4. Distribution is predominantly a passive
process - The driving force is the
concentration gradient between the blood and
extravascular tissues
Process occurs by the diffusion of free drug
until equilibrium is established
5. As the pharmacological action of a drug depends
upon its concentration at the site of action
distribution plays a significant role in the onset,
intensity, and duration of action.
Distribution of a drug is not uniform throughout
the body because different tissues receive the
drug from plasma at different rates and to
different extents.
6. Steps in drug distribution
Permeation of free or unbound drug into interstitial
/ extracellular fluid
Permeation of drug present in extracellular fluid into
intracellular fluid { rate limiting step}
7. Factors affecting distribution of
drugs
Tissue permeability of drug
Organ / tissue size & perfusion rate
Binding to tissue components
9. Physicochemical properties of
the drug
Molecular size –
< 500-600 d easily cross capillary
membrane.
Water soluble molecules & ions of
size < 50 d pass through aqueous
filled channels.
9
10. pKa - pH of blood & ECF (7.4) play a role in
degree of ionization, unionized drug diffuse
rapidly.
eg. Acidosis →↓ ionization of acidic drugs → ↑
concentration and duration of action
Alkalosis (sodium bicarbonate)→↑ ionization of
acidic drug like barbiturate → prevents further
entry into CNS and promote urinary excretion
11. Lipid solubility - Lipoidal drug penetrate the
tissue rapidly.
Among drugs with same lipid solubility but
difference in ionization of blood pH
Less ionized drug - Better distribution.
E.g. Phenobarbital > salicylic acid
11
13. Simple capillary endothelial barrier
All drugs ionised / unionised with molecular
size < 600 daltons diffuse through capillary
endothelium into interstitial fluid
Simple cell membrane barrier
Similar to lipoidal barrier in GIT
15. A solute may enter to brain via
1} Passive diffusion through the lipoidal barrier
2} Active transport of essential nutrients like
sugars and amino acids
As a rule only lipid soluble, nonionized form of
drug penetrate more easily to brain
16. Blood brain barrier
Constraints passage of drug to brain and
CSF
Numerous efflux transporters at BBB (
Molecular barrier)
Clinical importance - Protects brain
tissue
1] Toxic substances in blood
2] Peripheral neurotransmitters
17. Only lipid soluble non ionised drugs
penetrate easily to brain
• e.g. volatile anaesthetics, ultra short acting
barbiturates, narcotic analgesic, dopamine
precursors and sympathomimetics
Water soluble ionised drug fail to
penetrate BBB.
• e.g. dopamine ,serotonine , streptomycin,
quaternary substances
18. Inflammatory conditions ( meningitis,
viral infection of brain , heat stress)
alter permeability of BBB
Examples-
Penicillins
19. Blood CSF barrier
Mainly formed by choroid
plexus of lateral, third &
fourth ventricle
The capillary endothelium
that line choroid plexus
have open junctions
however the choroid cells
are joined to each other
by tight junctions
Only highly lipid soluble,
unionized drugs can pass
through it
20. Blood cerebrospinal fluid barrier:
But CSF-brain barrier is not connected
with tight junction extremely
permeable to drug molecule
Clinical significance - Penicillin being
less lipid soluble has poor penetration
through BBB but if given by intrathecal
route cross CSF-brain barrier to
treat the condition like brain abscess
20
21. Blood placental barrier
Maternal & fetal blood
vessels are separated
by a number of tissue
layers made of fetal
trophoblast , basement
membrane &
endothelium -placental
barrier
Drugs having molecular
size less than 1000 D
and moderate lipid
solubility cross the
placental barrier
21
22. Blood placental barrier
Transfer of substances -
Passive diffusion – Non polar lipid soluble substances
Active transport - Amino acids and glucose
Pinocytosis - Maternal immunoglobulins
Drugs that can cross Blood-Placental barrier
Ethanol, sulfonamides, barbiturates, gaseous
anesthetics, steroids, narcotics, anticonvulsants etc.
Teratogen - Agent that causes toxic effect on
fetus
Teratogenicity - Fetal abnormality caused by
administration of drugs during pregnancy
22
23. Blood placental barrier
Drug administered in last trimester
affect vital functions of fetus
Morphine - Fetal asphyxia
Antithyroid drugs - Neonatal goitre
Hypoxia increase placental permeability
for drugs
Fetus to some extend is exposed to all
drugs taken by mother hence drug
administration should be severly restricted
in pregnancy
24. Blood testis barrier
Located at the
sertoli-sertoli cell
junction
Tight junction
between neighboring
sertoli cells that act
as barrier
Restrict the passage
of drugs to
spermatocyte and
spermatids
24
25. Organ /tissue size & perfusion
rate
Distribution is permeability related in following
cases
1] When the drug is ionic/polar/water soluble
2] Where the highly selective physiology
barrier restrict the diffusion of such drugs to the
inside of cell.
Distribution will be perfusion rate limited
1] When the drug is highly lipophilic
2] When the membrane is highly permeable.
25
26. When highly lipid soluble drug passes through the
highly permeable membrane rate limiting step is
rate of blood flow / perfusion
Greater faster
Perfusion rate - It is defined as the volume of the
blood that flows per unit time per unit volume of the
tissue
Unit : ml/min/ml
Highly perfused organs are -
Lungs > Kidneys > Adrenals > Liver > Heart > Brain
26
27. Special compartments for
drug distributions
Drugs that have high affinity to tissue proteins
1. Digoxin , emetine – Skeletal muscle , heart , liver ,
kidney
2. Iodine – Thyroid
3. Chloroquine - Liver , retina
4. Cadmium , lead , mercury - Kidney
Cellular reservoir
28. Fat as reservoir
Highly lipid soluble drugs {DDT ,
Organophosphate compounds &thiopentone ( if
given repeatedly )} accumulate in adipose tissue
Starvation - Drug toxicity
29. Bones and connective tissue
Tetracyclines , cisplatin , lead , arsenic ,
flourides – Form complex with bones
Antifungal drugs accumulates in skin and finger
nails
Phosphonates – Sodium etidronate - Forms
complex with hydoxyappetite crystals in bone
30. Plasma protein binding as drug
reservoir
Drugs bind to plasma proteins or cellular
proteins in reversible and dynamic equillibrium
Protein bound drug not accessible
Capillary diffusion
Metabolism
Excretion
31. Important proteins - drug
binding
Plasma albumin (acidic drugs)
1. Warfarin
2. Penicillin
3. Sulfonamides
4. Tolbutamide
5. Salycylic acid
32. Several drugs are
capable to binding at
more than one binding
site
e.g.- Flucoxacillin ,
flurbiprofen ,
ketoprofen ,
tamoxifen and
dicoumarol bind to
both primary and
secondary site of
albumin
Indomethacin binds at
three different site
32
Site 1
Site 2
Site 3
Site 4
Drug binding site on
Human Serum Albumin
Warfarin binding site
Diazapam
binding site
Digitoxin
binding site
Tamoxifen
binding site
33. Other drugs binding at sites on
albumin
Site I – on albumin
1. Several NSAIDS (phenylbutazone, naproxane,
indomethacin),
2. Sulphonamides
3. Phenytoin
4. Sodium valproate
5. Bilirubin
33
34. Site II – on albumin
1. Medium chain fatty acids
2. Ibuprofen, ketoprofen
3. Tryptophan
4. Cloxacillin
5. Probenecid
Very few drugs bind to site III and site IV
34
35. Drugs that bind more than one site
Main binding site – Primary site
Other – Secondary site
Groups of drugs that bind to same site
compete with each other for binding
35
36. Protein binding
drug displacement
Plasma Tissue
Drug A
protein bound
Drug A
free
Drug A
free
Drug B
Drugs A and B both bind to the same plasma
protein & when drug B has higher affinity to
site on plasma protein than drug A
37. Displacement interaction and toxicity
37
Displacement interactions Drug A Drug B
% Drug before displacement
Bound
Free
99
1
90
10
% Drug after displacement
Bound
Free
98
2
89
11
% Increase in free drug
concentration
100 10
Interaction is clinically significant if drug bind more than 95%
40. Drugs bound to
tissue proteins and
nucleoproteins
(High aVd)
Example
1. Digoxin
2. Emetine
3. Chloroquine
Miscellanous protein
binding
1. Corticosteroid -
Transcortin globulin
2. Thyroxine-Alpha
globulin
41. Clinically important aspects of plasma protein
binding
1. High plasma protein bound drug - Vd lower
2. High protein bound-
3. Binding of drugs to plasma proteins is capacity
limited and saturable
Difficult to remove
by dialysis
42. 4.Disease state
Disease Influence on
plasma protein
Influence on protein
drug binding
Renal failure
(uremia) Albumin content
Decrease binding of
acidic drug , neutral
or basic drug are
unaffected
Hepatic failure
Albumin
synthesis
Decrease binding of
acidic drug ,binding of
basic drug is normal
or reduced depending
on AAG level.
Inflammatory state
(trauma , burn,
infection )
AAG levels
Increase binding of
basic drug , neutral
and acidic drug
unaffected
42
43. Apparent volume of
distribution
Total space which should be available in body to
contain known amount of drug
aVd = Total amount of drug (mg/kg)
Concentration of drug in plasma
(mg/l)
44. Apparent volume of
distribution
Drugs doesn’t cross capillary wall
High molecular weight – Heparin, insulin ( Vd =
plasma water= 3L)
Lesser lipid soluble drugs
Drugs that bind to proteins
Highly bound to plasma proteins – Low aVd
(tolbutamide, furosemide & warfarin)
Lesser bound to plasma proteins – High aVd
(chloroquine, metoprolol)
45. aVd of some drugs is much more than actual
body volume
Widely distributed in body
Digoxin, imipramine, phenobarbitone &
analogues of morphine
Difficult to remove by dialysis if toxicity
occurs
Drugs good candidates for dialysis – drugs with
low Vd & low plasma protien bound
46. Clinical significance of large volume of
distribution
May require a loading dose initially for
quick onset of action
E.g. chloroquine used in malaria
Tb Chloroquine 600mg stat as loading
dose followed by 300mg after 8hrs &
then 300mg daily for next 2days
47. • Drug is retained in vascular
compartment
• e.g. Heparin ,insulin ,warfarin &
furosemide
aVd < 5L
• Drug is restricted to extracellular fluid
• e.g.aspirin,tolbutamide ,gentamicin ,d
tubocurarineaVd≈15L
• Drug is distributed through total body
water (e.g. Ethanol, phenytoin methyl dopa
& theophylline) or penetration in various
tissues (e.g. Digoxin ,imipramine
,morphine,chloroquine)
aVd>20L
48. Redistribution
Highly lipid soluble drugs when given by I.V. or
by inhalation initially get distributed to organs
with high blood flow, e.g. brain, heart, kidney etc.
Later, less vascular but more bulky tissues
(muscles, fat) take up the drug and plasma
concentration falls and drug is withdrawn from
these sites.
48
49. If the site of action of the drug was in one
of the highly perfused organs, redistribution
results in termination of the drug action.
Greater the lipid solubility of the drug,
faster is its redistribution.
E.g Thiopentone sodium
50. Conclusion
Study of distribution of drug is an important
aspect of the pharmacokinetic study
Plasma protein binding ,tissue storage &
distribution in adipose tissue have important
clinical implications. These along with barriers
like BBB give us insight into unequal
distribution of drugs
aVd is an important pharmacokinetic
parameter.Knowledge of aVd helps us to
understand why some drugs require loading
dose
51. Refrences
Goodman & gillman’s 12th edition, the
pharmacological basis of therapeutics
Principles of pharmacology 2nd by H. L. Sharma
& K .K. Sharma
Biopharmaceutics and pharmacokinetics a
treatise 2nd edition by D. M. Brahmankar and
Sunil B. Jaiswal
52.
53. Stages of teratogenicity
53
Period Significance Effect
1st 2 weeks Fertilization and
implantation
Miscarriage
2-8 weeks Period of
organogenesis
Cleft palate,
optic atrophy,
mental
retardation,
neural tube
defect etc.
8 weeks onwards Growth and
development
Development and
functional
abnormilities
55. miscellanous
Differences are due to
a) Total body water – More in infants
b) Fat content - More in infants
c) Skeletal muscles – Lesser in infants and
elderly
d) Organ composition – BBB is poorly developed in
infants
e) Plasma protein content – Low albumin content in
infants and elderly
55
56. ↑ In plasma & ECF volume and ↓ in
albumin
Adipose tissue has high affinity to
lipophilic drugs ( hence high concentration )
- High fatty acid levels → Alters binding
characteristics of acidic drugs
High fatty diet → High free fatty acid
levels
Changes distribution due to
Altered albumin and other proteins
Altered / reduced perfusion
Altered tissue ph
56