Drug distribution and elimination

1. DISTRIBUTION AND
ELIMINATION OF DRUGS
By:-
Dr. Roohana Hasan
JR-1
Moderator:-
Dr. Dilshad Ali Rizvi

2. DRUG
DISTRIBUTION:

3. AFTER ABSORPTION OF A DRUG IT MAY:-
 Reversibly attached with its site of action.
 Bound to plasma Proteins.
 Accumulate in various storage sites.
 Enter into tissues.
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4. BARRIERS TO DRUG DISTRIBUTION:
Blood-Brain Barrier [BBB] (by glial
cells)
Blood-CSF and CSF-Brain Barrier.
Placental Barrier.
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5. BLOOD BRAIN BARRIER
BBB Protects brain tissue from toxic substances.
Only lipid soluble non ionised drug can pass
through BBB.
 Inflammatory conditions like cerebral meningitis
alter permeability of BBB
Drugs like Penicillin, Chloramphenicol exhibit
increased permeability. 5

6. BLOOD CSF AND CSF BRAIN BARRIER
 CSF secreted by the epithelial cells and lined by occluding
zonulae.
 But CSF brain barrier is composed epithelial cells lining the
ventricles , not connected by occluding zonulae.
 CSF-Brain barrier permeable to drug molecules
If drug given by intrathecal route it reach the brain in sufficient
concentrations.
eg: Penicillin in Brain Abscess.
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7. PLACENTAL BARRIER
 Placental membrane – lipid in nature.
 The transfer of drugs across the placenta is of critical
importance because drugs may cause anomalies in the
developing fetus.
 Administered immediately before delivery, eg;-tocolytics in
the treatment of preterm labor, they also may have adverse
effects on the neonate.
 The fetal plasma is slightly more acidic than that of the
mother (pH 7.0-7.2 vs 7.4), so that ion trapping of basic
drugs occurs.

8. SPECIAL COMPARTMENTS FOR DRUG
DISTRIBUTION:
 Cellular Reservoir.
 Fat as Reservoir.
 Transcellular Reservoir.
 Bones & Connective Tissue as Reservoir.
 Plasma protein binding as Drug Reservoir.
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9. CELLULAR RESERVOIR
 If the tissue has higher affinity for the drug.
 Binding to tissue proteins or nucleoproteins.
 Eg:- digoxin and emetine- skeletal muscles,
heart,liver,kidney( bound to muscle proteins)
 Iodine in thyroid, chloroquine in liver (tissue proteins)
 Cadmium, lead, mercury in kidney (muscle protein)

10.  Fat as Reservoir.- Highly lipid soluble drugs.eg.
Thiopentone & DDT
Sluggish reservoir due to decreased blood flow- may cause toxicity.
 Transcellular Reservoir. eg. Chloramphenicol in aqueous
humour, CSF (amino sugars), pericardial and peritoneal
sacs serve as drug reservoirs.
 Bones & Connective Tissue as Reservoir. Many drugs
like tetracyclines,cisplatin,lead, fluorides form complexes
with bone salts and get deposited in nails,bones and
teeth.
eg. Griseofulvin in Keratin precursor cells, selectively
accumulated in skin and nails.

11. PLASMA PROTEIN BINDING AS DRUG
RESERVOIR
 Drugs bind to plasma proteins and cellular proteins
in a reversible manner and in dynamic equilibrium.
Free drug + protein Drug-Protein complex.
 Extensive protein binding does not prevent drug
from reaching its site of action but prolongs the
drug availability and duration of action.

12. IMPORTANT PROTEINS THAT
CONTRIBUTE TO DRUG BINDING:
1) Plasma Albumin. [acidic drugs]
2) α1-Acid Glycoproteins (α1-AGP). [basic drug]
3) Tissue Proteins & Nucleoproteins. [drugs with high aVd]
4) Miscellaneous Binding Proteins. [thyroxin to α globulin,
antigens to gamma globulins]
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13. CLINICAL IMPORTANCE OF PLASMA PROTEIN
BINDING:
 Highly plasma protein bound drugs
Restricts to vascular compartment and have lower Vd.
 Highly protein bound drugs are Difficult to remove by
Dialysis
 In diseases causing hypoalbuminemia therapeutic dose can
lead to higher conc. of drug.
 Plasma α1-AGP = acute phase reactant protein. Increases in
MI, Crohn’s disease etc. Binding of basic drug increases. eg.
Propanolol
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14.  Displacement interactions increase free drug concentration (of
the displaced drug) causing adverse effects.
Displacement is significant when:-
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Displaced drug is more than 95% protein bound
Displaced drug with extensive protein bounding but lower aVd

15. Volume of distribution: It has physiological
meaning, & related to the Body Water.
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16.  Digoxin is widely
distributed in the body
including muscles and
adipose tissue, leaving a
small fraction to be
distributed in the plasma.
 Volume of distribution does not
represent a real volume but must
be regarded as the size of the
body or fluids that would be
required if the drug was
distributed eqaully in all portions
of the body.

17. APPARENT VOLUME OF DISTRIBUTION (AVD):
aVd = Total amount of drug in body (mg/kg)_
Conc. Of the Drug in the Plasma (mg/L)
It is the total space which should apparently be available in the
body to contain the known amount of the drug.
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18. a. If a drug does not capillary walls and is given by IV route ,
aVd = plasma water ie; 3L.
b. Drugs highly bound to plasma proteins have low aVd.
c. The lesser the plasma protein binding ,greater is the aVd.
d. aVd is > actual body volume
- widely distributed in the body
- difficult to remove by dialysis.

19.  aVd < 5L – vascular compartment
 aVd~ 15L – extracellular fluid
 aVd > 20L – distribution through out the body.
 Pathological states can alter aVd of many drugs by altering
distribution of body water and protein binding.
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20. REDISTRIBUTION OF DRUGS:
 Typical mode of drug distribution
observed with highly Lipid-soluble
drugs.
eg: Anaesthetic effect of
Thiopentone is rapid but effect get
terminated due to redistribution in
muscle and fat.
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21. DRUG
ELIMINATION:
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22. ROUTES OF ELIMINATION:
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Major Routes Minor Routes
Renal Milk
Biliary Skin
Fecal Hair
Alveolar Sweat & Saliva

23. CLEARANCE
 Volume of plasma that is cleared of drug per unit time.
 Unit= volume/time.
 Clearance is the propotionality factor used to determine
the rate of elimination.
 Rate of elimination = CL * concentration
 CLtotal = CLrenal + CLhepatic + CLlungs

24. RENAL EXCRETION:
 Most important organ for
Elimination.
 Free drugs (eg. Furosemide,
gentamicin)
 Drug Metabolites. 24

25. PROCESSES THAT DETERMINE RENAL EXCRETION:
i. Glomerular filtration.
ii. Active tubular Secretion.
iii. Passive tubular reabsorption.
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26. FACTORS OF GLOMERULAR FILTRATION:
i. Molecular size.
ii. Plasma protein
binding
iii. Renal Blood Flow.
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27. TUBULAR SECRETION:
 Energy, requiring carrier mediated active transport.
 Two independent carrier systems
 For acidic drug (eg. Penicillin, salicylic acid)
 For basic drugs (eg. Morphine)
 Clinical Importance:
Weakly acidic drug (salicylic acid, lactic acid) interfere with secretion of
Uric Acid
Increase plasma Uric acid Level
Precipitates GOUT
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28.  Probenecid (a weak acid) competitively inhibits the
tubular secretion of penicillins and amoxycillin,
increase plasma half-life and effectiveness of
penicillians in the treatment of infective diseases.

29. TUBULAR REABSORPTION:
 Reabsorption takes place through
Passive diffusion.
 Factors :
Lipid solubility.
Ionisation constant (pKa)
pH of Urine.
Clinical Importance:
Alkalisation of Urine in Salicylate or barbiturate
poisoning.
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30. BILIARY EXCRETION & ENTEROHEPATIC
CIRCULATION:
 Drugs excreted in Bile:-Quinine, Colchicines, Corticosteroids.
 Some drugs secreted through bile but after being delivered
to intestine, are reabsorbed back and the cycle is repeated.
Eg: Digitoxin.
 Other drugs with enterohepatic circulation:
Morphine, Chloramphenicol, Tetracycline etc.
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31. Clinical Importance of Biliary excretion and
Enterohepatic circulation:
 In morphine poisoning Gastric lavage is done to
prevent Enterohepatic Circulation.
 Enterohepatic circulation prolongs the drug action.
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32. FECAL ELIMINATION:
 Orally ingested drug not absorbed in Gut
eg. MgSO4, Neomycin, Certain purgatives
 Drugs excreted in bile & not absorbed from
intestinal tract.
eg. Erythromycin, Corticosteroids.
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33. ALVEOLAR EXCRETION:
 Gases & Volatile liquids
eg: General Anaesthetics, Ether, Alcohol
 Depends on partial pressure in the blood.
 Eucalyptus oil and garlic oil eliminated through
expectoration.
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34. ELIMINATION THROUGH BREAST MILK:
 May cause unwanted effect in Nursing infant.
 Drugs transferred to breast milk according to pH partition
principle.
 Basic drugs not ionised at plasma alkaline pH, get
accumulated in Milk.
Eg: Chloramphenicol, Tetracycline, Morphine etc.
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35. Certain acidic drugs may also be secreted in the milk and
can cause
Sulfonamides- kericterus and allergy
Penicillin- allergy
 Dapsone- heamolytic anemia
 Phenobarbiton- drowsiness
 Phenytoin- methaemoglobineamia
 Infants are sensitive to drug induced hemolysis-
chloramphenicol, quinine, quinidine, dapsone etc. should
not be given to breastfeeding mother.

36. EXCRETION THROUGH SKIN, HAIR, SWEAT &
SALIVA:
 Griseofulvin is secreted through keratin precursor cells.
 Arsenic, Mercury salts & Iodides Hair Follicles.
 Iodine, KI, Li & Phenytoin  Saliva.
 Amines & Urea derivatives  Sweat.
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37. KINETICS OF DRUG
ELIMINATION:
 First order kinetics.
 Zero order kinetics.
 Mixed order kinetics.
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38. FIRST ORDER KINETICS:
 Majority of the drugs follow this type of
elimination.
 A constant fraction of the drug is
eliminated at a constant interval of time.
 eg: Plasma concentration declining at a
rate of 50% per two hours:
100 µg/ ml  50 µg/ml  25 µg/ ml
12.5 µg/ml and so on. 38

39.  The rate of drug elimination is directly proportional to the
plasma concentration.
eg: 200-> 100-> 50-> 25-> 12.5 so on.
 The t ½ of any drug would always remain constant
irrespective of the dose.
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40.  Plasma concentration is plotted against time , the resultant “
plasma fall-out curve”  curvilinear,
 Log of plasma concentration are plotted against time , the
resultant curve  linear.
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41.  After a single dose, about 97% of the drug gets eliminated
after 4-5 half-lives (t ½) interval.
 Only 3% of the drug remains in the plasma after 5th half life.
 100 (mcg/ml) 50 25 12.5 6.25 3.125
 If the fixed dose of the drug is administered at every half life,
5 half lives would be needed for 97% of steady state level.
 Plasma concentration reaches the steady state level
rate of absorption = rate of elimination.
Clinically steady state plasma concentration is maintained
within the effective therapeutic range.
41
1s
t
2n
d
3rd 4t
h
5t
h

42.  If the dose of the drug is doubled, its duration of action is
prolonged for one more half-life.
 The “log plasma concentration fall-out curve” of a drug
having high aVd, exhibits 2 slopes.
An initial rapid declining phase due to
distribution (called as α phase)
Later linearly declining phase due to
elimination (called as β phase)
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43. FIG : Α AND Β-PHASE OF DRUG
CLEARANCE 43

44. ZERO ORDER KINETICS:
 A constant or a fixed quantity of drug is eliminated per unit
time.
 Ethyl alcohol exhibit zero order at virtually all
plasma concentrations.
 For eg: if plasma concentration falls at a rate of 25 µg per
hour then 50 25 nil
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45.  The rate of elimination is independent of the concentration of
the drug in the plasma. So increasing the dose does not
result in a proportionate rise in the extent of elimination.
100 75 50 25 Nil
 The t ½ of a drug following zero order is never constant.
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46.  If such a fall in plasma concentration is plotted against time,
the resultant “plasma fall-out curve” is steeply linear, but if
logarithm of plasma concentration are plotted against time ,
then the curve becomes curvilinear.
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47. MIXED ORDER KINETICS/ SATURATION KINETICS /
MICHAELIS-MENTEN KINETICS:
 Dose-dependent kinetics where smaller doses are
eliminated by first order kinetics but as the plasma
concentration reaches higher values ,the rate of drug
elimination becomes zero order.
 Phenytoin, warfarin, digoxin, dicumarol.
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48.  After a single dose administration, if the plasma
concentrations are plotted against time, the resultant
plasma fall out curve remains linear in the beginning (zero
order) and then become predominantly exponential (
curvilinear i.e. first order).
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Fig : Plasma concentration fall-out curve in mixed order kinetics.

49. CLINICAL IMPORTANCE:
 Drugs having very short half-life are given by constant i.v.
infusion to maintain steady state concentration.
 Drugs having t1/2 = 30 mins to 2 hrs , it becomes incovenient
to administer it every half life. In such cases, provides the
drug is having high safety margin and obeying 1st order
kinetics , dose can be so increased that the drug can be
administered every 6-8 hours.
 The drugs having t1/2 = 4-12 hours, administered at every
half life interval. 49

50.  The drugs having medium half life usually given at 12 hours
interval.
 Drugs having 24 hours half life, half of the therapeutic dose is
given at every half of half life.
 For drugs having longer t ½, with high Vd & slow rate of
clearance also are cumulative in nature. To reach steady state
 Loading dose given  Maintenance dose.
 Loading dose= Desired plasma conc. (mg/L) * aVd (L/kg).
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