3.12
Distribuzione dei Farmaci: Legame alle Proteine Plasmatiche
I farmaci si legano prevalentemente alle proteine plasmatiche, con solo una piccola percentuale che rimane libera. La parte non legata può essere ca…
La maggior parte dei farmaci si lega principalmente alle proteine plasmatiche come l'albumina, con solo una piccola frazione che rimane non legata. Questa frazione libera non legata è uguale a uno meno la frazione associata.
I farmaci acidi si legano in modo reversibile all'albumina plasmatica per formare grandi complessi inattivi che non sono in grado di diffondersi attraverso le barriere biologiche.
Tali complessi farmaco-proteina fungono da serbatoi di farmaci. Quando la concentrazione di droghe libere diminuisce, i complessi si dissociano rapidamente, rilasciando la droga libera e mantenendo la frazione libera.
La quantità di farmaci legati alle proteine è influenzata dalla concentrazione di farmaco libero e proteina, dal numero di siti di legame e dall'affinità tra il farmaco e i siti di legame.
Diversi farmaci o sostanze endogene possono legarsi in modo competitivo alle proteine plasmatiche.
Ad esempio, il legame competitivo della sulfonamide riduce l'affinità dell'albumina per la bilirubina, causando il rilascio di bilirubina libera. Questo può aumentare il rischio di encefalopatia da bilirubina nei neonati.
Allo stesso modo, durante l'esercizio, il metabolismo dei grassi rilascia alte concentrazioni di acidi grassi liberi nel plasma. Questi acidi grassi sostituiscono i farmaci legati all'albumina e aumentano la concentrazione di farmaci liberi.
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Q1: What fraction of drugs remains unbound in plasma?
Only a small fraction of drugs remains unbound in plasma, while most bind to plasma proteins like albumin. The unbound free fraction equals one minus the fraction that is bound. This free fraction is pharmacologically active and capable of producing drug effects and crossing biological barriers to reach target tissues.
Q2: How do drug-protein complexes function as drug reservoirs?
Acidic drugs reversibly bind to plasma albumin, forming large inactive complexes that cannot diffuse across biological barriers. When free drug concentration declines, these complexes rapidly dissociate to release free drug, maintaining the unbound fraction. This reservoir mechanism helps sustain drug availability and therapeutic effects throughout the body.
Q3: What factors determine the amount of protein-bound drug?
Protein-bound drug quantity depends on the concentration of free drug and protein, the number of available binding sites, and the affinity between drug and binding sites. These factors work together to establish equilibrium between bound and unbound drug states, influencing overall drug distribution and pharmacological activity.
Q4: How does competitive binding affect drug and bilirubin levels?
Different drugs and endogenous substances compete for plasma protein binding sites. When sulfonamide competitively binds to albumin, it reduces albumin's affinity for bilirubin, causing free bilirubin release. This increases bilirubin encephalopathy risk in newborns by elevating unbound bilirubin concentrations in the bloodstream.
Q5: What happens to drug-protein binding during exercise?
During exercise, fat metabolism releases high concentrations of free fatty acids into plasma. These fatty acids displace drugs bound to albumin through competitive binding, increasing the concentration of free, unbound drugs. This displacement can enhance drug bioavailability and potentially alter therapeutic effects and drug efficacy.
Q6: Why are acidic drugs unable to cross biological barriers when protein-bound?
Acidic drugs form large, inactive complexes when reversibly bound to plasma albumin. These complexes are too large and polar to diffuse across biological membranes, effectively sequestering the drug in the vascular compartment. Only the unbound free fraction can penetrate tissues and exert pharmacological effects at target sites.
Q7: How does the unbound drug fraction relate to drug efficacy?
Only the unbound free fraction of drug is pharmacologically active and capable of producing therapeutic effects. The unbound fraction is calculated as one minus the bound fraction. Changes in protein binding through competitive displacement or altered protein concentrations directly affect drug efficacy, clinical outcomes, and therapeutic success.