A drug in the body can interact with several tissue components of which the two major categories are blood and extravascular tissues.
The interacting molecules are generally the macromolecules such as
proteins, DNS and adipose tissue.
The phenomenon of complex formation of drugs with protein is called protein binding.
As a protein-bound drug is neither metabolized or excreted, it is pharmacologically inactive.
Protein + drug ⇌Protein-drug complex
Protein binding may be divided into:
1. Intracellular binding.
2. Extracellular binding.
MECHANISMS OF PROTEIN DRUG BINDING.
Binding of drugs to proteins is generally reversible & irreversible.
Reversible generally involves weak chemical bonds such as:
1. Hydrogen bonds
2. Hydrophobic bonds
3. Ionic bonds
4. Van der waals forces.
Irreversible drug binding, though rare, arises as a result of covalent binding and is often a reason for the carcinogenicity or tissue toxicity of the drug.
BINDING OF DRUG TO BLOOD COMPONENTS:
A. Plasma protein-drug binding:-
The binding of drugs to plasma proteins is reversible.
The extent or order of binding of drug to plasma proteins is:
Albumin ›ὰ1-Acid glycoprotein ›Lipoproteins ›Globulins.
1. Binding of drug to Human Serum Albumin (HSA):
Most abundant plasma protein (59%),
M.W.: 65,000
Large drug binding capacity.
Both endogenous compounds such as fatty acid, bilirubin as well as drugs bind to HSA.
Four different sites on HSA for drug binding.
Site I: warfarin & azapropazone binding site.
Site II: diazepam binding site.
Site III: digitoxin binding site.
Site IV: tamoxifen binding site.
2. Binding of drug to α1-Acid glycoprotein:
α1-Acid glycoprotein is als called “Orosomucoid”.
Plasma conc. range of 0.04 to 0.1 g%.
M.W. 44,000.
Binds to no. of basic drugs like imipramine, lidocaine, propranolol,n quinidine etc.
3. Binding of drug to Lipoproteins:
Four types,
Chylomicrons.
Verl Low Density Lipoproteins (VLDL).
Low Density Lipoproteins (LDL).
High Density Lipoproteins (HDL).
Binding by: Hydrophobic Bonds,
Non-competitive.
Mol wt: 2 L -34 L dalton.
Lipid core composed of:
Inside: triglyceride & cholesteryl esters.
Outside:Apoprotein.
E.g of drugs:
Acidic: Diclofenac.
Neutral: CyclosporinA.
Basic: Chlorpromazine.
4. Binding of Drugs to Globulines:
Globulines are mainly used for transportation of internal substances; however, certain drugs also bind with them.
They are of the following types,
𝞪 Globulines 1.
𝞪 Globulines 2.
𝞫 Globulines 1.
𝞫 Globulines 2.
𝜸 Globulines.
𝞪 Globulines 1 are also called Corticoplasmins, they transfer corticosteroids, certain drugs like Hydrocortisone and Prednisolone are known to bind with them.
𝞪 Globulines 2 are also called Ceruloplasmins, they transfer Fat Soluble vitamins like Vit. A, D, E, K.
𝞫 Globulines 1 are called Transferrin and are involved in transport of Iron.
𝞫 Globulines 2 are involved in transport of carotenoids.
𝜸 Globulines are mainly involved in Antigen Antibody reaction and are now a days explored for Antiviral actions.
B. BINDING OF DRUG TO BLOOD CELLS:
Blood contains 40% of blood cells of which the major component is RBC (95%).
The RBC is 500 times in diameter as the albumin.
The rate & extent of entry into RBC is more for lipophilic drugs.
The RBC comprises 3 components
a) Hemoglobin: It has a M.W. of 64,500 Dal. Drugs like phenytoin, pentobarbitone bind to hemoglobin.
b) Carbonic anhydrase: Carbonic anhydrase inhibitors drugs are bound to it like acetazolamide & chlorthalidone.
c) Cell membrane: Basic drugs like Imipramine & chlorpromazine are reported to bind with the RBC membrane.
BINDING OF DRUG TO EXTRAVASCULAR TISSUE PROTEINS.
Rare phenomenon.
Usually irreversible and is the result of toxicity of the drugs.
Drugs showing higher binding to extracellular proteins have a higher apparent volume of distribution.
There is no competition for binding sites.
Factors affecting: lipophilicity, structural feature of drug, perfusion rate, pH differences.
Binding order: Liver › Kidney › Lung › Muscles.
Liver: Metabolites of Chloroform And Paracetamol bind with liver components causing toxicity.
Lungs: Basic drugs accumulate in lungs e.g. Imipramine, propranolol, Antihistamines etc.
Kidney: Heavy metals bind with Metallothionein protein in the kidney causing nephrotoxicity.
Skin and Eye: Chloroquine and Phenothiazines bind with melanin.
Hairs: Arsenic, Chloroquine and Phenothiazines.
Bones: Tetracyclines.