distribution of drugs

1. Distribution of drugs
Dr Shinde Viraj Ashok
Jr1 pharmacology

2. overview
Introduction
Factors affecting distribution
Barriers to distribution
Special compartments for drug
distribution
Plasma protein binding
Volume of distribution

3. Distribution
 Reversible transfer of drugs
between one compartment and
another ( between blood &
extravascular fluids & tissues)

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

8. Tissue permeability
 Physicochemical properties of drug
1. Molecular size
2. Degree of ionisation
3. Oil/Water partition coefficient

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.
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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
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12. Physiological barriers
1) Simple capillary endothelial barrier
2) Simple cell membrane barrier
3) Blood brain barrier
4) Blood CSF barrier
5) Blood placental barrier
6) Blood testis barrier

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

14. Blood brain barrier

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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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%

38. Phenylbutazone,Salicylates ,Sulfonamides displace
tolbutamide
Salicylates,Indomethacin,Phenytoin,
Tolbutamide displace warfarin
Sulfonamides,Vitamin k displace billirubin
Salicylates displace methotrexate
More than one drug can bind to same site of albumin
give rise to displacement reaction
 Clinically important displacement reactions

39.  Alpha 1 acid glycoprotein {Acute phase reactant}
(basic drugs)
1. Quinidine
2. Imipramine
3. Lidocaine
4. Chlorpromazine
5. Propranalol

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
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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.
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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

53. Stages of teratogenicity
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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

54. Transcellular reservoir
 Aqueous humour – Chloramphenicol ,
prednisolone
 CSF- Aminosugars and sucrose
 Joint fluid – Ampicillin
 Pleural fluid – Imipramine and methadone

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
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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
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