Drug Interactions

Chapter 3: 2025 Naplex Book

What is a pharmacodynamic drug interaction?

A pharmacodynamic interaction is an effect or change that a drug has on the body.

When do pharmacodynamic interactions occur?

They occur when two or more drugs are given together and their effects impact each other.

What types of pharmacodynamic interactions can occur?

Additive, antagonistic, and synergistic.

What is a pharmacokinetic drug interaction?

A pharmacokinetic interaction occurs when one drug affects the absorption, distribution, metabolism, or excretion (ADME) of another drug. (effect that the BODY has on a drug)

What causes additive pharmacodynamic effects at the same receptor?

Multiple drugs acting as agonists at the same receptor can produce additive effects.

What is an example of additive effects from drugs acting at the same receptor?

Opioids are mu-receptor agonists. Taking two opioids together can cause additive effects.

What adverse effects can occur when two opioids are taken together?

Increased sedation, respiratory depression, and risk of death.

Can drugs acting at different receptors still produce additive effects?

Yes. Drugs with different MOAs or receptors can still produce additive effects if they have similar end effects.

How do benzodiazepines and opioids produce additive effects despite different receptors?

Benzodiazepines enhance GABA activity while opioids act at mu receptors, but both cause sedation and respiratory depression.

What safety concerns exist with concurrent benzodiazepine and opioid use?

The combination can cause fatal overdose, carries a boxed warning (BBW), and requires close patient monitoring.

Where does absorption of most oral drugs occur?

The small intestine.

What are distribution, metabolism, and excretion?

Distribution = movement through blood and tissues; Metabolism = enzymatic reactions; Excretion = removal of the drug or metabolites from the body.

Which medications should generally be separated from polyvalent cations or other binding agents?

Quinolones, tetracyclines, levothyroxine, and oral bisphosphonates.

How can increased gastrointestinal pH affect drug absorption?

Some drugs require an acidic gut for absorption; increasing GI pH can decrease their absorption.

Which acid-suppressing drugs commonly increase gastrointestinal pH?

H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs).

What is an example of a drug interaction caused by increased gastrointestinal pH?

H2RAs and PPIs can decrease the absorption of itraconazole.

What can happen when itraconazole absorption is decreased by acid-suppressing drugs?

It can result in untreated or resistant infections.

Where do most pharmacokinetic drug interactions involving metabolism occur?

During metabolism (Phase I or Phase II reactions) in the liver.

Can metabolism-based drug interactions be beneficial or harmful?

Yes, they can be either beneficial or harmful.

How is ritonavir used to beneficially affect darunavir therapy?

Ritonavir inhibits the metabolism of darunavir, boosting darunavir levels and increasing its efficacy in treating HIV.

How does clarithromycin affect warfarin therapy?

Clarithromycin inhibits warfarin metabolism, increasing INR and bleeding risk.

How does rifampin affect warfarin therapy?

Rifampin induces warfarin metabolism, decreasing INR and increasing clotting risk.

How may warfarin dosing need to be adjusted when interacting drugs are used?

The warfarin dose may need to be decreased with clarithromycin or increased with rifampin to maintain the desired INR.

What is the primary route of drug excretion?

Renal excretion.

How can drug interactions affect renal excretion?

Drug interactions can either decrease or increase renal excretion.

How does probenecid affect penicillin excretion?

Probenecid blocks the renal excretion of penicillin.

Why might probenecid be given with penicillin?

It increases penicillin levels, which can help the drug cross the blood-brain barrier (BBB) and treat neurosyphilis.

What are signs of salicylate (aspirin) toxicity?

Tinnitus and metabolic acidosis.

What is the primary function of CYP450 enzymes?

CYP450 enzymes catalyze Phase I reactions.

How do CYP450 enzymes help facilitate renal excretion?

They can uncover or add a polar (water-loving) group to a compound.

What important endogenous compounds can be produced through CYP450 Phase I reactions?

Examples include cholesterol and cortisol.

Where are CYP450 enzymes primarily expressed?

In the liver.

Approximately how many CYP enzymes have been identified, and how many metabolize most drugs?

More than 50 CYP enzymes have been identified, and 6 of them metabolize most drugs.

Which CYP enzyme metabolizes the largest proportion of drug substrates?

CYP3A4 metabolizes approximately 34% of all CYP450 drug substrates.

What factors can affect CYP450 enzyme function?

Genetics and drugs that act as enzyme inhibitors or inducers.

Why are prodrugs used by manufacturers?

To increase bioavailability or help prevent drug abuse.

What is the active metabolite of codeine?

Morphine.

Which phase of metabolism primarily involves CYP450 enzymes?

Phase I metabolism.

Can non-CYP450 enzymes affect drug metabolism?

Yes. Other enzymes, including Phase II enzymes, can alter drug levels.

What is UGT1A1?

UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) is a Phase II enzyme involved in drug metabolism.

Why is bictegravir commonly used as an example of non-CYP450 metabolism?

Bictegravir is a substrate of both CYP3A4 and UGT1A1.

How can CYP3A4 or UGT1A1 inhibitors and inducers affect bictegravir?

They can alter the metabolism of bictegravir.

What is N-acetyltransferase (NAT)?

NAT is a Phase II enzyme involved in acetylation reactions.

Why is NAT important in pharmacogenomics?

NAT is highly polymorphic, meaning genetic differences can affect enzyme activity.

Why can patients experience different levels of isoniazid toxicity?

Differences in NAT activity can cause different rates of acetylation, leading to differences in isoniazid toxicity.

How do CYP enzyme inhibitors affect substrate drug concentrations?

CYP inhibitors decrease enzyme function and metabolism, causing substrate drug concentrations to increase.

How do CYP enzyme inhibitors affect prodrugs?

CYP inhibitors reduce conversion of prodrugs to their active forms, decreasing active drug concentrations.

How quickly does CYP enzyme inhibition occur?

Enzyme inhibition is fast; effects are typically seen within a few days and end soon after the inhibitor is discontinued.

How are CYP inhibitors classified and why are some drugs involved in many interactions?

FDA labels CYP inhibitors as strong, moderate, or weak. Many interactions involve moderate or strong CYP3A4 inhibitors, while some drugs (e.g., amiodarone) inhibit multiple CYP enzymes.

How do CYP enzyme inducers affect substrate drug concentrations?

CYP inducers increase enzyme production or activity, increasing metabolism and decreasing substrate drug concentrations.

What clinical problem can CYP enzyme inducers cause?

Therapeutic failure.

How do CYP enzyme inducers affect prodrugs?

CYP inducers increase conversion of prodrugs to their active forms, increasing active drug concentrations.

How are CYP enzyme inducers classified?

FDA labels CYP inducers as strong, moderate, or weak.

Why are some CYP inducers involved in many drug interactions?

Many are moderate or strong CYP3A4 inducers and/or induce multiple CYP enzymes (e.g., rifampin).

What does the G ♥ PACMAN mnemonic stand for?

Grapefruit; Protease inhibitors (especially ritonavir); Azole antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, isavuconazonium); Cyclosporine and cobicistat; Macrolides (clarithromycin and erythromycin, not azithromycin); Amiodarone (and dronedarone); Non-DHP calcium channel blockers (diltiazem and verapamil).

what menmonic is used to remember the common CYP450 inhibitors?

G ♥ PACMAN

How should CYP inhibitor interactions be managed?

Perform therapeutic drug monitoring; monitor for therapeutic effects, ADRs, and toxicity; consider decreasing the substrate dose (unless it is a prodrug) or using an alternative drug.

What does the PS PORCS mnemonic stand for?

Phenytoin, Smoking, Phenobarbital, Oxcarbazepine, Rifampin (including rifabutin and rifapentine), Carbamazepine, and St. John's wort.

Which CYP inducer is also an auto-inducer?

Carbamazepine.

Why do CYP inducer interactions have a lag time?

Induction requires production of additional enzymes, so full effects may take up to 4 weeks to appear and 2–4 weeks to disappear after the inducer is stopped.

What is the function of P-glycoprotein (P-gp) efflux pumps?

P-gp efflux pumps protect against foreign substances by transporting them out of cells.

What does "efflux" mean, and how do P-gp pumps affect drugs in the GI tract?

Efflux means "to flow out." P-gp pumps drugs and metabolites into the gut, where they can be excreted in the stool.

How does inhibition of P-gp affect a P-gp substrate?

P-gp inhibition decreases drug efflux into the gut, increasing absorption and substrate drug levels.

How can efflux pumps contribute to chemotherapy resistance?

Some efflux pumps remove chemotherapeutic agents from cancer cells, reducing drug effectiveness.

What is the function of the OATP1B1/3 transporter?

OATP1B1/3 transports drugs and other compounds from the blood into the liver.

What are the common P-gp substrate anticoagulants and cardiovascular drugs?

Anticoagulants: apixaban and rivaroxaban.

Cardiovascular drugs: digoxin, diltiazem, verapamil.

What are the common P-gp substrate HCV drugs, immunosuppressants, and other substrates?

HCV: sofosbuvir.

Immunosuppressants: cyclosporine, tacrolimus.

Others: colchicine

What are the common P-gp inducers?

Carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John's wort, and tipranavir.

What anti-infectives are common P-gp inhibitors?

Clarithromycin, itraconazole, and posaconazole.

What cardiovascular drugs are common P-gp inhibitors?

Amiodarone and verapamil.

What HCV drugs, HIV drugs, and other agents are common P-gp inhibitors?

HCV: ledipasvir. HIV: cobicistat and ritonavir. Others: cyclosporine, flibanserin, and ticagrelor.

What is enterohepatic recycling?

After a drug is metabolized in the liver, it can be transported through the bile to the gut, reabsorbed (primarily in the small intestine), return to the liver through the portal vein, and be reused.

What is the effect of enterohepatic recycling on drug therapy?

Enterohepatic recycling increases the duration of action of many drugs.

Which drugs commonly undergo enterohepatic recycling?

Some antibiotics, some NSAIDs, mycophenolate, and ezetimibe.

Why does amiodarone increase the effects of warfarin?

Amiodarone inhibits CYP2C9, decreasing metabolism of the more potent warfarin isomer and increasing INR and bleeding risk.

How should warfarin be managed when used with amiodarone?

If starting warfarin in a patient already taking amiodarone, start at ≤5 mg. If adding amiodarone to warfarin, decrease the warfarin dose by 30–50% and monitor INR.

Why does amiodarone increase digoxin toxicity risk?

Amiodarone inhibits P-gp, and digoxin is a P-gp substrate, causing decreased digoxin excretion and increased digoxin levels and toxicity.

What cardiovascular risks occur when amiodarone and digoxin are used together?

Both lower heart rate, increasing the risk of bradycardia, arrhythmias, and death.

How should digoxin be managed when used with amiodarone?

If starting digoxin in a patient on amiodarone, use a low dose (e.g., 0.125 mg daily). If adding amiodarone to digoxin, decrease the oral digoxin dose by 50%.

What monitoring is required when patients take both amiodarone and digoxin?

Monitor for digoxin toxicity (nausea, vomiting, vision changes) and monitor heart rate.

How do loop diuretics affect electrolyte levels?

Loop diuretics decrease potassium, magnesium, calcium, and sodium.

How do electrolyte abnormalities affect digoxin toxicity risk?

Low potassium, magnesium, or calcium worsen arrhythmias. Low potassium and magnesium and high calcium increase digoxin toxicity risk.

How should digoxin and loop diuretics be managed together?

Monitor electrolytes and correct abnormalities. Digoxin is cleared by P-gp and excreted by the kidneys, so renal impairment increases digoxin levels and toxicity risk; decrease the digoxin dose or frequency, or discontinue if needed.

Which drugs commonly cause additive decreases in heart rate when used together?

Amiodarone, digoxin, beta-blockers, clonidine, diltiazem, verapamil, and dexmedetomidine (Precedex). Diltiazem/verapamil and beta-blockers are often used for rate control; clonidine and beta-blockers are also used to lower blood pressure.

How should patients taking multiple heart rate-lowering drugs be monitored?

Monitor heart rate; normal is generally 60–100 BPM (may be lower depending on patient history and physical state).

Which statins are CYP3A4 substrates commonly involved in interactions?

Lovastatin, simvastatin, and atorvastatin.

Which drugs are considered strong CYP3A4 inhibitors that interact with statins?

Protease inhibitors (including ritonavir), cobicistat, clarithromycin, erythromycin, azole antifungals, cyclosporine, and grapefruit/grapefruit juice.

What is the risk of combining CYP3A4 substrate statins with strong CYP3A4 inhibitors?

Increased statin levels increase the risk of myopathy; severe cases with high CPK can cause rhabdomyolysis and acute renal failure (ARF).

Which statins are contraindicated with strong CYP3A4 inhibitors, and what alternatives are recommended?

Simvastatin and lovastatin are contraindicated. Consider pitavastatin, pravastatin, or rosuvastatin instead.

How do CYP2C9 inhibitors and inducers affect warfarin?

CYP2C9 inhibitors increase warfarin levels, INR, and bleeding risk; CYP2C9 inducers decrease warfarin levels and INR and increase clotting risk.

Which drugs commonly interact with warfarin through CYP2C9, and how should patients be monitored?

Inhibitors: azole antifungals, sulfamethoxazole/trimethoprim, amiodarone, metronidazole. Inducers: rifampin and St. John's wort. Monitor INR (usually goal 2–3; 2.5–3.5 for some high-risk indications such as a mechanical mitral valve). Some drugs, such as amiodarone, may require prophylactic warfarin dose adjustment.

Why should codeine be avoided in CYP2D6 ultra-rapid metabolizers?

They convert codeine to morphine rapidly, increasing the risk of morphine toxicity; avoid codeine.

Why is codeine ineffective in CYP2D6 poor metabolizers and what should be done?

They convert less codeine to morphine, resulting in poor analgesia; use an alternative analgesic.

Why can clopidogrel become less effective? which enzyme activates it?

CYP2C19; inhibitors of CYP2C19 (omeprazole etc) and poor metabolizers reduce the conversion to the active form which decreases antiplatelet activity

What is chelation and give a common example?

Chelation occurs when a drug binds polyvalent cations, forming an insoluble complex that reduces absorption. Example: quinolones bind calcium-containing products and are not absorbed

How does sodium bicarbonate increase salicylate excretion?

Sodium bicarbonate alkalinizes the urine, causing salicylate to become ionized. Ionized drugs are more water-soluble, remain in the urine, and are less likely to be reabsorbed, increasing excretion.

Why is valacyclovir preferred over acyclovir?

Valacyclovir is a prodrug converted to acyclovir and has higher bioavailability, allowing less frequent dosing.

How are CYP inducer interactions monitored and managed?

Monitor therapeutic drug levels and clinical response. Consider increasing the substrate dose (unless it is a prodrug) or using an alternative drug.