reversible inhibitor

**Definition:** A reversible inhibitor forms an enzyme–inhibitor (EI) complex through weak, noncovalent bonds. The EI complex is in equilibrium with free enzyme and inhibitor (Ki = dissociation constant), so inhibition depends on inhibitor concentration and can be overcome or removed by dilution, dialysis, or drug clearance.

**Types (Michaelis-Menten / Lineweaver-Burk):** 1. **Competitive** - Binds the active site and competes with substrate. - Vmax unchanged. Km increased (apparent affinity decreased). - Overcome by ↑ substrate. - Lineweaver-Burk: lines intersect on the y-axis (same 1/Vmax), with a steeper slope and a x-intercept closer to zero. - Examples: statins (HMG-CoA reductase), methotrexate (DHFR), sulfonamides (dihydropteroate synthase, vs PABA), neostigmine/physostigmine (acetylcholinesterase), captopril/enalapril (ACE), allopurinol (xanthine oxidase), ethanol for methanol/ethylene glycol toxicity with fomepizole (alcohol dehydrogenase), finasteride (5α-reductase), protease inhibitors. 2. **Noncompetitive (allosteric)** - Binds an allosteric site, which can be on the free enzyme or the ES complex. It lowers the amount of functional enzyme. - Vmax decreased. Km unchanged. - NOT overcome by ↑ substrate. - Lineweaver-Burk: lines intersect on the x-axis. - Examples: some descriptions list calcitriol/aspirin-like or heavy metals, but classic board examples are **febuxostat** (xanthine oxidase, nonpurine) and **cyanide** (cytochrome oxidase, though more often treated as irreversible or noncompetitive). Many boards simply use the generic concept. 3. **Uncompetitive** - Binds only the enzyme–substrate complex. - Both Vmax and Km decreased. - Not overcome by ↑ substrate. - Lineweaver-Burk: parallel lines. - Example: lithium (inositol monophosphatase). - Rare in USMLE.

**Comparison with irreversible inhibitors:** Irreversible inhibitors form covalent bonds (or near-permanent binding), which decreases Vmax like noncompetitive inhibition and is not overcome by substrate. Recovery requires new enzyme synthesis (e.g., aspirin on COX-1 in platelets, which lasts ~7–10 days, the platelet lifespan), or an antidote/reactivator in some cases. Other examples: organophosphates (acetylcholinesterase; pralidoxime can reactivate before "aging"), PPIs (H+/K+ ATPase), clopidogrel/prasugrel (P2Y12), MAOIs (phenelzine, tranylcypromine), fluorouracil (thymidylate synthase), disulfiram (aldehyde dehydrogenase), penicillins (transpeptidase), and sarin.

**Clinical significance:** - Reversible competitive inhibitors can be outcompeted by high substrate (e.g., ↑ ACh at the neuromuscular junction), so efficacy varies with substrate levels. - Reversible inhibition produces a shorter, more titratable duration of effect than irreversible inhibition, which is often governed by enzyme turnover rather than drug half-life. This affects dosing and the need to stop drugs before surgery (e.g., stopping aspirin or clopidogrel several days beforehand). - Potency is described by Ki, and a lower Ki means a more potent inhibitor. - Pharmacology parallel: **competitive antagonists** at receptors (e.g., naloxone, atropine) shift the dose-response curve right (↑ EC50, same Emax), while **noncompetitive antagonists** decrease Emax.

**High-yield memory aids:** - Competitive: "Km goes up, Vmax stays the same" (resembles substrate, binds the active site). - Noncompetitive: "Vmax goes down, Km stays the same" (allosteric). - Uncompetitive: "Both go down" (binds ES complex only; parallel lines). - Irreversible: acts like noncompetitive (↓Vmax) with covalent binding.