Module 4: Drug Interactions Flashcards
Example of Increased Therapeutic Effects
Example: Sulbactam and Ampicillin
Mechanism: Sulbactam is a beta-lactamase inhibitor, while ampicillin is a beta-lactam antibiotic. Many bacteria produce beta-lactamase enzymes that degrade the beta-lactam ring, rendering antibiotics like ampicillin ineffective. Sulbactam protects ampicillin from degradation by inhibiting these enzymes, thereby enhancing ampicillin’s antibacterial activity.
Clinical Implication: The combination is used to treat infections caused by beta-lactamase-producing bacteria, providing a broader spectrum of action than ampicillin alone.
Example of Increased Adverse Effects
Example: Aspirin and Warfarin
Mechanism: Both aspirin and warfarin have anticoagulant effects, but they work through different pathways. Aspirin inhibits platelet aggregation, while warfarin inhibits the synthesis of vitamin K-dependent clotting factors. When used together, the risk of bleeding is significantly increased due to the additive anticoagulant effects.
Clinical Implication: Concomitant use should be approached with caution, especially in patients at high risk for bleeding. Regular monitoring of coagulation parameters (e.g., INR for warfarin) and clinical signs of bleeding is necessary.
Pharmacokinetic Interactions
Pharmacokinetic Interactions: One drug may alter the concentration of another drug in the body, potentially by affecting its absorption (e.g., antacids reducing the absorption of certain antibiotics), metabolism (e.g., drugs that induce or inhibit liver enzymes affecting the metabolism of other drugs), or excretion (e.g., drugs affecting renal blood flow altering the excretion of others).
Pharmacodynamic Interactions
Drugs may have additive, synergistic, or antagonistic effects when used together. Additive effects occur when two drugs with similar actions are combined (e.g., using two antihypertensive drugs from different classes), potentially leading to an increased risk of adverse effects. Synergistic effects are when the combined effect of two drugs is greater than the sum of their individual effects (e.g., sulbactam and ampicillin). Antagonistic interactions occur when one drug reduces the effect of another (e.g., NSAIDs reducing the antihypertensive effect of beta-blockers).
Reduced Therapeutic Effects
Propranolol and Albuterol
Mechanism: Propranolol is a non-selective beta-blocker that inhibits both β₁ (beta-1) and β₂ (beta-2) adrenergic receptors. Albuterol is a β₂ agonist used as a bronchodilator to manage asthma symptoms. When propranolol is taken with albuterol, it can block the β₂ receptors in the lungs that albuterol is meant to activate, thereby reducing the bronchodilatory effect of albuterol.
Clinical Implication: The use of non-selective beta-blockers in asthma patients is generally avoided to prevent interference with β₂ agonist treatments. If a beta-blocker is necessary, a cardioselective β₁ blocker may be preferred to minimize the risk of inhibiting the therapeutic effects of β₂ agonists like albuterol.
Reduce Adverse Effects
Example: Naloxone to Treat Morphine Overdose
Mechanism: Naloxone is an opioid antagonist that competitively binds to opioid receptors without activating them, effectively displacing opioids like morphine from these receptors. This action rapidly reverses the effects of opioid overdose, including respiratory depression, sedation, and hypotension.
Clinical Implication: Naloxone is used in emergency situations to treat opioid overdose, significantly reducing the life-threatening adverse effects of opioids. It can be administered intravenously, intramuscularly, subcutaneously, or intranasally, with effects typically seen within minutes.
Unique interactions: Alcohol with disulfiram
The combination of alcohol and disulfiram represents a unique drug-drug interaction that intentionally creates an adverse response to discourage the consumption of alcohol. Disulfiram is used in the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (alcohol).
Mechanism of Interaction:
Disulfiram Inhibition: Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase (ALDH), which is involved in the metabolism of ethanol. Normally, ethanol is first metabolized to acetaldehyde by the enzyme alcohol dehydrogenase (ADH), and then acetaldehyde is further metabolized to acetic acid by ALDH. Disulfiram’s inhibition of ALDH leads to the accumulation of acetaldehyde in the blood when ethanol is consumed.
Acetaldehyde Accumulation: The buildup of acetaldehyde results in a highly unpleasant reaction that can include symptoms such as flushing, headache, nausea, vomiting, sweating, thirst, chest pain, palpitations, dyspnea, vertigo, blurred vision, and confusion. This reaction is known as the disulfiram-ethanol reaction (DER).
Basic Drug Interaction Mechanisms
Drugs can interact through four basic
mechanisms:
1. Direct chemical or physical interaction
2. Pharmacokinetic interaction
3. Pharmacodynamic interaction
4. Combined toxicity
Direct Chemical or
Physical Interaction
Never combine drugs in the same container
without establishing compatibility
Most common in intravenous solution
Precipitate: Do not administer
Basic Mechanisms of
Drug-Drug Interactions - Altered Absorption
Pharmacokinetic interactions occur when one drug affects the absorption, distribution, metabolism, or excretion of another drug, altering its concentration in the body.
Mechanism: The presence of one drug can alter the gastrointestinal environment or directly interact with another drug, affecting its absorption. This can be due to changes in gastric pH, interference with transport proteins, or formation of complexes that are not easily absorbed.
Example: Antacids can increase gastric pH, reducing the absorption of drugs that require an acidic environment, like ketoconazole.
Altered Distribution
Mechanism: Drugs can compete for binding sites on plasma proteins, primarily albumin, leading to an increased concentration of free (unbound) drug in the bloodstream, which may enhance drug activity or toxicity.
Example: Warfarin and aspirin both bind to albumin. If given together, they can compete for binding sites, potentially increasing the free fraction of warfarin and leading to an increased risk of bleeding.
Renal Excretion
Mechanism: Drugs can alter renal blood flow, glomerular filtration rate, tubular secretion, or reabsorption, affecting the renal excretion of other drugs.
Example: NSAIDs can reduce renal blood flow, potentially decreasing the excretion of drugs like lithium, leading to increased lithium levels and toxicity.
Altered Metabolism
Mechanism: Drugs can induce or inhibit the activity of drug-metabolizing enzymes, particularly those in the cytochrome P450 (CYP) system, affecting the metabolism rate of other drugs.
Induction: Some drugs can increase the activity of metabolic enzymes, leading to increased metabolism of co-administered drugs, potentially reducing their therapeutic effect.
Example: Rifampin is a strong inducer of CYP enzymes and can reduce the plasma levels of drugs like warfarin, necessitating a dosage adjustment.
Inhibition: Other drugs can inhibit enzyme activity, leading to decreased metabolism and increased plasma levels of certain drugs, which can enhance their effects or toxicity.
Example: Grapefruit juice contains compounds that inhibit CYP3A4, potentially increasing the levels of drugs metabolized by this enzyme, such as certain statins, leading to increased risk of side effects.
Cytochrome P450 (CYP) Group of Enzymes
Role: The CYP enzymes play a central role in drug metabolism, being responsible for the oxidation of many drugs. They are a common pathway for drug-drug interactions.
Substrates, Inhibitors, and Inducers: Drugs can be substrates (metabolized by), inhibitors (block the activity of), or inducers (increase the activity of) specific CYP enzymes. The interaction between substrates and inhibitors or inducers of the same enzyme can lead to significant pharmacokinetic interactions.
Pharmacokinetic Interactions: Alternated Absorption, Elevated Gastric pH
Elevated Gastric pH
Mechanism: Certain medications or conditions can increase gastric pH (make it less acidic), which can affect the solubility and absorption of acid-labile drugs.
Example: Proton pump inhibitors (PPIs) like omeprazole are used to reduce stomach acid but can decrease the absorption of drugs that require an acidic environment, such as ketoconazole or atazanavir.
Pharmacokinetic Interactions: Alternated Absorption, Laxatives
Mechanism: Laxatives increase bowel movements and can decrease the transit time in the GI tract, reducing the time available for drug absorption.
Example: The use of stimulant laxatives like bisacodyl may reduce the absorption of other orally administered medications due to accelerated GI transit time.
Pharmacokinetic Interactions: Alternated Absorption, Drugs that Depress Peristalsis
Mechanism: Medications that decrease GI motility can prolong the transit time, potentially increasing the absorption of certain drugs but also risking constipation and delayed gastric emptying.
Example: Opioids like morphine can decrease GI motility, which might increase the exposure of the GI tract to certain drugs, altering their absorption profile.
Pharmacokinetic Interactions: Alternated Absorption, Drugs that Induce Vomiting
Mechanism: Drugs that trigger vomiting can prematurely expel ingested substances from the stomach, reducing the absorption of orally administered drugs.
Example: Ipecac syrup, used in the past for emergency treatment of certain poisonings, can significantly reduce the absorption of ingested drugs or toxins by inducing vomiting.
Pharmacokinetic Interactions: Alternated Absorption, Adsorbent Drugs
Mechanism: Adsorbents can bind to other drugs in the GI tract, reducing their bioavailability by preventing their absorption.
Example: Activated charcoal is often used in overdose situations to adsorb drugs in the GI tract, but it can also adsorb and reduce the absorption of other concurrently administered oral medications.
Pharmacokinetic Interactions: Alternated Absorption, Drugs that Reduce Regional Blood Flow
Mechanism: Medications that decrease splanchnic (GI) blood flow can reduce the absorption of drugs by limiting their delivery to the absorption sites in the GI tract.
Example: Sympathomimetics like pseudoephedrine can cause vasoconstriction, potentially reducing GI blood flow and thereby the absorption of co-administered oral drugs.
Altered Distribution
Altered distribution of drugs within the body can significantly impact their efficacy and potential for adverse effects. Two key factors that can lead to altered drug distribution are competition for protein binding and alterations in extracellular pH.
Competition for Protein Binding
Mechanism: Many drugs bind to plasma proteins (primarily albumin) in the bloodstream, which affects their distribution, metabolism, and excretion. Only the unbound (free) fraction of a drug is pharmacologically active. When two drugs that bind to the same plasma protein are present, they can compete for binding sites, potentially displacing each other.
Implications: Displacement from protein-binding sites can increase the concentration of the free form of one or both drugs, leading to enhanced effects or toxicity. For drugs with a narrow therapeutic index, even small changes in the free drug concentration can be significant.
Example: Warfarin and phenytoin both bind to albumin. If administered concurrently, they can compete for binding sites, potentially increasing the free fraction of warfarin, leading to an increased risk of bleeding.
Alteration of Extracellular pH
Mechanism: The pH of extracellular fluid can influence the ionization of drugs, affecting their ability to cross cell membranes and altering their distribution. The pH partition hypothesis suggests that drugs tend to accumulate on the side of a membrane where they are more ionized because the ionized form is less lipophilic and less able to cross back over the membrane.
Implications: Changes in extracellular pH can lead to altered drug distribution, especially for weak acids and bases. This can affect drug accumulation in various tissues and alter drug efficacy and toxicity.
Example: Alkalinization of urine (increasing urine pH) can increase the excretion of weakly acidic drugs like aspirin by making them more ionized in the renal tubules, reducing their reabsorption and increasing their elimination.
Clinical Considerations
Careful Drug Selection: Be aware of the protein-binding characteristics of drugs, especially when initiating therapy with medications known to have high protein binding or when treating patients with conditions that may alter protein levels, such as liver disease or malnutrition.
Monitoring: Closely monitor patients for signs of drug toxicity or reduced efficacy when introducing or discontinuing medications that may affect drug binding or when treating conditions that can alter extracellular pH.
Dosing Adjustments: Consider dose adjustments based on the patient’s overall clinical status, and other medications they are taking, particularly for drugs with narrow therapeutic windows.
Patient Education: Educate patients about the potential for drug interactions and the importance of informing healthcare providers about all medications they are taking, including over-the-counter drugs and supplements.
Altered Renal Excretion
Altered renal excretion of drugs is a significant pharmacokinetic interaction that can affect drug clearance, leading to altered drug levels and potential toxicity or subtherapeutic effects. The kidneys play a crucial role in eliminating drugs and their metabolites from the body. Renal excretion involves three main processes: filtration, reabsorption, and active secretion. Drugs can interfere with these processes, leading to changes in the excretion rates of other drugs.
Alteration of Filtration
Mechanism: Glomerular filtration is the process by which drugs passively move from the bloodstream into the renal tubules. Drugs that alter renal blood flow or glomerular filtration rate (GFR) can affect this process.
Example: NSAIDs can reduce renal blood flow by inhibiting prostaglandin synthesis, which can decrease GFR and thus reduce the filtration and elimination of drugs that are primarily excreted unchanged in the urine, such as lithium or aminoglycoside antibiotics.
Alteration of Reabsorption
Mechanism: After filtration, some drugs are reabsorbed back into the bloodstream from the renal tubules. Changes in urine pH can affect the ionization of drugs, altering their reabsorption.
Example: Alkalinizing agents like sodium bicarbonate can increase the urine pH, reducing the reabsorption and promoting the excretion of weakly acidic drugs (e.g., aspirin), while acidifying agents can have the opposite effect, increasing the reabsorption of acidic drugs and reducing that of basic drugs.
Alteration of Active Secretion
Mechanism: Active secretion involves the active transport of drugs from the blood into the renal tubules. Competition for or inhibition of these transport systems can reduce the excretion of drugs that rely on this pathway.
Example: Probenecid inhibits the renal tubular secretion of penicillin, thereby prolonging the action of penicillin by reducing its renal excretion. This interaction has been used therapeutically to extend penicillin’s duration of action.
Clinical Considerations
Assessment of Renal Function: Regular monitoring of renal function, including serum creatinine and estimation of GFR, is crucial for detecting renal impairment and adjusting dosages of renally excreted drugs accordingly.
Avoiding Nephrotoxic Agents: Be cautious when using drugs known to affect renal function, especially in patients with pre-existing renal impairment. Minimize the use of nephrotoxic drugs, and ensure adequate hydration to support renal function.
Monitoring for Drug Interactions: Be vigilant for potential drug interactions that could affect renal excretion, especially in patients taking multiple medications. Adjust dosages as needed and monitor for signs of drug toxicity or decreased therapeutic effects.
Patient Education: Educate patients about the importance of maintaining adequate hydration, especially when taking medications that can affect renal excretion, and advise them to report any signs of renal dysfunction (e.g., decreased urine output, swelling, changes in urine color).
Altered Metabolism: Cytochrome P450 (CYP) Enzymes - Inducing Agents
Altered metabolism, particularly involving the cytochrome P450 (CYP) enzyme system, is a critical factor in drug-drug interactions. The CYP enzymes, located primarily in the liver, play a significant role in the metabolism of many drugs. Interactions that result in induction or inhibition of these enzymes can significantly affect the plasma levels of drugs metabolized by the same enzymes, leading to changes in drug efficacy and risk of adverse effects.
Function: The CYP enzymes metabolize a wide variety of endogenous and exogenous substances, including many medications. Different CYP isoforms metabolize different substrates, and a single drug can be a substrate, inhibitor, or inducer of multiple CYP enzymes.
Inducing Agents
Mechanism: Inducers of CYP enzymes increase the rate of enzyme synthesis, leading to an increased rate of metabolism of drugs that are substrates for those enzymes. This can result in decreased plasma concentrations of the affected drugs, potentially reducing their efficacy.
Example: Phenobarbital
Phenobarbital is a known inducer of several CYP enzymes, including CYP3A4 and CYP2C9. Chronic use of phenobarbital can lead to a two- to threefold increase in the metabolism of drugs metabolized by these enzymes, such as warfarin and certain statins. The induction effect builds up over 7 to 10 days of continuous phenobarbital use and similarly resolves over 7 to 10 days after withdrawal.
Altered Metabolism: Inhibition of CYP Isoenzymes
Mechanism: Inhibitors of CYP enzymes decrease the metabolism of drugs that are substrates for those enzymes, leading to increased plasma concentrations, which can increase the risk of toxicity.
Example: Grapefruit Juice
Grapefruit juice contains compounds that inhibit CYP3A4, one of the most important enzymes for drug metabolism. Consuming grapefruit juice can lead to increased plasma levels of drugs metabolized by CYP3A4, such as certain calcium channel blockers (e.g., felodipine), statins (e.g., simvastatin), and others.
Clinical Considerations
Risk Assessment: When prescribing medications, assess the potential for interactions with the patient’s existing medication regimen, considering both inducers and inhibitors of CYP enzymes.
Monitoring and Adjustment: Monitor patients for signs of altered drug efficacy or toxicity when initiating or discontinuing medications known to affect CYP enzyme activity. Dosage adjustments may be necessary to maintain therapeutic drug levels.
Patient Education: Educate patients about potential interactions between their prescribed medications and over-the-counter products, supplements, or dietary factors known to affect drug metabolism, such as grapefruit juice.
Alternative Therapies: When possible, consider prescribing alternative medications that do not have a significant potential for CYP-mediated interactions, especially in patients on complex medication regimens.
