Pharmacology - DRUG INTERACTIONS (MADE EASY)

Summary

This video covers the basics of drug-drug interactions, focusing on how multiple medications can affect each other when used together. It explains how drugs interact through mechanisms like cytochrome P450 (CYP450) inhibition, including reversible, non-competitive, and irreversible inhibition. The video delves into concepts such as enzyme binding affinity, Michaelis-Menten kinetics, and intrinsic clearance, with practical examples of how drug interactions can lead to increased toxicity or decreased efficacy. The lecture also highlights the importance of understanding these interactions for effective clinical management and drug safety.

Takeaways

• 😀 Drug-drug interactions can occur when one drug (the perpetrator) alters the disposition of another (the victim), potentially leading to harmful side effects.
• 😀 CYP450 enzymes, primarily found in the liver and gut, play a key role in the metabolism of many drugs, and their inhibition is a common mechanism for drug-drug interactions.
• 😀 CYP450 inhibition can be reversible (competitive or non-competitive) or irreversible (mechanism-based), with each type requiring a different clinical management strategy.
• 😀 The active site of an enzyme is where substrate molecules bind and undergo catalytic reactions, while the allosteric site can influence enzyme activity without directly competing for the active site.
• 😀 Binding affinity, represented by the Michaelis constant (Km), determines how strongly a substrate binds to an enzyme. A lower Km means a higher binding affinity and vice versa.
• 😀 Liver metabolism is crucial for drug elimination, and intrinsic clearance (CLint) reflects the liver's ability to clear unbound drugs, which is affected by binding affinity (Km).
• 😀 Competitive inhibition occurs when two drugs compete for the same CYP450 enzyme's active site, with the drug that binds more strongly displacing the weaker one, affecting drug metabolism.
• 😀 Non-competitive inhibition involves binding to an allosteric site, leading to a structural change in the enzyme that prevents substrate binding, and this type of inhibition cannot be overcome by increasing substrate concentration.
• 😀 Mixed inhibition occurs when an inhibitor binds to either the enzyme's active or allosteric site, making it more potent than competitive or non-competitive inhibition.
• 😀 Irreversible inhibition (mechanism-based inhibition) occurs when a stable intermediate or reactive metabolite forms covalent bonds with the enzyme, preventing its function, as seen with drugs like Esomeprazole and Clopidogrel.

Q & A

What is the main focus of this lecture?

The main focus of the lecture is to explain the basics of drug-drug interactions, with a specific emphasis on CYP450 enzyme-mediated inhibition and its clinical implications.

Why are drug-drug interactions common in clinical practice?

Drug-drug interactions are common because patients often have multiple chronic diseases and require several medications concurrently, which increases the risk of interactions between the drugs.

What role do CYP450 enzymes play in drug metabolism?

CYP450 enzymes are crucial for the clearance of various compounds from the bloodstream, as they metabolize many drugs primarily in the liver and gut mucosa.

How are CYP450 inhibitors classified?

CYP450 inhibitors are classified as reversible (which include competitive and non-competitive inhibition) and irreversible (such as mechanism-based inhibition).

What is the difference between active sites and allosteric sites in enzymes?

The active site is where the substrate binds and undergoes a chemical reaction, while the allosteric site is a separate site that can influence enzyme activity by binding molecules, either enhancing or inhibiting the enzyme's function.

How does the Michaelis-Menten plot relate to drug metabolism?

The Michaelis-Menten plot shows how the reaction velocity increases as the substrate concentration increases, eventually plateauing when Vmax is reached. The Km value represents the binding affinity between the enzyme and substrate, influencing the rate of drug metabolism.

What is intrinsic clearance and how does it relate to drug metabolism?

Intrinsic clearance (CLint) measures the liver's ability to clear unbound drug. It is calculated as Vmax/Km, where a lower Km (strong binding) results in higher intrinsic clearance, and a higher Km (weak binding) results in lower clearance.

What happens during competitive inhibition?

During competitive inhibition, two drugs compete for the same enzyme active site. The drug with higher binding affinity (perpetrator) will displace the other drug (victim), leading to altered drug metabolism and potential adverse effects or reduced efficacy.

Can competitive inhibition be reversed? How?

Yes, competitive inhibition is reversible. If the concentration of the weaker-affinity drug (victim) is increased, it can displace the stronger-affinity drug (perpetrator), restoring normal enzyme function.

What is non-competitive inhibition, and how does it affect enzyme activity?

Non-competitive inhibition occurs when a drug binds to an allosteric site on the enzyme, causing a conformational change that prevents the substrate from binding to the active site. This type of inhibition is typically long-lasting and cannot be reversed by increasing substrate concentration.

What is the difference between mixed inhibition and other types of inhibition?

Mixed inhibition occurs when an inhibitor can bind either to the enzyme's active site or allosteric site, preventing substrate binding. It is typically more potent than competitive or non-competitive inhibition.

What is irreversible inhibition, and what are its two types?

Irreversible inhibition, also known as mechanism-based inhibition, involves a drug forming a stable, covalent bond with the enzyme, rendering it inactive. The two types are alternate substrate inhibition, where an intermediate binds covalently to the enzyme, and suicide inhibition, where a reactive intermediate irreversibly alters the enzyme's structure.