Pharmacokinetics: Drug-Drug Interactions (DDI)
Pharmacokinetics: Drug-Drug Interactions (DDI)
Introduction to Drug-Drug Interactions (DDIs)
Definition: The action of one drug to modify the action of another within the body.
Therapeutic Purposes: DDIs can be intentionally utilized to reduce side effects by prescribing lower doses of two drugs that work together to achieve the same therapeutic effect.
Adverse Effects: DDIs can cause adverse effects, including reducing drug efficacy and increasing drug toxicity, even at therapeutic ranges.
Scope: DDI considerations extend beyond prescription and over-the-counter medications to include herbal medications and supplements.
Distinction from Drug Incompatibility: DDIs are distinct from drug incompatibilities, which describe drug interactions when mixed outside the body.
Populations at Risk for DDIs
Elderly Patients: Often have age-related physiological changes (e.g., reduced renal/hepatic function) and commonly take multiple medications (polypharmacy).
Patients with Polypharmacy: Taking five or more medications concurrently significantly increases the risk of DDIs due to the higher probability of interacting drug combinations.
Patients with Impaired Organ Function: Individuals with pre-existing renal or hepatic impairment are more susceptible to DDI-induced toxicity due to altered drug metabolism and excretion.
Genetically Predisposed Individuals: Genetic polymorphisms in drug-metabolizing enzymes (e.g., CYP450) or transporters can alter drug responses and increase DDI risk.
Types and Mechanisms of DDIs
DDIs are approached from both pharmacodynamic and pharmacokinetic standpoints.
Pharmacodynamic Effects of DDIs
Pharmacodynamic DDIs involve how interacting drugs affect the body's response.
Antagonistic Effects: Diminish the effect of one or more interacting drugs.
Receptor-Level Antagonism: Molecules block the effect of an agonist drug.
Competitive Antagonism: Antagonist drug competes for the same receptor binding site as the agonist.
Non-Competitive Antagonism: Antagonist binds to a different site, altering the receptor's response to the agonist.
Example (Competitive): Naloxone (opioid antagonist) for opioid overdose reversal. Naloxone has a stronger affinity for the opioid receptor, displacing opioids and restoring breathing.
Chemical-Level Antagonism: Two drugs or chemicals interact to form an inactive product.
Example 1: Treatment for metal poisoning, where metal ions bind to a chelating agent.
Example 2: Antacids neutralizing stomach acid.
Example 3: Protamine as an antidote for heparin. In cardiac surgeries, high doses of heparin are used to prevent coagulation. Protamine, being highly positively charged, has a high binding affinity for heparin, displacing heparin from coagulation proteins and forming an inactive complex, thereby reversing anticoagulative effects.
Physiological/Functional-Level Antagonism: Two drugs given simultaneously have opposing effects.
Same Receptor Population (Opposing Effects):
Beta-2 Adrenoreceptors: Bronchodilator medications like albuterol are agonists that activate beta-2 adrenoreceptors in the lungs for bronchodilation. Non-selective beta-blockers (e.g., propranolol) block both cardiac beta-1 and widespread beta-2 receptors (including those in the lungs). Thus, non-selective beta-blockers can counter the bronchodilatory effects of beta-2 agonists.
Different Receptor Pools (Targeting Same Physiology):
Heart Rate Regulation: Isoprotenerol (beta-agonist) activates cardiac beta-1 adrenoreceptors to increase heart rate in heart failure. Acetylcholinesterase inhibitors (e.g., donepezil) for Alzheimer's disease increase acetylcholine levels, which stimulate cardiac muscarinic receptors, thereby decreasing heart rate. Through different receptor pathways, these drugs have opposing effects on heart rate.
Agonistic Interactions: Increase the effect of one or more interacting drugs.
Additive Effects: The combined effect of two drugs is equivalent to the sum of each drug's individual effect ().
Example 1 (Anticholinergic Side Effects): Tricyclic antidepressants and first-generation antihistamines both block muscarinic receptors, increasing the likelihood of anticholinergic side effects when taken together.
Example 2 (Anticoagulation): Warfarin (anticoagulant with narrow therapeutic window) taken with NSAIDs (e.g., aspirin) leads to additional inhibition of the COX-1 enzyme, causing an antiplatelet effect. Other drugs impacting clotting factors include broad-spectrum antibiotics (killing intestinal bacteria producing vitamin K) and cephalosporins (directly blocking vitamin K metabolism). Levothyroxine also results in the breakdown of clotting factors. All these interactions increase the risk for bleeding complications.
Synergistic (Super-Additive) Effects: The combined effect of drugs exceeds the sum of the drugs' individual effects (Effect{A+B} > EffectA + Effect_B).
Example 1 (Life-Threatening Sympathomimetic Response): Monoamine oxidase inhibitors (MAOIs, e.g., isocarboxazid) block monoamine oxidase, causing monoamine neurotransmitters to accumulate in nerve terminals. Indirect sympathomimetics (e.g., pseudoephedrine) stimulate the release of monoamine neurotransmitters into the synapse. When combined, a large pool of built-up monoamine neurotransmitters is suddenly released, causing an excessive, life-threatening adrenergic response (e.g., hypertensive crisis).
Example 2 (Beneficial Synergism - Multimodal Analgesia): Used for more effective pain relief at lower individual doses and fewer side effects. Involves multiple drugs with different mechanisms (e.g., local anesthetics like lidocaine, NSAIDs, low-dose opioids, alpha-2 agonists like clonidine) working together on central pain inhibition pathways.
Potentiation: One drug with no therapeutic effect alone enhances the effect of another drug when given in concert.
Example: Beta-lactam antibiotics (e.g., penicillin) and beta-lactamase inhibitors (e.g., clavulanic acid). Bacteria with beta-lactamase enzymes can break down beta-lactam antibiotics. Clavulanic acid does not directly kill bacteria but blocks beta-lactamase, preventing the breakdown of the antibiotic and enhancing its effect.
Pharmacokinetic Effects of DDIs
Pharmacokinetic DDIs involve how drug interactions affect their absorption, distribution, metabolism, and excretion in the body.
Absorption: Drugs can impact absorption by:
Altering GI pH:
Antacids, proton pump inhibitors (PPIs), and H2 blockers all raise GI pH.
Effect on Acid-Dependent Drugs: Drugs requiring an acidic environment for dissolution (e.g., the antifungal ketoconazole) will show decreased absorption in a higher pH GI environment.
Effect on Enteric-Coated Tablets: Increasing pH can cause enteric-coated tablets (designed to dissolve in the more basic small intestine) to dissolve prematurely in the stomach.
Altering GI Motility:
Increased motility (e.g., metoclopramide) generally results in increased drug absorption rates.
Decreased motility (e.g., antimuscarinics) generally results in decreased drug absorption rates.
Drug Binding to Other Drugs: As seen in chemical antagonism, drugs can bind to each other in the GI tract, reducing their absorption.
Altering Subcutaneous Absorption: Reducing blood flow and tissue perfusion.
Vasoconstrictors: Epinephrine (often given with local anesthetics) intentionally slows their absorption by reducing blood flow at the injection site.
Cardiac Suppressants: Beta-blockers can reduce blood flow, leading to decreased absorption of other drugs.
Distribution and Binding:
Plasma Protein Binding Competition: Drugs can compete with other plasma protein-bound drugs, displacing them. This effectively increases free drug levels of the displaced drug in plasma, potentially resulting in unexpected toxicity or increased effect.
Membrane Transporters: Crucial for drug disposition and a major site of DDIs.
P-glycoprotein (P-gp): An efflux transporter found in the gut, blood-brain barrier, liver, and kidneys.
Inhibition: P-gp inhibitors (e.g., verapamil, quinidine) prevent efflux, increasing systemic concentrations and potentially toxicity of substrate drugs.
Induction: P-gp inducers will have the opposite effect, decreasing systemic concentrations of substrate drugs.
A wide range of drugs are known inhibitors, inducers, or substrates for P-gp.
Organic Anion Transporters (OATP1B1 & OATP1B3): Primarily active in the liver, pumping drugs (especially statins) from the bloodstream into liver cells for metabolism.
Renal Transporters (OAT, OCT, MATE): Organic Anion Transporters (OAT) and Organic Cation Transporters (OCT) transport drugs from blood into kidney cells, while Multidrug and Toxin Extrusion (MATE) transporters move drugs from kidney cells into urine for excretion.
Inhibition: Inhibition of these transporters (e.g., by thyroxine, cimetidine, pyrimethamine) can result in increased systemic drug concentrations and potentially toxicity due to decreased clearance.
Increased Renal Exposure: If MATE transporters are more affected than OATs/OCTs, it can lead to increased buildup of the drug inside the renal proximal tubules, resulting in increased renal effect and potentially renal toxicity.
Metabolic Clearance (Cytochrome P450 Enzymes):
Primary Enzymes: CYP2D6 and CYP3A4 are the two most implicated CYP enzymes in drug metabolism and DDIs.
CYP Inhibitor Effects: CYP inhibitors result in decreased metabolism of substrate drugs, leading to increased plasma concentrations and often increased toxicity. This can occur through:
Direct binding to the enzyme (competitive or allosteric site).
Substrates competing for the active site, reducing metabolism of competitor substrates.
Example (CYP2D6): SSRIs like fluoxetine and paroxetine. Fluoxetine inhibits CYP2D6 by competitively binding, while paroxetine forms an irreversible complex. When taken with risperidone (a CYP2D6 substrate), risperidone levels rise, increasing the risk of extrapyramidal motor side effects.
Impact of Hepatic Blood Flow: Drugs like propranolol, which reduce hepatic blood flow, can also reduce overall hepatic clearance rates for drugs with a high hepatic extraction ratio. Other drugs like and can also reduce overall hepatic clearance, through mechanisms such as enzyme inhibition or alteration of transporter activity, or by competing for metabolic pathways, leading to increased systemic drug concentrations.
Excretion (Renal Function):
Drugs can alter renal function and thus drug excretion by:
Altering renal blood flow.
Modifying glomerular filtration rate (GFR).
Modifying urinary pH.
”Triple Whammy” of Acute Kidney Injury (AKI): The simultaneous use of three common drug classes significantly increases the risk of AKI:
ACE inhibitors or Angiotensin Receptor Blockers (ARBs): Reduce glomerular efferent arteriolar tone, decreasing intraglomerular pressure.
Diuretics: Cause intravascular volume depletion, reducing renal perfusion.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Inhibit renal prostaglandin synthesis, leading to afferent arteriolar vasoconstriction and decreased renal blood flow.
When combined, these drugs synergistically reduce glomerular filtration rate (GFR) and renal blood flow, predisposing patients to AKI, especially in vulnerable populations.
Learning Objectives
Upon reviewing this note, you should be able to:
Define drug-drug interactions (DDIs) and differentiate them from drug incompatibilities.
Explain the therapeutic and adverse consequences of DDIs.
Identify populations at increased risk for experiencing DDIs.
Describe pharmacodynamic mechanisms of DDIs, including antagonistic (receptor, chemical, physiological) and agonistic (additive, synergistic, potentiation) effects.
Describe pharmacokinetic mechanisms of DDIs, encompassing effects on absorption, distribution, metabolism (especially CYP enzymes and hepatic blood flow), and excretion.
Provide examples of specific drugs and their interacting mechanisms for each DDI type.
Understand the concept of the “triple whammy” in acute kidney injury due to DDI.