This document discusses drug distribution and elimination in the body. It covers topics like absorption, distribution, protein binding, volume of distribution, clearance and elimination routes. Absorption involves movement of drugs from the site of administration to tissues. Distribution is the reversible process by which drugs enter tissues, depending on factors like blood flow and lipid solubility. Drugs are eliminated from the body through various routes like the kidneys, liver, lungs and intestines. Key elimination processes involve glomerular filtration, tubular secretion and reabsorption in the kidneys. The rates of drug distribution and elimination determine properties like half-life and whether kinetics are first-order or zero-order.

1. DRUG DISTRIBUTION & DRUG ELIMINATION
Dr.G.Vishnu Priya
1

2. Absorption
Absorption is movement of a drug from site of
administration to the central compartment and the
extent to which this occurs.
Only lipid soluble drugs can cross the biological
Membranes
Lipid soluble drugs is unionised ,ionised form is water
soluble
2

3. DISTRIBUTION :
Process by which drug reversibly leaves the blood
Stream and enters interstitium (ECF) & cells of the
tissues.
Delivery of drug from plasma to interstitium
depends on :
 Regional blood flow
 Capillary permeability,
Tissue volume,
Degree of binding ,
 Relative hydrophobicity of the drug.
3

4. Permeability of barriers
Blood brain barrier :
 Endothelial cells of capillaries are continues
tight junction.
 lipid soluble non ionised form of drugs
penetrate more easily to brain.
 More lipophilic a drug,more likely to cross the
blood brain barrier.
 BBB involves membrane transporters limits
access of drugs to tissues
4

5.  BBB involves membrane transporters
limits access of drugs to tissues.
 Inflammatory condition alter permeability
charecterestics of BBB allowing entry of drugs that are
restricted.
E.g- Penicillin, Chloramphenicol,Ampicillin
5

6. • DRUGS - BBB
• Volatile anesthetic- Ether,chloroform.
• Ultra short acting barbiturates-Thiopental.
• Narcotic analgesic-Morphine,heroin.
• Dopamine precursor - L-dopa.
• Sympathomimetics- Amphetimine & Ephedrine.
• Propranolol & Diazepam
• DOES NOT CROSS-
• Dopamine, serotonin& Streptomycin
• quaternery substances- d-tubocurarine,
• Hexamethonium, Neostigmine, Acetylcholine
6

7. 7
Blood CSF Barrier :
Epithelial cells joined by tight junctions
allows non ionised lipid soluble drugs

8. Placental barrier
It is lipid in nature
Lipid solubility,extent of plasma binding & degree of
ionization of week acids & bases are determinants in drug
transfer
8

9.  Fetal plasma is slight acidic than the mother
 7.0vs 7.4 – ion trapping of basic drugs
occurs
 As in brain ,P-gp & other export transporters
present in placenta limits fetal exposure to
toxic agents
e.x pentobarbital,alcohol ,certain antibiotics.
9

10. Binding of drugs-
Plasma protein binding :
 It’s a non linear & saturable process.
 prolongs the drug availability & Duration of action.
 Delays metabolic degradation & excretion of drugs
 Fraction of total bound drug in plasma determined
by drug concentration,affinity of binding sites,number
of binding sites
10

11.  Diminishes its penetration into the CNS.
 Hypoalbuminemia , secondary severe liver disease
or nephrotic syndrome ↓ binding.
 Cancer, Arthritis, MI, Crohn’s disease -↑ level of α1
acid glycoprotein & enhanced binding of basic
drugs.
 As free drug is active & gets eliminated to replace
the lost drug ,bound drug dissociates.
11

12.  Therapeutic range of plasma concentration is
limited ,extent of binding & unbound fraction is
constant
 acidic drugs binds to plasma albumin
e.g- warfarin, Penicillins, Sulfonamides, Tolbutamide
& Salicylic acid.
 basic drugs binds to αı acid glycoprotien
e.g- Propranolol, Lignocain, Quinidine.
 Displacement interactions where drug bound with
higher affinity will displace the one having lower
affinity.
12

13.  e.g- Phenylbutazone, Salicylates & Sulfonamides
displaces Tolbutamide → hypoglycemia
 Salicylates,Indomethacin,Phenytoin & Tolbutamide
displaces Warfarin → haemorrhage.
 Sulfonamides & vitamin K displace endogenous
ligands like bilirubin→ kernicterus in neonates.
 Drug extensively protien binding has smaller
apparent volume of distribution.
13

14. warfarin- 99% bound, Tolbutamide- 98% bound,
Phenytoin- 90% bound causes toxicity after getting
displaced from plasma protein binding sites.
Tissue binding:
Drug accumlate in tissues at higher concentration
than in ECF & blood.
Some drugs have high apparent volume of
distribution,e.g- Digoxin, Emetine, Chloroquine
Chloroquine-1300 l/kg- high volume of distribution
14

15. Reversible binding of drugs occurs with cellular
constituents - Protiens,phospholipids&nuclear
protiens.
Tissue binding & accumlation produces local toxicity
Griseofulvin in skin & finger nails
Fat-many
lipid soluble drugs stored by physical
solution in neutral fat.
Serves as staable reservoir for lipid soluble drugs
Barbiturates,Thiopental present 3hrs after admin.
15

16. Bone –
Metal ions & chelating agents & heavy metals
accumlate in bone by adsorption onto crystal
surface incorporate into crystal latice.
Bone can be reservoir for slow release of toxic agents-lead
& radium.
Redistribution-termination
of drug effect, after withdrawl of drug
Usually is by excretion but may also result from
redistibution
16

17. when highly lipid soluble drugs given rapidly by i.v or
inhalation that act on brain & CVS redistribution takes
place.
i.V anesthetic Thiopental- reaches maximal conc in
brain within a minute of I.V. after injection is given
the plasma conc falls as it diffuses into other tissues-
Onset of anesthesia is rapid ,termination is also fast-both
related to conc of drug in brain.
17

18. Volume of distribution:
Apparent volume of distribution :
volume of fluid required to contain the total amount
of drug in the body at the same concentration as that
present in the plasma.
aVd = Total amt of drug
plasma conc
18

19. Fluid substances Volume (liter) Test
Extracellular Fluid 19 Inulin, thiosulfate
Plasma 3 Evans blue, I125
albumin
Interstitial fluids 16
Intracellular fluids 23
Total body water 42 Antipyrine, D2O,
ethanol
19

20. Plasma-
High ionised,very large molecular weight & protein
bound drugs
e.x -Heparin
Extracellular fluid –
 Low molecular weight
 Large molecules
e.x-mannitol
Total body water -
 Small water soluble mol
 drug low molecular weight,
e.x-Alcohol
20

21. ELIMINATION:
Most common routes kidney via urine , others are
bile, intestine, sweat,saliva,lung ,& breast milk .
Renal elimination :
 Glomerular filteration.
 Proximal tubular secretion.
 Tubular reabsorption.
21

22. Glomerular filteration:
Allows drugs size below 20 000 to pass.
heparin is restricted
Only free drug is filtered, greater the glomerular
perfusion, faster drug removal from plasma.
Does not depend on lipid solubility
22

23. Tubular secretion:
80% drug passes to proximal tubule remaining 20%
drug is removed by glomerular filteration.
Its an Energy requiring carrier mediated active
transport
e
23

24. Each carrier are non-selective they compete for same
Carrier System
e.g- Probenicid- Penicillins ↑ plasma half life &
effectiveness of penicillins
Acidic drugs- uric acid ↑ in levels
Two carrier system are involved
One for acidic drug – penicillin,salicylic acid
another is for basic drugs
e.x- Morphine, Quinidine, Procaine, Neostigmine,
Dopamine, Histamine.
24

25. Tubular reabsorption:
Reabsorption takes place by passive diffusion depends
-lipid solubility.
-pKa of drug.
-pH of urine
Acidic drugs → non ionisable
↓
reabsorption
↓ -alkalanization of urine
excretion
25

26. This can be used in case of Salicylate & Barbiturate
poisoning by making urine alkaline.
weak basic drugs ionisable
↓ ascorbic acid
excreted
↓-alkalinization
reabsorbed
Strong acidic & basic drugs – ionised at all pH gets
eliminated
26

27. Enterohepatic circulation:
 Drugs with low molecular weight reaches
hepatic extra cellular fluid.
 Active& passive diffusion involved.
 High protein bound & ionised drug do not
diffuse back into intestinal blood vessels get excreted
in faeces.
 Most of drugs undergo passive reabsorption carried
back to liver till drugs get metabolised & excreted
by kidney.
27

28. They act like reservoir for endogenous substances like
vitaminD3,B12,Folic acid
 Condition where liver function impaired-accumlation
of drugs will take place.
28

29. Other routes:
Pulmunory -
Volatile anesthetics- simple diffusion
Solubility of gas in blood is guiding factor-e.
x- nitrous oxide – rapid excretion
Agents with ↑ blood & tissue solubility
slowly excreted
e.x- Ethanol used to measure concentration in breath
of vehicle drivers.
29

30. .
Sweat & saliva-
 Non ionised, lipid soluble drugs diffuse in epithelial
cells of glands.
 pKa of drugs, Ph of secretion important regulate
excretion.
By sweat – Bromide, iodide.
saliva - phenytoin
30

31. Clearance-
Important concept to consider when designing a
rational regimen for long-term drug administration
important because metabolizing enzymes and
transporters are not saturated, and thus the absolute
rate of elimination of the drug is essentially a linear
function of its concentration in
plasma.
31

32. Amount of drug cleared from body/unit time.
Total clearance includes all mechanism of drug
elimination
CL =0.693×Vd
t1/2
Clearance is derived in units of volume/time.
Clearance of drug by several organs is additive.
32

33. Added together, these separate clearances will equal
systemic clearance:
Cl (renal )+ CL (hepatic) + CL (other) = CL
clearance useful for understanding the effects of
pathological and physiological variables on drug
elimination, particularly with respect to an individual
organ
Cl organ = Q.E
E is the extraction ratio
33

34. Kinetics of elimination –
First order kinetics –
A constant fraction of the drug is eliminated at
a constant interval of a time.
50% 50% 50% 50% 50%
100(μg/ml) → 50(μg/ml) → 25(μg/ml)→12.5(μg/ml)→6.25→3.125
2hr 2 hr 2 hr 2hr 2hr
50% 50% 50%
200μg/m →100(μg/ml) → 50(μg/ml) → 25(μg/ml)
2hr 2 hr 2 hr
The t1/2 of any drug following first order kinetics
would always remain constant irrespective of the
Drug, clearance also remains constant
34

35. Rate of drug elimination is directly proportional to
plasma concentration
97% drugs gets eliminated after 5 t 1/2 .
steady state= (dosing rate =CL × Css)
upto 5th half life plasma Concentration keeps on
increasing thereafter reaches steady state level.
The rate of absorption equals the rate of
elimination and thus subsequent administration of
same doses thereafter no effect on plasma conc 35

36. Zero order kinetics ( saturation
kinetics) :-
Constant or fixed quantity of the drug is
eliminated per unit time
Rate of elimination is independent of
plasma conc
Clearance is more at low conc less in high conc
Half life is less at low conc & more at high conc
36

37. Very few drugs follow this kinetics like alcohol
Any drug at higher conc may show zero order kinetics
Eg:Alcohol,Phenytoin,Aspirin,warfarin,tolbutamine,
theophiline
37

38. 25μg 25μg 25μg
100 μg/ml→ 75 → 50 → 25
1hr 1hr 1hr
25μg 25μg 25μg
200 μg/ml→175→150→125→100 & so on
1hr 1hr 1hr 1hr
-high plasma conc would also decline at the rate of
25μg/hr
38

39. On arithmetic scale –plasma fall out curve – Linear
Logarithm- plasma fall out curve – Curvilinear
39

40. ά- and β-phase of Drug Clearance :
α phase (distribution)
Β phase (elimination)
Time
I.V. Drug
40

41. HALF LIFE-time
duration in which plasma concentration of
Drug falls by 50% of the earlier value.
If metabolism is more half life is less vice
versa
Drugs having shorter half life are administered
more frequently
41

42. t1/2 = 0.693 × vd
cl
Therapeutic drug monitoring -
dose of drug adjusted according to plasma conc
drugs having correlation between serum level &
toxicity
Done in drugs with wide variation in pharmacokinetics
42

43. • Done for drugs having low therapeutic index
Digitalis,aminoglycosides,theophylline,lithium&
anti epileptics
• Done for drugs having known correlation between
serum level & toxicity
• Done whose effects can be measured
• Not done for drugs which are activated in body
43

44. H.L Sharma & K.K Sharma – The
Principles of Pharmacology
second Edition.
 Goodman & Gilman-pharmacological
basis of therapeutics
 R.S.Satoskar - Pharmacology
&Therapeutics -Twentieth Edition.
Rang & Dale - Pharmacology –
sixthEdition
44

45. 45

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48. 48