key role in its excretion? A. Enterohepatic recirculation B. Alteration active transport pathways C. Alkalinization of the urine D. Induction of P-glycoprotein Copyright © 2017 Wolters Kluwer · All Rights Reserved Answer • C. Alkalinization of the urine • Rationale: Administration of bicarbonate can potentially increase the urine pH. This leads to the increased excretion of acidic drugs and the increased reabsorption of basic drugs. Copyright © 2017 Wolters Kluwer · All Rights Reserved Pharmacodynamic Interactions • Pharmacodynamic profile: responses or effects produced by a drug’s actions. • Drugs that have a similar characteristic in their pharmacodynamic profile may produce an exaggerated response. • Drugs may also produce opposing pharmacodynamic effects causing the expected drug response to be diminished or even abolished. Copyright © 2017 Wolters Kluwer · All Rights Reserved Drug–Food Interactions • Absorption: food can alter extent of drug absorption or change rate of drug absorption. • Metabolism: grapefruit juice inhibits the 3A4 subset of intestinal cytochrome P-450 enzymes and increases the serum concentration of drugs dependent on these enzymes for metabolism; food may also induce drug metabolism and therefore decrease drug efficacy. • Excretion: ingestion of certain fruit juices can alter the urinary pH and affect the elimination and reabsorption of drugs such as quinidine and amphetamine. Copyright © 2017 Wolters Kluwer · All Rights Reserved Typical Effects of Food on Pharmacodynamics • Food may oppose or potentiate pharmacologic action. • Warfarin reacts with foods containing vitamin K. • MAO inhibitors can react with foods containing tyramine. • Some drugs can deplete nutrients or minerals found in foods. • Drug-induced malabsorption can occur in patients with preexisting poor nutritional status. • Drugs can change nutrient excretion. Copyright © 2017 Wolters Kluwer · All Rights Reserved Question • A health care practitioner prescribes warfarin for a patient who Afib. The patient should avoid foods high in: A. Potassium B. Tyramine C. Vitamin C D. Vitamin K Copyright © 2017 Wolters Kluwer · All Rights Reserved Answer • D. Vitamin K • Rationale: Warfarin exerts its anticoagulant effects by inhibiting synthesis of vitamin K–dependent clotting factors. Vitamin K is required for activation by several protein factors of the clotting cascade, namely, factors II, VII, IX, and X. When foods rich in vitamin K are ingested, they can significantly oppose the anticoagulatory efficacy of warfarin. Copyright © 2017 Wolters Kluwer · All Rights Reserved Pharmacokinetic Drug–Herb Interactions • Most herbal supplements are not regulated by the FDA. • Some herbs can prevent absorption of medications and reduce the effectiveness of those medications. – Acacia may impair the absorption of amoxicillin. – Dandelion may reduce effectiveness of quinolones. – Meadowsweet and black willow may displace highly protein-bound drugs. – Certain herbs can be inducers or inhibitors of the cytochrome P-450 enzyme system. Copyright © 2017 Wolters Kluwer · All Rights Reserved Pharmacodynamic Drug–Herb Interactions • Some herbs may inhibit platelet activity and/or increase the INR. • Kava, lavender, and valerian may potentiate effects of CNS depressants such as barbiturates and narcotics. • Kava may interfere with effects of dopamine or dopamine antagonists and is potentially hepatotoxic. • Aloe may cause hypoglycemia in patients taking glibenclamide. • Bitter orange may interfere with MAO inhibitor action. Copyright © 2017 Wolters Kluwer · All Rights Reserved Pharmacokinetic Drug–Disease Interactions: Absorption • Absorption depends on the physiologic processes that maintain normal GI function. • Vitamin B12 deficiency is common in patients undergoing stomach surgery. • Diarrhea, a manifestation of many diseases, can pose a problem for oral absorption of drugs as well as food and nutrients. Copyright © 2017 Wolters Kluwer · All Rights Reserved Effect of Diseases on Distribution of Drugs • Conditions that may decrease plasma albumin levels: – Burns, bone fractures, acute infections, inflammatory disease, liver disease, malnutrition, and renal disease • Conditions that may increase plasma albumin levels: – Benign tumors, gynecologic disorders, myalgia, and surgical procedures Copyright © 2017 Wolters Kluwer · All Rights Reserved Effect of Diseases on Metabolism of Drugs • Metabolism of drugs can be altered by disease that affect the functions of the liver (cirrhosis). • Heart failure is another disease that can cause direct reduction in ability of liver to metabolize drugs. • Use of a prodrug in patients with liver dysfunction can potentially reduce the efficacy of the drug. Copyright © 2017 Wolters Kluwer · All Rights Reserved Effect of Diseases on Excretion of Drugs • Renal function can influence serum drug concentrations. • Glomerulonephritis, interstitial nephritis, long-term and uncontrolled diabetes, and hypertension are primary causes of declining renal function. • Drugs such as H2 receptor antagonists and fluoroquinolone antibiotics commonly require dose adjustments for patients with renal insufficiency. Copyright © 2017 Wolters Kluwer · All Rights Reserved Effects of Drugs on Coexisting Disease • Drugs used to treat one medical condition can exacerbate the status of another comorbid disease. – This is particularly important in the elderly who have multiple concomitant diseases and often take multiple medications. – Detected rates of drug–disease interactions range from 6% to 30% in older adults. Copyright © 2017 Wolters Kluwer · All Rights Reserved Patient Factors Influencing Drug Interactions • Heredity • Existing disease state • Environment • Smoking • Diet and nutrition • Alcohol intake Copyright © 2017 Wolters Kluwer · All Rights Reserved Adverse Drug Reactions • Definition: drug-induced toxic reactions • Two types of drug reactions – Type A reactions: exaggeration of the principal pharmacologic action of the drug – Type B reactions: unrelated to the principal pharmacologic action of the drug itself; precipitated by the secondary pharmacologic actions of the drug Copyright © 2017 Wolters Kluwer · All Rights Reserved Medication Errors and Tracking ADRs • Causes of medication errors: look-alike and sound-alike drugs, dosage conversions, foreign drugs, illegible handwriting, unacceptable abbreviations • Tracking drug interactions and ADRs – The initial source of documented ADRs comes primarily from the experience gained while using a drug during clinical trials – MedWatch program: enhances the effectiveness of surveillance of drugs and medical products after they are marketed and as they are used in clinical practice Copyright © 2017 Wolters Kluwer · All Rights Reserved Summary • As the quantity and types of pharmacologic agents continue to expand, the likelihood of drug interactions and adverse reactions increases. • ADRs present an alarming problem that warrants significant attention from health care practitioners. • Not only do ADRs affect morbidity and mortality, they also dramatically increase health care costs. • Prescribers must be aware of the mechanisms of drug interactions and their potential consequences. 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