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Renin Angiotensin Mechanism.

FACTORS AFFECTING PROTEIN DRUG BINDING.

 

FACTORS AFFECTING PROTEIN DRUG BINDING.

  • Different factors that affect plasma protein binding of a drug are as follows,

    • 1) Drug-related factors.

      • a) Physicochemical characteristics of the drug.

      • b) Concentration of the drug in the body.

      • c) Affinity of a drug for a particular binding component.

    • 2) Protein/ tissue related factors:

      • a) Physicochemical characteristics of protein or binding agent.

      • b) Concentration of protein or binding component.

    • 3) Drug interactions:

      • a) Competition between drugs for the binding sites[ Displacement interactions.

      • b) Competition between drug & normal body constituents.

      • c) Allosteric changes in protein molecules.

    • 4) Patient-related factors:

      • a) Age, Sex, Body Weight:

      • b) Intersubject variability.

      • c) Disease states.

  1. Drug Related Factors:

  1. Physicochemical characteristics of the drug:

    • Protein binding is directly related to the lipophilicity of the drug.

    • An increase in lipophilicity increases the extent of binding

    • Drugs bind to specific binding sites as per their nature i.e. Acidic, basic and neutral.

  2. Concentration of the  drug in the body:

    • Alteration in the concentration of a drug substance as well as the  molecules or binding surfaces ultimately brings changes in the binding process.

  3. Affinity of a drug for a particular binding component:

    • Plasma protein binding of a drug depends upon the degree of attraction or affinity the protein molecule or tissues have towards the particular drug molecule.

    • Digoxin has more affinity for cardiac muscle proteins as compared to proteins of skeletal muscles and plasma proteins like HSA.

2) Protein/ tissue related factors:

  1. Physicochemical characteristics of protein or binding agent:

    • Lipoproteins & adipose tissue tend to bind lipophilic drug by 

    • dissolving them in their lipid core.

    • The physiological pH determines the presence of active anionic & cationic groups on the albumin to bind a variety of drugs.

  2. Concentration of protein or binding component:

    • Among the plasma proteins , binding predominantly occurs with  albumin, as it is present in higher concentration in comparison to  other plasma proteins.

    • The amount of several proteins and tissue components available for binding, changes during disease state

3) Drug interactions:

  1. Competition between drugs for the binding sites[ Displacement interactions]:-

    • When two drugs are administered together, one drug displaces another drug from its plasma protein binding site as both drugs have affinity towards the same binding site.

    • The displaced drug concentration in blood rises suddenly, causing adverse effects.

    • e.g. When a patient on Warfarin therapy is given Phenylbutazone, the phenylbutazone displaces Warfarin from its binding site, the free warfarin concentration causes hemorrhagic complications in the patients.

  2. Competition between drug & normal body constituents:-

    • The free fatty acids are known to interact with a no. of drugs that binds primarily to HSA.

    • The free fatty acid level increases in certain physiological, pathological conditions.

  3. Allosteric changes in protein molecule:-

    • This process involves change in the protein structure by the drug or its metabolite thereby modifying its binding capacity of other drugs.

    • e.g. aspirin acetylates albumin thereby modifying its capacity to bind NSAIDs like phenylbutazone

4) Patient-related factors:

  1. Age, Sex, Body Weight:

    • Neonates: Low albumin content: More free drug.

    • Young infants: High dose of Digoxin needed due to large renal clearance.

    • Elderly: Low albumin: So more free drug.

    • Male has more blood as compared to the female.

  2.  Intersubject variability:

    • This happens due to genetic makeup and surrounding of the individual.

  3. Disease states:-

    • Many diseases affect different parameters that can define plasma protein binding, e.g.

      1. In Renal failure there is decreased Albumin content  which causes decrease in binding of acidic drugs; neutral and basic drugs are unaffected

      2. In Hepatic failure there is decreased Albumin content  which causes decrease in binding of acidic drugs; binding of basic drugs remain normal or dependent on AAG levels and neutral drugs are unaffected.

      3. In case of inflammatory conditions like trauma, surgeries etc there are elevated levels of AAG which causes increased binding of basic drugs.
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