Drug to drug interaction at the level of Distribution

1. DRUG TO DRUG
INTERACTION
AT THE LEVEL OF DISTRIBUTION

2. Drug distribution : Is the process by which a drug reversibly
leaves the bloodstream and enters the interstitium (extracellular
fluid) and the tissues.
DEFINITION OF TERMS:
Drug interactions : is defined as the pharmacological activity
of one drug is altered by the concomitant use of another drug or
by the presence of some other substance.

3.  Drug-drug interactions.
 Drug-food interactions.
 Chemical-drug interactions.
 Drug-laboratory test interactions.
 Drug-disease interactions.
TYPES OF DRUG INTERACTION

4. Pharmacokinetic Interactions:
 Absorption
 Distribution
 Metabolism
 Excretion
Pharmacodynamics Interactions:
 Receptor interaction
 Receptor sensitivity
Pharmaceutical Interactions:
MECHANISM OF DRUG INTERACTION:

5. The mechanisms by which drug-interactions alter drug distribution
include:-
 competition for plasma protein binding,
 displacement from tissue binding sites, and
 alterations in local tissue barriers,
e.g., P-glycoprotein inhibition in the blood brain barrier.
Distribution.

6.  Although competition for plasma protein binding can increase
the free concentration (and thus the effect) of the displaced
drug in plasma, the increase will be transient owing to a
compensatory increase in drug disposition.
 The clinical importance of protein binding displacement has
been over emphasized; current evidence suggests that such
interactions are unlikely to result in adverse effects.
 Displacement from tissue binding sites would tend to
transiently increase the blood concentration of the displaced
drug.

7.  Displaced protein binding depends on the affinity of the drug to
plasma protein. The mostly bound drugs is likely to be
displaced. For example
Highly bound to plasma protein :
 Phenytoin (90%),
 Tolbutamide (96%)
 warfarin (99%)
Drugs :-
 Aspirin
 Sulfonamides
 phenylbutazone
 The free drug is increased by displacement by another drug with higher
affinity.
 Saturation of binding sites is the basis of displacement interactions among
drugs
(Displaces)

8. Concomitant administration of warfarin with phenylbutazone or other highly
protein bound drugs leads to increased levels of warfarin, with the clinical
implication of frequent monitoring of current international normalized
ratio (INR) and prothrombin time (PT) to prevent bleeding.
Continued….
COMPETITIVE DISPLACEMENT INTERACTIONS
Anti
coagulants
Phenylbutazone, (NSAID)
Chloral hydrate (HYPNOTICS)
Increased clotting time
Increased risk of hemorrhage.
Tolbutamide Sulphonamides Increased hypoglycemic
 Accumulation of drugs in tissues or body compartments can prolong drug
action because the tissues release the accumulated drug as plasma drug
concentration decreases.
 Thus, for lipid soluble drugs, their storage in fat initially shortens the drug’s
effect but then prolongs it.

9. Altered distribution, occurs when the concentration of drug at the
site of action is changed without necessarily altering its circulating
concentration. This is particularly an issue for drugs with
intracellular or central nervous system targets. Some drugs cause
significant changes in the cell membrane transport of other drugs.
For example, verapamil inhibits efflux transporters (e.g. P-
glycoprotein) increasing the concentrations of substrates such as
digoxin and cyclosporin. Probenecid inhibits anion transporters
(e.g. OAT-1) increasing the concentrations of substrates such as
methotrexate and penicillins. Drug interactions involving
transport are less well understood than drug interactions involving
metabolism.

10. The drugs most likely to lead to clinically significant
interactions are those that are: 90% or more protein bound, those
bound to tissues or having a small volume of distribution,
having a low therapeutic index, low hepatic extraction ratios, or
those that are administered I.V. Drugs that are more likely to
displace other drugs from protein binding sites include
NSAID’s, phenylbutazone, salicylic acid, and sulfonamides
Note:

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