Binding Of drug for distribution

 C. binding of drug to tissue component

1. Binding of drug to blood/ plasma protein

Plasma protein binding

• Most drugs, after absorption from gut, transported in to forms: free form and bind form.
  
• In case of free form, the drug is solubilised in plasma and transported. If the drug is in the bind form it means that it is bound with the plasma components like proteins, blood cells etc.
• The drug may be bound with the proteins like albumin, globulin, lipoprotein (very less or not bind with fibrinogen), glycoprotein transferrin etc. and it also can bind with RBC, on the small extent with WBC.
• Albumin is a major carrier for weak acidic drug & α1 glycoprotein (gp) binds to basic drugs. Albumin & α1 gp binds to drug non specifically. Other proteins are also acts as binding site on small extent.
• The binding of drug influences distribution, metabolism and elimination. These type of bound drugs are not available for the mechanism of action. Only free drug shows the pharmacological activity.
• Drugs that are circulated in the body as bound and unbound form, they are in equilibrium.
• It means the drugs which are bind with plasmaprotein (pp) cannot diffuse through capillary wall to reach the site of action.
• At the low dose, the drug is execcively bind with pp or any other substances. So free drug conc. is less. But with the same drug, during repeated dose or high dose the free drug conc. is increased but there is no effect on binding because the binding sites are saturated. Increased in the free drug conc. and if the drug having low therapeutic index causes toxic effect in the body.

ALBUMIN: It is produced by the liver, having molecular wt. of 69000, is abundant in pp. In the blood around 7% of protein is present out of which 54-55% of the albumin is there. They are smaller and most of the weak acids are bind to them. The albumin is binds with both +ve & -ve charge drugs. The bonds are not so strong but weak like H-bond, Vander waal’s forces, hydrophobic forces etc.

α1 GP: the carbohydrate (c.h) molecule binds to protein and forms gp. α1- acid gp binds the most of the basic drug .

LIPOPROTEIN: lipidic substance binds to the protein term as lipoprotein .the are present in the low extent than albumin. The drug molecule dissolve in the lipid portion of the lipoprotein .its lipid core is made up of the triglycerides, cholesterol. All type of acidic, basic or neutral drug can be bind with the lipoprotein but mostly weak basic. They are classified into LDL, HDL, VLDL , can binds to drug out of which VLDL binds easily then LDL & HDL

GLOBULIN: there are 3 types of globulin α, β, γ produce by the liver. γ globulins are nothing but Abs. that binds with the Ags. α & β globulin acts as binding site for drug.
α- steroidal drugs and fat soluble vitamin. β1-gloublin is nothing but transferrin which bind & transfer ferrous ion.

The bound and free drugs are always in the equilibrium. so loss of free drug causes the release of drug as free from the bound. Thus , it act as reservoir for the drug the free drug is lost by excretion and metabolism.

The drugs which bind to pp are mostly competed by other drugs, due to similar physicochemical property. So, displacement of drug can be possible due to other drug. Ex-1) Salicylates reduces the binding of thyroxine to protein.2) The displacement of bilirubin from albumin by sulphonamide leads to increased risk of bilirubin encephalopathy.3) The warfarin (anti coagulant) is replaced by phenoimidazole and increased its conc. leads to more bleeding in minor injury.

If the drug is bound to pp can’t filter from glomerulas but can be secreted.

Binding with blood cells
      • The drugs mostly bind with the RBC.
      • Hb: drugs like phenytoin, phenobarbitol can bind with it.
      • Carbonic anhydrase: acetazolamide.
      • Cell membrane of RBC: imipramine.

Binding of drug component with tissue & extra vascular component:

• For the pharmacological action of the drug, it has to bind with particular tissue or receptor.
• Some drug concentrated more site to site other than blood and interstitial fluid. Lipid soluble drug easily penetrate the cells & accumulate where as water soluble drugs mainly binds to receptor of the cells.
• The drug molecule binds reversibly with the tissue. But if irreversible binding occurs, it causes toxicity. Ex- paracetamol binds irreversibly with liver.
• Due to binding of the drug molecule with the tissue, it is isolated from the blood and presence as bind form. It means free drug conc. Is less and it is acting by sustained release of the drug, so elimination time is decrease and increase t ½ of the drug
• This type of drug during repeated doses for long time increase conc. in such tissues which leads to toxicity.
  Ex-liver : paracetamol
  Lung : Imipiramine
  Kidney : Heavy metals like lead,mercury.
  Skin : Chloroquine
  Eye : retinal pigment contain melanin
  Hair : Osnicles
  Bones : Tetracycline, phenytoin
  Fat : DDT, thiopental
• Drugs like paracetamol metabolites to carbon tetrachloride which binds irreversibly with the liver & leads to hepatic toxicity.
• In the obese person the adipose tissue or fat content is high so the drugs which are bind to the fat can’t be given where fat is acts as depot site for drug. fat is low perfused site in the body, so acting as reservoir for the drug. Same in case of phenytoin which accumulate in the bone by absorption at a surface. It acts on noctinal epileptic attack decrease risk of attack during night.