PHT414 [ Lec. 4]
Drug distribution
Alteration of drug distribution and plasma protein binding
-following absorption, drugs are rapidly distributed around the body by the circulation.
-some drugs are totally dissolved in the plasma water, but many others are bound to plasma proteins.
-the extent of binding varies greatly.
-drugs can also become bound to albumin in the intestinal fluid and digoxin for example can bind to the
heart muscle tissue.
-drug bound to plasma proteins is restricted since plasma proteins are incapable to pass across
capillaries or cell membranes.
-only that fraction of the drug that is freely circulating or unbound in extracellular water penetrate cell
membranes. Hepatic metabolism of most drugs is also limited by the free fraction of the drug in the
blood.
-the binding to plasma proteins is a rapidly reversible process.
-Binding may involve ionic, von der waels, hydrophobic or hydrogen bonds.
Plasma proteins:
1-Albumin
-Comprises about half of the total plasma proteins so the most of binding is to plasma albumin
-Its conc. In healthy individuals is (4 gm/100 ml ) plasma, lowers levels of albumin are found during the
pregnancy (3.5 gm/ 100 ml)
*In disease state its conc. is altered, it decreases:
1) in acute injury due to increased degradation.
2) in burns, due to direct loss of proteins.
3) in neoplastic diseases and acute viral hepatitis due to reduced synthesis and accumulation of
biochemical inhibitors e.g. bilirubin
-Albumin binds to acidic drugs as; sulforamides, phyntoin, salicylates and barbiturates.
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2-
a1-acid glycoprotein:
-it is an important binding protein for basic drugs as; imipramine, lidocaine, propranolol, and quinidine.
-it is a low M.wt protein, a range conc. In plasma (40-100) mg/ 100ml
-its conc. Rises, in inflammation and malignant diseases, stress and its conc. decreases in hepatic
diseases.
3-Transcortin:
-binds certain steroids like prednisolone and cortisone, also binds thyroxine and vit.B12
4-Lipoproteins, Erythrocytes (RBCS)
*Drug-Protein Interaction:.
- drug-protein interaction may be described by the low of mass action
Where:
Df and DB are the free and bound drug respectively.
Ka and Kd rate constants for association and dissociation respectively
*K (eq. assoc. constant)
Where
n= number of binding sites per mole of protein
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[Df], [DB], [p]; are the molar concentration of free, bound drug and protein respectively.
The fraction of drug in the plasma that is free or unbound fD is given by:
Where
[DT]: is the molar total conc. of drug in the plasma.
- for a given amount of drug in the body, the greater the binding of drug to plasma proteins, the Larger
is the total drug conc. in plasma.
*Protein binding and absorption :.
-increase the protein binding lead to rapid absorption of drugs because of high conc. gradient.
*Protein binding and distribution:.
-As consequences of increased binding to proteins the drug takes longer time to equilibrate, the
intensity of response diminished and the effect is prolonged. The actual Vd is smaller as a result of
increased binding.
Binding
intensity of response
effect (prolonged)
Vd
e.g Ampicillin and cloxacillin, both penetrate well to the synovial fluids but ampicillin is preferred in the
treatment of rheumatic arthritis because:
*Cloxacillin is 95% bound to plasma protein so the free conc. (5%) only is available for the treatment.
*on the otherhand, ampicillin is only 10% bound to plasma proteins so 40% is available for treatment.
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*competition on Protein binding site:.
-Displacement from plasma proteins is likely to lead to a sustained chang in steady state free plasma
conc. only for ddrugs which are extensively found to plasma proteins and non-restrictively cleared.
-Examples for these drugs; alfentanil, fentanyl, hydralazine, and verapamil.
1- warfarin is displaced by salicylates and aspirin leading to increased circulating warfarin and
hemorrhage
2-phenytoin is displaced by sulfafurazole, saliculates, phenyldutazone, and acetazolamide
so the drug conc.
increased in potency than required.
3- Tolbutamide is displaced by sulfonamides, phenylbutazone and salicylates leading to hypoglycemia.
4-sulfonamides are displaced by caumarine anticoagulants and enhanced activity is noticed.
5-Methotrexate is displaced by sulfonamides and salicylates and increased drug levels are obtained and manifested
as blood dyscriasis.
-the binding tendencies of some drugs are changed as a result of interaction with other drugs:
1-Pemidine is not normally bound to plasma proteins, but becomes extensively bound in the presence
of chlorothiazide
2-Tetracycline increase the binding of both promazine and chlorpromazine
Displacement of bilirubin from albumin binding sites under the effect of some drugs is of a very important clinical
significance specially in infants and neoborns
-thus, prescribing any sulfonamides or salicylate to young infants and neoborns cause displacement of bilirubin since
these drugs showing higher affinity to albumin binding sites
hyperbilirubinemia and jaundice
-the lack of enzyme glucorony hydrogenase in those patients exacerbates the case and neurologic complication
produced.
Determination of protein binding:
drug-protein binding is influenced by a number of important factors, including the following:
1-The drug:
-physicichemical properties of drug.
-Total conc. of drug in body.
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2-The protein:
-quantity of protein available for drug-protein binding.
-quality or physicochemical nature of protein synthesized.
3-affinity between drug and protein:
-includes the magnitude of association constant.
4-drug interactions:
-competition for the drug by other substance of a protein-binding site.
-alteration of the protein by a substance that modifies the affinity of drug for a protein.
5-the pathophysiologic condition of the patient:
-for example, drug-protein binding may be reduced in uremic patients and in patients with hepatic diseases.
Clinical significance of drug- protein binding
The fraction of drug bound can change with; plasma drug conc. , dise of drug administered, patient's plasma protein
conc.
If a patient has low plasma protein conc.
bioactive drug is higher than anticipated.
for any given close of the drug
the conc. of free
The plasma protein conc. is controlled by a number of variables:
1-protein synthesis
2-protein catabolism
3-distribution of albumin between the intravascular and extravascular space
4-exessive elimination of plasma protein
physiologic and pathologic conditions altering protein conc.
A) factors that decrease plasma protein conc.
1- decreased protein synthesis (liver disease)
2- increased protein catabolism (surgery and trauma)
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3-distribution the albumin into extravascular space (Burns)
4-excessive elimination of protein (renal disease)
B) factors that increase plasma protein conc.
-exercise
-schizophrenia
-hypothyroidism
-benign tumer
-Neurological disease
-stress
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