Drug interaction, Pharmacokinetic, protein binding of drug and effect of tissue binding interaction.

1. Faculty of Pharmacy, BBDNIIT Lucknow
Drug Interaction
Presented by-
Manish Kumar Singh
M.Pharm, I Year (Pharmaceutics)
Presented to-
Ms. Shipra Tripathi
Assistant Professor

2. Content
 Pharmacokinetic
 Drug interaction
 Factor contributing to drug interactions
 Protein binding of drug
 Effect of protein binding interaction
 Effect of tissue binding interaction

3. Pharmacokinetics
 Pharmacokinetics is a study of what the
body does to drug.
 It is a science of kinetics of ADME.
 It is also defined as movement of drug
in the body.
 Elimination occur by two processes-
Metabolism and Excretion.

4. Drug Interactions
 When the pharmacological activity of a drug is altered by the concomitant use of
another drug or by the presence of some other substance.
 The drug whose activity is affected by such an interaction is called as the object
drug.
 The agent which precipitates such an interaction is referred to as the precipitant.
Drug interactions include
1. Drug-drug interactions.
2. Food-drug interactions, for example, inhibition of metabolism of several drugs
by grapefruit juice.
3. Chemical-drug interactions, for example, interaction of a drug with alcohol,
tobacco or environmental chemicals.
4. Drug-laboratory test interaction, for example, alteration of diagnostic laboratory
test results by the presence of drug.
5. Drug-disease interactions, for example, worsening of disease condition by the
drug.

5. Factors Contributing to Drug
Interactions
Some of the more important risk factors that lead to drug interactions
include –
1. Multiple drug therapy
2. Multiple prescribers
3. Multiple pharmacological effects of drug
4. Multiple diseases/Predisposing illness
5. Poor patient compliance
6. Advancing age of patient
7. Drug related factors

6. Protein binding of drug
The phenomenon of complex formation with proteins is called as protein
binding of drugs.
The formation of a drug–protein complex is often named drug–protein
binding.
The drug protein binding may be of two types-
Reversible-
When the drug bind the protein with weaker chemical bonds such as hydrogen
bond or vander waal’s forces.
Irreversible-
Irreversible drug protein binding is usually a result of chemical activation of
the drugs, which then attaches strongly to the protein or macromolecules by
covalent chemical bonding.

7. BINDING OF DRUGS TO BLOOD
COMPONENTS
 Albumin
 Alpha 1- Acid Glycoprotein
 Lipoprotein
 Erythrocytes (RBC)
 Immunoglobulins
The extent or order of binding of drugs to various plasma proteins is:
Abumin > alpha1-Acid Glycoprotein > Lipoproteins > Globulins

8. Effect of protein binding interactions
Apparent volume of distribution :
It is defined as the hypothetical volume of body fluid into which a drug is dissolved
or distributed. It is called as apparent volume because all parts of the body
equilibrated with the drug do not have equal concentration.
Effect Of Protein Binding On The Apparent Volume Of Distribution :
 The extent of drug protein binding affects VD.
 Drugs that are highly bound to plasma proteins have a low fraction of free drug
(fu = unbound or free drug fraction).
 The plasma protein-bound drug does not diffuse easily and is therefore less
extensively distributed to tissues
Apparent volume of distribution = Amount of the drug in the body
Plasma drug concentration

9.  Drugs with low plasma protein binding have larger fu, generally diffuse more
easily into tissues, and have a greater volume of distribution.
 Drugs such as furosemide, sulfisoxazole, tolbutamide, and warfarin are bound
greater than 90% to plasma proteins and have a VD value ranging from 7.7 to
11.2 L per 70-kg body weight.
 Basic drugs such as imipramine, nortriptyline, and propranolol are extensively
bound to both tissue and plasma proteins and have very large VD values.
Displacement of drugs from plasma proteins can affect the pharmacokinetics of a
drug in several ways : directly increase the free (unbound) drug concentration as a
result -
1. Reduced binding in the blood;
2. Reaches the receptor sites directly, causing a more intense pharmacodynamic
(or toxic) response;
3. Causing a transient increase in VD and decreasing partly some of the increase
in free plasma drug concentration;
4. More drug diffusion into tissues of eliminating organs, particularly the liver
and kidney, resulting in a transient increase in drug elimination.

10. Effect Of Protein Binding On Elimination Of Drug :
 Protein binding decreases the renal excretion of the drugs and enhance the
biological half –life. Only the free drugs excreted through filtration for
example tetracycline.
 The binding of drugs in extravascular organs decreases their concentration in
blood and thereby shows their elimination by liver, kidney and lungs.
 However, the binding of drug to plasma protein may retard the elimination of
drugs depending on the mechanism of elimination, for example the binding
of drug to the plasma protein lowers their unbound concentration in blood
and thereby decreases their rate of elimination by glomerular filtration and by
inefficient transport system in the kidney.
 Binding to plasma protein would decreases the rate of elimination of lipid
soluble drugs that diffuse rapidly from the glomerular filtration back into the
blood, even though they are rapidly transported by active transport system.
 In addition, the binding of drug to plasma protein would also decreases the
rate of drug metabolism by relatively inactive enzyme system in liver.

11. Effect Of Protein Binding On Patient With Kidney Disease :
 Albumin is primarily responsible for the binding of acidic drugs whereas
basic drugs appear to bind preferentially to AAG (alpha-amino glycoprotein).
 The low concentration of albumin and AAG in patients with liver disease
indicates the inability of the liver to synthesize these drug-binding proteins.
 Impaired binding of acidic and basic drugs is well documented in patients
with liver disease.
 The albumin concentrations in the transplant patients were low despite stable
biochemical liver tests. Because albumin is primarily responsible for binding
of acidic drugs, liver transplant patients would not be able to bind acidic
drugs as efficiently as the normal subjects.
 However, the AAG concentrations were elevated in all the transplant patients
studied. AAG is an acute-phase reactant and is primarily synthesized in the
liver.
 AAG concentrations are known to increase in plasma.

12. Effect Of Protein Binding On Patients With Hepatic Disease :
 Protein binding affects distribution.
 The impaired liver is unable to synthesize plasma proteins (albumin)
adequately.
 Liver impairment causes accumulation of substances (bilirubin) that displace
drugs from protein-binding sites.
 A statistics on this case shows that liver disease patients with normal
concentration of albumin and bilirubin have unbound percentages of
frusemide similar to those in healthy subjects.

13. Effect of tissue binding interactions
TISSUE BINDING OF DRUGS (TISSUE LOCALIZATION OF DRUGS)
A drug can bind to one or more of the several tissue components. Tissue-drug
binding is important in distribution from two viewpoints :
 It increases the apparent volume of distribution of drugs in contrast to plasma
protein binding which decreases it.
 Tissue-drug binding results in localization of a drug at a specific site in the
body (with a subsequent increase in biological half-life). This is more so
because a number of drugs bind irreversibly with the tissues (contrast to
plasma protein-drug binding); for example, oxidation products of
paracetamol, phenacetin, chloroform, carbon tetrachloride and bromobenzene
bind covalently to hepatic tissues.

14. Factors influencing localization of drugs in tissues include :
1. lipophilicity and structural features of the drug,
2. perfusion rate,
3. pH differences, etc.
Extensive tissue-drug binding suggests that a tissue can act as the storage site
for drugs. Drugs that bind to both tissue and plasma components result in
competition between drug binding sites.
For majority of drugs that bind to extravascular tissues, the order of binding is:
Liver > Kidney > Lung > Muscles

15. Several Examples Of Extravascular Tissue-drug Binding Are
1. Liver: Paracetamol bind irreversibly to liver tissues resulting in hepatotoxicity.
2. Lungs: Basic drugs like imipramine, chlorpromazine and antihistamines
accumulate in lungs.
3. Kidneys: Metallothionin, a protein present in kidneys, binds to heavy metals
such as lead, mercury, and cadmium and results in their renal accumulation
and toxicity.
4. Skin: Chloroquine and phenothiazines accumulate in skin by interacting with
melanin.
5. Eyes: The retinal pigments of the eye also contain melanin. Binding of
chloroquine and phenothiazines to it is responsible for retinopathy.
6. Hairs: Arsenicals, chloroquine and phenothiazines are reported to deposit in
hair shafts.

16. 7. Bones: Tetracycline is a well-known example of a drug that binds to bones
and teeth. Administration of this antibiotic to infants or children during
odontogenesis results in permanent brown-yellow discoloration of teeth.
8. Fats: Lipophilic drugs such as thiopental and the pesticide DDT accumulate
in adipose tissues by partitioning into it.
9. Nucleic Acids: Molecular components of cells such as DNA interact
strongly with drugs like chloroquine and quinacrine resulting in distortion of
its double helical structure.

17. References
 Shargel L. ,” Applied Biopharmaceutics & Pharmacokinetics”, 7th
Edition, 2005, Published by McGraw Hill, New York, Page no –
267,276,277.
 Brahmankar D.M. , Jaiswal S.B. , “Biopharmaceutics and
Pharmacokinetics- A Treatise”, 1995, Published by Vallabh Prakashan,
New Delhi, Page no- 116-123.
 https://www.slideshare.net/azamushahiullahprottoy/effects-of-protein-
binding