3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.1. Pharmacology principles
                      3.1.3.1.1. Pharmacokinetics
                          3.1.3.1.1.3. Distribution of drugs
 3.1.3.1.1.3.3. Protein-binding 

Protein-binding

[SH4:p12]

Carriers

  • Most acidic drugs binds to albumin
    * High binding capacity
  • Basic drugs bind to alpha1-acid glycoprotein
    * Lower binding capacity

Importance of protein-binding

  • Only free (i.e. unbound) fraction is able to cross cell membrane

 

Thus,

  • When protein binding is high
    --> Drugs kept in plasma
    --> Plasma concentration is high
    --> Calculated Vd is lower
  • Only unbound fraction can enter hepatocytes and cross glomurulus
    --> Only unbound fraction can undergo hepatic metabolism and glomerular filtration

Changes in protein binding

  • Especially important for drugs which are normally highly protein-bound
  • Because small changes in binding
    --> Large changes in free fraction
  • e.g. propanolol, phenytoin, diazepam

Determinants of protein binding

  • Lipid solubility
    * Protein-binding parallels lipid solubility
    --> Higher lipid solubility is accompanied by higher protein-binding
  • Plasma concentration of the drug
    * Low plasma concentration is more likely to be higher protein bound
  • Number of available binding sites (plasma protein)

Competition for carrier protein

  • Plasma albumin binding is non-selective
    --> Many drugs can compete with each other

For example,

  • Sulfonamides can displace unconjugated bilirubin from albumin
    --> Higher risk of bilirubin encephalopathy in neonates

Drugs carried by proteins

[???]

  • Albumin binds mostly to acidic drugs
    * Salicylates
    * Sulphonamides
    * Barbiturates
  • Alpha1-acid glycoprotein binds mostly to basic drugs
    * Fentanyl
    * Propanolol
    * Diazepam
    * Bupivacaine
    * Ropivacaine
    * Warfarin [???]
    * Quinidine [???]
    * Chlorpromazine [???]
    * Methadone
    * Verapamil [???]
    * Lignocaine [???]

Protein binding and renal failure

In renal failure,
--> Protein-bound fraction of a drug decreases

  • Even when plasma protein level is normal
  • Possibly due to:
    * Alteration of protein
    * Displacement by a metabolic factor which is normally excreted by kidney

Determinants of alpha1-acid glycoprotein level

Alpha1-acid glycoprotein may increase in response to:

  • Surgery
  • Chronic pain
  • Acute MI

 

Alpha1-acid glycoprotein are decreased in neonates
--> Decreased protein binding of diazepam, propanolol, sufentanil, lidocaine