irreversible inhibitor

**Mechanism:** Irreversible inhibitors form stable covalent bonds with amino acid residues in or near the active site (or sometimes bind so tightly that dissociation is negligible). The enzyme is permanently inactivated. Recovery of activity requires synthesis of new enzyme (or new cells/platelets), so duration of effect depends on enzyme/cell turnover rather than drug half-life.

**Kinetics (Lineweaver-Burk):** - Vmax decreases because functional enzyme is effectively removed. - Km is unchanged because the remaining active enzyme has normal substrate affinity. - Increasing substrate cannot overcome the inhibition, so the pattern resembles noncompetitive inhibition (lines intersect on the x-axis). - Contrast with competitive reversible inhibitors, which raise Km, leave Vmax unchanged, and are overcome by more substrate. - Inhibition is often time-dependent, because it accumulates as more enzyme is modified.

**Suicide (mechanism-based) inhibitors:** The enzyme processes the inhibitor as a substrate, converting it to a reactive intermediate that covalently binds and inactivates the enzyme. Examples: allopurinol/oxypurinol (xanthine oxidase), 5-FU (thymidylate synthase via FdUMP), clavulanic acid/sulbactam/tazobactam (β-lactamase), selegiline/rasagiline (MAO-B), eflornithine (ornithine decarboxylase), and finasteride (5α-reductase).

**High-yield clinical examples:** - **Aspirin:** irreversibly acetylates COX-1 and COX-2 (Ser529 in COX-1). Platelets lack a nucleus and cannot make new COX, so the antiplatelet effect lasts 7–10 days, until new platelets are produced. - **Clopidogrel, prasugrel, ticagrelor-class note:** clopidogrel and prasugrel irreversibly bind the P2Y12 ADP receptor. Ticagrelor is reversible, which is why it can have a faster offset. - **PPIs (omeprazole etc.):** irreversibly inhibit the H+/K+ ATPase of gastric parietal cells. Acid secretion returns only after new pumps are made. - **β-lactams (penicillins, cephalosporins):** covalently acylate the transpeptidase (penicillin-binding protein), blocking peptidoglycan cross-linking. - **Disulfiram:** inhibits aldehyde dehydrogenase, causing acetaldehyde accumulation with alcohol. - **MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid):** irreversible nonselective MAO inhibitors. Risks include hypertensive crisis with tyramine and serotonin syndrome. Wait about 2 weeks after stopping before starting an SSRI, since new enzyme must be synthesized. - **Organophosphates (parathion, malathion, sarin):** covalently phosphorylate acetylcholinesterase. "Aging" of the bond makes it permanent. Treat with atropine and pralidoxime (which regenerates the enzyme before aging). - **Fomepizole vs. ethanol:** these are competitive inhibitors, not irreversible (useful contrast). - **Others:** warfarin is NOT an irreversible inhibitor in this sense (it is a reversible VKORC1 inhibitor). Methotrexate is a reversible competitive DHFR inhibitor. Heavy metals (lead, arsenic) can inhibit enzymes irreversibly, as with lead on ferrochelatase and ALA dehydratase. Cyanide inhibits cytochrome oxidase (complex IV), and fluoroacetate inhibits aconitase.

**Pharmacology implications:** - Clinical effect outlasts plasma drug levels. The pharmacodynamic duration is set by the enzyme resynthesis rate. - Dosing can be infrequent (e.g., daily PPI, daily low-dose aspirin). - Toxicity can be prolonged and hard to reverse. Reversal may require new enzyme (or platelet transfusion for aspirin/P2Y12 bleeding). - Potency is described by kinact/KI rather than a simple IC50 or Ki.

**Test tip:** If a question describes a drug whose effect persists after it is cleared, with decreased Vmax and unchanged Km that is not overcome by more substrate, think irreversible inhibitor (covalent). Recovery requires new enzyme synthesis.