4b.Distribution & Plasma protein binding_08 Mar 2024.ppt

Drug distribution and plasma protein binding

1. DISTRIBUTION
Definition –The reversible
transfer of drugs between
body fluid compartments

2. Distribution
•After absorption drug enters systemic
circulation
•Drug that has gained access to the blood
stream:
-gets distributed to other tissues that initially
had no drug;
-concentration gradient being in the direction
from plasma to tissues.

3. •Drug distributes into:
PLASMA / INTERSTITIAL FLUID /
TRANSCELLULAR FLUID / CELLULAR FLUID
•Equilibrium is established between
unbound drug in plasma and tissue fluids

5. In 70 Kg person-
Total Body Water-
42L
ECF 14 L ICF 28 L
•Plasma -3L
•Interstitial Fluid 10.5 L
•Transcellular Fluid
Compartment 0.5 L

7. Apparent Volume of
Distribution
Apparent volume of
distribution (aVd) is defined
as the hypothetical volume of
body fluid into which a drug is
uniformly distributed at a
concentrationequal to that in
plasma, assuming the body to
be a single compartment.

8. Factors affecting Distribution of a drug :
1.Drugs with Hg Mol.wt (heparin/Warfarin) –Extremely bound to
plasma protein, hence aVd is low.
2.If aVd of drug is 14-16L it indicates drug is in ECF-Ex
Gentamycin
3.Drugs that accumulates in tissues have aVD exceeds TBW (Ex.
Chloroquine 13,000 L &Digoxin 5000L)
4.Hemodialysis is not useful in overdosage of large aVd drugs
5.InCCF aVd of drug is due increased due to increase in ECF
(Ex.Alcohol)
6.In Uraemia TBW is increased hence increase in Vd of small
water soluble drugs.
7.Fat:Lean , Body mass ratio High lipid soluble drugs get
distributed to adipose tissues hence acts as reservoir.

9. FACTORS AFFECTING aVd
1.its lipid solubility –its lipid: water partition
coefficient
2.ionization at physiological pHand pKaof
the drug
3.extent of binding to plasma proteindand
tissue proteins
4.Affinity for diff. tissues
5.Fat : lean body mass ratio –which varies
with age, sex, obesity, etc.
6.Pathological state of the patient. (Disease-
CHF, Renal Failure)

10. •Highly lipid-soluble drugs (Thiopentone –Inducing agent) get initially
distributed to organs with high blood flow,i.e. brain & Cause GA, heart,
kidney, etc.
•Later, Immediately with in few minutes, it diffuses across BBB into blood
and less vascular but more bulky tissues like muscle and fat called as
Redistribution
•Plasma concentration falls and the drug is withdrawn from these sites
(Short Duration of action –5-10 Minutes)
Redistribution

12. Redistribution –Terminating Factor
Brain
Muscle Plasma Fat
Greater the Lipid solubility Faster is its
redistribution
•Thiopentone -Ultra shortacting
•One arm –brain circulation( 6-8 secs )

13. Redistribution –Drug Reservoir/
Tissue storage
Brain
Muscle Plasma Fat
Some drugs are concentrated or accumulated in tissues
or some organs of the body.
Continuous administrationless perfused sites
progressively filled up drug becomes long acting
Reservoirs of drug
Thiopentone-Fat/ Tetracycline-Bone & Teeth
Chloroquine-Liver & retina, Digoxin-heart,

14. Penetration into brain and CSF
•The capillary endothelial cells in brain havetight
junctions and lack large intercellular pores.
•Further, an investment of neural tissue covers the
capillaries.
•Together they constitute the so called blood-brain
barrier.

17. •Blood-CSF barrieris located in the choroid plexus:
capillaries are lined by choroidalepithelium
having tight junctions.
•Both these barriersare lipoidal.
•They limit the entry of nonlipid-soluble drugs,
e.g. streptomycin

18. Passage across placenta
•Allow free passage of lipophilic drugs
•Placental efflux P-GP also serves to limit foetalexposure
•Incomplete barrier
•Almost any drug taken by the mother can affect the foetus
or the new born –Teratogenesis / Fetal Anomalies

20. Tissue storage
•Drug sequestrated in various tissues are
differentially distributed
•They tend to have large volume of distributionand
long duration of action
-Tetracyclines on bone and teeth
-Streptomycin on vestibular apparatus

21. Drug concentrated in tissues
•Skeletal muscle, heart-Digoxin
•Liver & retina -Chloroquine
•Kidney -Digoxin
•Thyroid -Iodine
•Brain -Chlorpromazine
•Iris -Atropine
•Bone and teeth -Tetracyclines
•Adipose tissue -Thiopentone

23. PLASMA PROTEIN
BINDING

24. ACIDIC DRUGS–ALBUMIN
BASIC DRUGS–ACID GLYCOPROTEIN
Free Form-Pharmacologically active
Bound form –temp.storage& inactive

26. 1Extent of Plasma Protein Bindingdepends on
individual compoundand Noton
pharmacological or chemical class
2. High degree of protein binding generally makes the
druglong acting
3. One drug canbind to many siteson the albumin
molecule.More than one drug canbind to the
same site.

27. 4High PPB drug –not available forDISTRIBUTION,
ACTION, METABOLISM OR EXCRETION
5plasma concentrationincludes both:
Bound + Free drug
6Hypoalbuminemia, uremia -PPB
7Drug interaction –commonwith drugs that bind
to Plasma Proteins.

31. •Salicylatesdisplacesulfonylureas
•Indomethacin, phenytoindisplacewarfarin
•Sulfonamides and vitKdisplacebilirubin
( kernicterusin neonates)
•PPB plays a role only when the displacing
drug also (-)s its clearance.

32. University Short Notes Questions
1.Mechanisms of drug transport
2.Bioavailability
3.Factors affecting drug absorption
4.Volume of distribution
5.Blood Brain Barrier
6.Placental barrier
7.Plasma protein binding