Drug Distribution

1. Drug Distribution
Presenter-Dr.Bharath kumar.D
Moderator-Dr.Manohar.V.R

2. Contents
1. Introduction.
2. Definition.
3. Different compartments of drug distribution.
4. Apparent volume of distribution.
5. Redistribution.
6. Different barriers to drug distribution.
7. Special compartments to drug distribution.
8. Plasma protein binding.
9. Conclusion
10. References.

3. Introduction
 Drug disposition is divided into four stages
designated by the acronym 'ADME‘.
 Absorption from the site of administration
 Distribution within the body
 Metabolism
 Excretion.

4. Definition
 It is defined as “process by which drug reversibly
leaves the blood stream & enters the interstitium
(ECF) and/or the cells of tissues”
 That is scattering of the specified amounts of drug
among the various locations within the body.
 When drug gain access to blood stream it
distributed to other tissues to which initially had no
drug in the direction of Plasma-Tissues.

5. Compartment models
 How to understand this compartment models??
What is this compartment models??
Right Atrium Right Ventricle
Left AtriumLeft Ventricle

6. One compartment model
 Drug enters central compartment and leaves the
body.
 Recirculation does not occur.
 This consists of entire body and all organs tissue.
Central compartment

7. Two compartment model
Central
compartment
Peripheral
compartment

8. Two compartment model
 Drug enters the central compartment
 Drug leaves the central compartment by one of the
two paths. 1-peripheral compartment. &
2- drug leaves the body.
 Recirculation is between central and peripheral
compartment once drug leaves it does not reenters
 Entire body has one & all organs tissues in
another.
 But drug has to leave through single one.

9. Drugs distribution in different
compartments of body.
Transcellular fluid(2.5%)– CSF, intraocular,
peritoneal, pleural, synovial, digestive
secretion, fetus is also special type. Drugs
will be in free or bound form.

10. Body compartment Types of drugs
Total body water Small, water soluble
alcohol and antipyrine.
Extracellular space Large, water soluble
mannitol
Intravascular space Very large, strongly
protein bound, heparin
Body fat Highly lipid soluble
DDT and thiopentone
Bones Fluoride and lead

11. Extent of Distribution depends on
 Lipid solubility
 Ionization at physiological PH
 Binding to plasma proteins
 Tissue specific transporters
 Cardiac output
 Regional blood flow
 Capillary permeability
 Tissue volume

12. Factors affecting distribution of
drugs
factors related to body-
1. Vascularity
2. Transport mechanisms
3. Blood barrier
4. Placental barrier
5. Drug interactions
6. Diseases states
7. Drug reservoir
8. Volume of distribution.

13. Phases of distribution
 Initially drug distributed in liver, kidney, brain
i.e. well perfused organs later muscle, skin,
fat and other viscera.
 Next phase takes min-hours before
concentration of drug in a tissue is
equilibrium with blood. It involves far larger
fraction of body mass(muscle).

14. Apparent volume of
distribution(Avd)
The volume that would accommodate all the
drug in body if concentration throughout
was same as in plasma.
V = dose administered IV
plasma concentration.
Amount of drug present in the body as a
multiple of that present in unit volume of
plasma

15. Factors determining Avd are-
 Drug with high molecular weight, less lipid
soluble when given IV, Avd=plasma=4 L.
 Drugs highly bound to plasma protein(less
to tissue protein) Example- Furosemide,
Warfarin has low Avd and vice versa.
 And for greater Avd example Chloroquine
and metoprolol.
 Dialysis is possible only for drugs with low
Avd and not for high Avd (Digoxin,
Phenobarbitone, & Imipramine)

16.  A drug with Avd, less than 5L-drug within
vascular compartment. Example Heparin,
Insulin, & Warfarin
 The Avd=15L=Drug is in ECF. Example Aspirin,
Tolbutamide and Gentamicin
 The Avd>20L, drug throughout TBW. Example
Ethanol, Phenytoin,& Methyldopa
 Pathological states like CHF, uraemia, cirrhosis
of liver alter Avd.

17.  If a drug does not cross capillary walls and
is given by i.v route its Avd is equal to
plasma volume
 Drugs highly bound to plasma protein have
a low Avd value
 Avd for many drugs may be much more
than the actual body volume.
 Drug dosage is reduced in elderly because
of decreased body water, body mass, renal
function.
 Loading dose is given to saturate tissues as
it is mainly depend on Vd.

18. Redistribution
 Highly lipid soluble drugs get initially distributed
in organs with high blood flow. Example- Brain,
Heart, Kidney
 Later less vascular more bulky(muscle,fat).
 When plasma concentration falls, drug is
withdrawn from highly perfused organs.
 Redistribution results in termination of action if
site of action is highly perfused organs ex-
thiopentone sodium.

19. Physiological Barriers to Drug
Distrubution
1. Blood Brain Barrrier
2. Blood-CSF Barrier
3. CSF-Brain Barrier
4. Placental Barrier

20. 1. Blood brain barrier

21. Blood-Brain Barrier

22.  Concept was introduced by Paul Ehrlich .
 Consists of Endothelial cells tightly joined
 Efflux transporters like p-gp, ABCC and
OATP
 Lipid soluble non-ionised ions easily pass
 Inflammtory condition usually alter
permiability
 Non polar compunds easily pass. Ex-ether,
choloroform, & thiopentone.

23.  Polar compunds doesn’t pass. Ex-
dopamine, sertonin, Ach, & Neostigmine.
 loratadine, achieve lower brain
concentrations than diphenhydramine
 BBB disruption has emerged as a strategy
in the treatment of certain brain tumors
such as primary CNS lymphomas.

24.  Peptides like Enkephalin & Bradykinin
permeability of BBB.
 Extreme stress renders BBB permeable to
drugs such as pyridostigmine.
 DA receptors in Basal ganglia is accessible to
drugs which cross BBB.
 Domperidone prevent nausea caused by
dopamine agonist by penetrating CTZ.
 Methylnaltrexone bromide used in opoid
antagonist doesn’t cross BBB.

25. • Only lipid soluble drugs can penetrate
BBB
 The BBB is deficient at:
• Pituitary gland
• Pineal body
• Area prostema (CTZ)
• Median eminence
• Choroid plexus

26. 2. Blood-CSF Barrier

27. 3.Blood-CSF Barrier
 Tight junctions with no pores in between
 Highly permiable.
 Penicillin directly access.
 Efflux transporters are present.
 Permeable in hypoxic conditions.

28. 4.Placental barrier

29.  Tight junction, no fenestration, surrounding chorionic
villi there is tight layer of trophoblastic cells around
capillary membrane.
 Nonpolar,Lipid soluble substance pass by passive
diffusion.
 Active transport. Ex-Amino acids & Glucose.
 Pinocytosis . Ex-maternal Ig.
 Lipid soluble ,non ionisable readily pass.
 Polar substance, quaternary compunds, high molecular
weight doesn’t pass.

30.  Foetal plasma is slightly acidic than the mother so
ion trapping of basic drugs,ex-morphine..
 Drugs given in first trimester causes congenital
anomaly.
 Drugs given in last trimester alter vital function
 Placenta allows free passage of lipophilic
& restricted amounts of hydrophilic drug.
incomplete barrier.

31. Special compartments for drug
distribution.
1. Cellular reservoir
2. Fat reservoir.
3. Transcellular reservoir.
4. Bones & connective tissue.
5. Plasma protein binding.

32. Cellular reservoir
 Those tissue which as higher affinity for drugs than
plasma proteins.ex-
 Digoxin & emetine-skeletal muscle, heart,liver &
kidney.
 Iodine-thyroid.
 Choroquine- liver(tissue protein), retina(nucleo
protein).
 Cadmium,lead & mercury-kidney(muscle protein).
 Chloropromazine-eye(retinal pigment melanin).

33. Fat as reservoir
 Highly lipid soluble drugs like thiopentone & DDT
accumulated in fat and adipose tissue.
 Fat is sluggish reservoir due to lesser blood flow.
 During starvation stored drug mobilize & toxicity.

34. Transcellular reservoir
 Aqueous humour-choloromphenicol, dapsone.
 CSF-Aminosugar & sucrose.
 Endolymph joint fluid- ampicillin.
 Pleural- imipramine, methadone.
 Pericardial & peritoneal reservoir

35. Bones & connective tissue
 Tetracycline, cisplatin, lead, aresnic, fluorides form
complex with bone salts –nails, bones & teeth.
 Griseofulvin – keratin precursor cells.

36. Plasma protein binding(PPB)
 Free drug + protein Drug – protein
complex.
 Plasma protein binding is inert.
 Free drug is pharmacological Active form.
 Only free drug diffuse through capillary,
metabolised and excreted.
 Protein bound drug does not.
t
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s

37. Plasma protein that contribute to
drug binding.
 Plasma Albumin-important plasma protein binds to
Acidic drugs ex-warfarin
,pencillin,sulfonamides,tolbutamide, & salicylic
acid.
 Alpha1 acid glycoprotein-Basic drugs ex-
quindine,impramine,lidocaine, & chloropromazine.
This is an acute phase reactant elevated in
Crohn’s, cancer, MI, arthritis.
 Tissue protein- those with high apparent Vd binds.
Ex-digoxin, emetine, & chloroquine.

38.  Miscellanous binding proteins- few drugs bind
other proteins. Ex-steroids-CBG(transcortin),
thyroxine-alpha globulin, Ag-Gamma globulin.
 In MI,stress,crohn’s,inflammation binding of basic
drugs like propronlol & quinidine increases due to
binding to alpha1 acid glycoprotein.
 Plasma protein binding = ↓Volume of distribution
Temporary drug reservoir
 ↑ Plasma protein binding = ↓ glomerular filtration
but ↑ tubular secretion
 temporary drug reservoir.

39. Clinicaly important aspects of
PPB
 High PPB drug restricted to vascular compartment.
 High PPB drugs difficult to be removed by dialysis.
 Capacity limited & saturable process
 Even therapeutic dose of drug will lead to toxicity in
liver disease, uraemia & hypoalbunemia.

40. Plasma protein binding of different
drugs.
Drugs Percentage of binding.
Diazepam , warfarin 95-99%
Furosemide ,
Tolbutamide
98
Amitryptlline,
choloropramizine
90-95
Indomethacin, digoxin,
atenolol
85-90
Quinidine 70
Lignocaine 50

41. Drug interaction due to PPB
 Phenylbutazone , salicylates , sulfonamides
displace tolbutamide leading to hypoglycemia.
 salicylates, indomethacin, phenytoin, tolbutamide
displace warfarin leading to increased risk
bleeding.
 Sulfonamide & vitamin k can displace lead to
kerincterus.
 Salicylates displace methotrexate.

42. Drug Unbound drug or free
drug% in therapeutic
dose
Normal Hepatic diseases
Diazepam 2 6 times
Theophylline 35 2 times
Normal Renal diseases
Frusemide 2 6 times
Clofibrate 4 11 times
Phenytoin 10 2 times
Triamentrene 19 2 times

43. Conclusion
Thus we came to know how drug is distributed after
absorption , its distribution in different
compartments, apparent volume of distribution ,
different barriers to distribution, different cellular
reservoir and plasma protein binding.

44. Refernces.
 Sharma book of pharmacology.
 Tripathi book of pharmacology.
 Goodman & gilman.
 Rang & dale
 Katzung.
 Bhattacharya book of pharmacology.
 Lippincott’s illustrated review of pharmacology
 Srivastva book of pharmacology.
 Satoskar book of pharmacology.
 Seth book of pharmacology.