Elimination of drug

1. Kailas K Mali

2. Contents
 Introduction
 Renal Excretion of Drug
2

3. Introduction
 Drug elimination refers to the irreversible removal of
drug from the body by all routes of elimination. Drug
elimination is usually divided into two major
components: excretion and biotransformation
 Excretion
 Renal Excretion
 Nonrenal Excretion of Drug
3

4. Renal Excretion of Drug
 Drug and metabolites
 Water soluble
 Non-volatile
 Small molecular size
 Metabolised slowly
 Basic functional unit of kidney
 Nephron
 Each kidney – 1 milions
4

5. Renal Excretion of Drug
 Nephron
5

6. 6
Arterial
supply
(1.2 l/min)
Venous
return
Proximal
tubule
Distal
tubule
Loop of Henle
Collecting
tubule
Urine
(1.5l/day)
Glomerulus
120 ml/min
Active secretion
Reabsorption
E.g. gentamicin, cephalexin
Renal Excretion

7. 7
Glome-
rulus
Proximal
tubule
Distal
tubule
Collecting
tubule
Flow
ml/min
pH control
100
1000
Water
Drugs
Filter
Filter
80% reabsorb.
secretion
Reabsorption
10 - 20 % reabsorbed
Handling of drugs by the nephron

8. Renal Excretion of Drug
 Principle Processes
 Glomerular Filtration
 Active tubular secretion
 Active or passive tubular reabsorption
8

9. Renal Excretion of Drug
 Glomerular Filtration
 Non selective
 Unidirectional
 Ionised and unionised drug filtered
 Except plasma proteins/ blood cells
 Promotes retention of anionic drugs
 Driving force- hydrostatic pressure
 25 % cardiac output (1.2 l/min)
 10% filtered (120 to 130 ml/min) GFR
 GFR estimated by using creatinine, inulin, mannitol, sodium
thiosulphate
9

10. Renal Excretion of Drug
 Active tubular secretion
 Carrier mediated transport
 Energy required
 Against concentration gradient
 Two active tubular secretion methods
 Secretion of organic acids/anions
 Uric acid, Salicylic acid, penicillins, sulphates
 Secretion of organic bases/ cations
 Endogenous amines, morphine,
 Both systems are bidirectional, non-selective, independent of
each other
10

11. Renal Excretion of Drug
 Active tubular secretion
 It is unaffected by changes in pH and protein binding
 It is dependent on renal blood flow
 ATS can be measured by using para amino hipuric acid
 Filtered and secreted 600 to 700 ml/min
 Proximal tubule region of nephron
 Probenecid + Penicillins (Decreased tubular secretion of Penicillins)
 Probenecid + nitrofurantoin (UTI) (Decreased secretion)
 Probenecid inhibit reabsorption of uric acid
11

12. Renal Excretion of Drug
 Active or passive tubular reabsorption
 Glucose
 GFR less than 120 ml/min
 Two types
 Active process
 Passive process
 Active process
 Endogenous material
 Glucose, uric acid, electrolytes, vitamins, amino acids
12

13. Renal Excretion of Drug
 Active or passive tubular reabsorption
 Passive process
 Exogenous materials including drugs
 Driving force concentration gradient developed by back
diffusion or reabsorption of water along with electrolytes.
 Determinant: lipophilicity, polarity, ionisation
 Factors: pH of urine, pKa of drug, Urine flow rate
13

14. Renal Excretion of Drug
 Urine pH
 pH varies from 4.5 to 7.5
 Depend on diet, drug intake and pathophysiology
 Carbohydrates food- increases urinary pH
 Protein food- decreases urinary pH
 Acetazolamide, sodium bicarbonate- alkaline urine
 Excretion of drug depend on lipophilicity and Pka of drug
 Very weak acids/ bases, polar drugs: reabsorption independent of
urine pH- excreated
 Weak acids (pKa > 8)/ Bases (pKa < 6), Nonpolar drugs: Unionised
at urine pH- reabsorbed.
 Strong acid/ bases: ionised all pH- excreted.
 Acidic (pKa 3-8)/ Basic (pKa 6-12): reabsorption depend on pH
14

15. Renal Excretion of Drug
 Urine flow
 Polar drug: Reabsorption unaffected by urine flow
 Drug with reabsorption is pH sensitive- inversely proportional to
urine flow.
 Urine flow increased by forced diuresis (mannitol).
15

16. Renal Excretion of Drug
Relationship between renal clearance and mechanism of clearance
* Renal Clearance ratio = Clr of drug/Clr of creatinine
16
Clr
ml/min
Clr Ratio
Drug to
Creatinine
Mechanism of renal clearance Example
0 0 Drug filtered & reabsorbed completely Glucose
< 130 Above 0,
below 1
Drug filtered & reabsorbed partially Lipophilic
drug
130 1 Drug filtered Creatinine
> 130 > 1 Drug filtered & secreted Polar ionic
drug
650 5 Cl = renal plasma flow rate PAH

17. Factors affecting renal excretion
 Physicochemical properties of drug
 Molecular size (300)
 pKa
 Lipid solubility
 Sterioselectivity
 Plasma concentration of drug
 I- Drug excreted by filtration
 II- Filtered + reabsorbed
 III- Filtered + secreted
17
PDC
RateofExcretion
III
I
II

18. Factors affecting renal excretion
 Distribution and binding of drug
 Clr is inversely proportional to Vd
 If drug present in blood compartment have high excretion
 Protein bound drug not filtered- macromolecules shows long
half life
 Actively secreted drug have little effect of binding.
 Influence of urine pH
 Blood flow to kidney
 GFR and active secretion affected
 Perfusion rate limited
18

19. Factors affecting renal excretion
 Biological factors
 Females: 10 % less than males
 Newborns: 30-40% less than normal adults
 Old age: altered GFR and tubular function
 Drug interaction
 Alteration in protein binding
 Furesimide + Gentamicin (Clr increased, nephrotoxicity)
 Alteration in urine pH
 Acidification (ammonium chloride, ascorbic acid) promotes excretion of basic
drugs.
 Alkalinisation (citrates, tartarates, bicarbonates) promotes excretion of acidic
drugs.
 Competition for active secretion (Probencid+Penicillins)
 Forced diuresis (Mannitol)
19

20. Factors affecting renal excretion
 Disease states
 Renal dysfunction
 Uraemia: impaired GFR
 Half life increased
20

21. Factors affecting renal excretion
 Disease states
 Renal dysfunction
 Uraemia: impaired GFR
 Half life increased
21

22. Renal Impairment
 Common Causes of Kidney Failure
22
Pyelonephritis Inflammation and deterioration of the pyelonephrons due to
infection, antigens, or other idiopathic causes.
Hypertension Chronic overloading of the kidney with fluid and electrolytes
may lead to kidney insufficiency.
Diabetes mellitus The disturbance of sugar metabolism and acid-base balance may
lead to or predispose a patient to degenerative renal disease.
Nephrotoxic
drugs/metals
Certain drugs taken chronically may cause irreversible kidney
damage—eg, the aminoglycosides, phenacetin, and heavy
metals, such as mercury and lead.
Hypovolemia Any condition that causes a reduction in renal blood flow will
eventually lead to renal ischemia and damage.
Neophroallergens Certain compounds may produce an immune type of sensitivity
reaction with nephritic syndrome—eg, quartan malaria
nephrotoxic serum.

23. Renal Impairment
 Kidney
 regulating body fluids,
 electrolyte balance,
 removal of metabolic waste,
 and drug excretion from the body
 Impairment or degeneration of kidney function
 affects the pharmacokinetics of drugs
 Causes of kidney failure
 disease, injury, and drug intoxication.
 Acute diseases or trauma to the kidney can cause uremia, in
which glomerular filtration is impaired or reduced, leading to
accumulation of excessive fluid and blood nitrogenous
products in the body.
23

24. Renal Impairment
 Uremia
 Reduces GFR and/or active secretion- leads to a decrease in
renal drug excretion- longer elimination half-life.
 Declining renal function leads to
 disturbances in electrolyte and fluid balance- physiologic and
metabolic changes- alters the pharmacokinetics and
pharmacodynamics of a drug.
 Drug distribution and elimination- altered.
 Uremic patients have special dosing considerations to
account for such pharmacokinetic and pharmacodynamic
alterations.
24

25. Renal Function
 Can be estimated by measuring GFR
 Markers should be used like Creatinine or inulin
 Inulin clearance
 Tedious method
 Creatinine clearance
 In body produced during muscle catabolism
 No need to collect urine
 Needs to measure serum creatinine
 Creatinine production varies with age, sex and weight
25

26. Renal Function
 Creatinine clearance
 Creatinine clearance (Clcr) is renal clearance (Clr) applied to
endogenous creatinine.
 It is used to monitor renal function and is a valuable
parameter for calculating dosage regimens in elderly patients
or those suffering fromrenal dysfunction.
 Normal creatinine clearance (Clcr) values are:
 adult males: 120±20mL/min.
 adult females: 108±20mL/min.
 Normal serum creatinine concentrations vary:
 adult men: 8.0 to 13mgL1 (0.8–1.3mg/dL)
 adult women: 6.0 to 10mgL1 (0.6–1.0mg/dL).
26

27. Renal Function
 For children (1 to 20 years)
 For adults (above 20 years)
 Males
 Females
27
7.0
70
48.0





W
S
H
Cl
cr
cr
cr
cr
S
WAge
Cl
72
)48.0( 

cr
cr
S
WAge
Cl
85
)48.0( 


28. Renal Function
 Direct method- creatinine clearance
 Collect urine samples- 24h
 RF is calculated by
28
%mgincreatinineSerum
excretioncreatinineofRate
rCl
personnormalaofCl
patientofCl
cr
cr
RF

29. Renal Function
 Renal Impairment Based on Creatinine Clearance
29
Group Description Estimated Creatinine
Clearance (mL/min)
1 Normal renal function >80 mL/min
2 Mild renal impairment 50–80 mL/min
3 Moderate renal impairment 30–50 mL/min
4 Severe renal impairment <30 mL/min
5 ESRDa Requires dialysis

30. Renal Function
30

31. Dose Adjustment in Renal Disease
 Required dose in patients with renal impairment can be
calculated by,
 Dosing interval in patients with renal impairment can be
calculated by,
31
personnormalaofCl
patientofCl
cr
cr
RF
RFdoseNormalimpairmentrenalindoseDrug 
RF
hoursinintervalNormal
intervalDosing 

32. Extracorporeal Removal of drugs
 Patients with end-stage renal disease and intoxicated patients –
 result of a drug overdose
 require supportive treatment
 to remove the accumulated drug and its metabolites.
 Several methods are available for the extracorporeal removal of
drugs,
 hemoperfusion,
 hemofiltration,
 dialysis.
 The objective of these methods is to rapidly remove the
undesirable drugs and metabolites from the body without
disturbing the fluid and electrolyte balance in the patient.
32

33. Extracorporeal Removal of drugs
 Dialysis
 Dialysis is an artificial process in which the accumulation of drugs
or waste metabolites is removed by diffusion from the body into the
dialysis fluid.
 Two common dialysis treatments are
 peritoneal dialysis
 hemodialysis.
 Both processes work on the principle that as the uremic blood or
fluid is equilibrated with the dialysis fluid across a dialysis
membrane, waste metabolites from the patient's blood or fluid
diffuse into the dialysis fluid and are removed.
 The dialysate contains water, dextrose, electrolytes (potassium,
sodium, chloride, bicarbonate, acetate, calcium, etc), and other
elements similar to normal body fluids without the toxins.
33

34. Extracorporeal Removal of drugs
 Peritoneal Dialysis
 Peritoneal membrane in the abdomen- used as the filter.
 Peritoneum consists of visceral and parietal components.
 Peritoneum membrane provides a large natural surface area
 Surface area for diffusion about 1–2 m2 .
 Membrane is permeable to solutes of molecular weights 30,000 Da .
 Approximately 70 mL/min comes into contact with the peritoneum.
 Placement of a peritoneal catheter is surgically simpler than hemodialysis .
 Does not require vascular surgery and heparinization.
 Dialysis fluid is pumped into the peritoneal cavity, where waste metabolites in
the body fluid are discharged rapidly.
 The dialysate is drained and fresh dialysate is reinstilled and then drained
periodically.
 Peritoneal dialysis is also more amenable to self-treatment.
 Slower drug clearance rates are obtained with peritoneal dialysis compared to
hemodialysis, and thus longer dialysis time is required.
34

35. Extracorporeal Removal of drugs
 Peritoneal Dialysis
 Continuous ambulatory peritoneal dialysis (CAPD) is the
most common form of peritoneal dialysis.
 Many diabetic patients become uremic as a result of lack of control
of their diabetes.
 About 2 L of dialysis fluid is instilled into the peritoneal cavity of the
patient through a surgically placed resident catheter.
 The objective is to remove accumulated urea and other metabolic
waste in the body.
 The catheter is sealed and the patient is able to continue in an
ambulatory mode.
 Every 4–6 hours, the fluid is emptied from the peritoneal cavity and
replaced with fresh dialysis fluid.
 The technique uses about 2 L of dialysis fluid;
 it does not require a dialysis machine and can be performed at home.
35

36. Extracorporeal Removal of drugs
 Hemodialysis
 Uses a dialysis machine and an artificial membrane.
 Requires access to the blood vessels to allow the blood to flow to the
dialysis machine and back to the body.
 One tube inserted into an artery and another tube inserted in a
vein.
 The tubes are joined above the skin.
 An arterial needle allows the blood to flow to the dialysis machine,
and blood is returned to the patient to the venous side. Heparin is
used to prevent blood clotting during the dialysis period.
 During hemodialysis the waste material is removed from the blood
by diffusion through an artificial membrane before the blood is
returned to the body.
36

37. Extracorporeal Removal of drugs
 Hemodialysis
 Hemodialysis is a much more effective method of drug removal in
overdose or poisoning.
 Dialysis may be required from once every 2 days to 3 times a week,
with each treatment period lasting 2 to 4 hours.
 Dosing of drugs in patients receiving hemodialysis is affected
greatly by the frequency and type of dialysis machine used and by
the physicochemical and pharmacokinetic properties of the drug.
37

38. Extracorporeal Removal of drugs
 Hemodialysis
38
Physicochemical and Pharmacokinetic Properties of the Drug
Water
solubility
Insoluble or fat-soluble drugs are not dialyzed. eg,
glutethimide, which is very water insoluble.
Protein
binding
Tightly bound drugs are not dialyzed because dialysis is
a passive process of diffusion. eg, propranolol is 94%
bound.
Molecular
weight
Only molecules with molecular weights of less than 500
are easily dialyzed. eg, vancomycin is poorly dialyzed
and has a molecular weight of 1800.
Drugs with
large volumes
of distribution
Drugs widely distributed are dialyzed more slowly
because the rate-limiting factor is the volume of blood
entering the machine. eg, for digoxin, V D = 250–300 L.
Drugs concentrated in the tissues are usually difficult to
remove by dialysis.

39. Extracorporeal Removal of drugs
 Hemodialysis
 Blood is pumped to the dialyzer by a roller pump at a rate of 300–
450 mL/min.
 Drug and metabolites diffuse from the blood through the
semipermeable membrane.
 Hydrostatic pressure forces drug molecules into dialysate by
ultrafiltration.
 Dialysis machines use a hollow fiber or capillary dialyzer in which
the semipermeable membrane is made into fine capillaries, of
which thousands are packed into bundles with blood flowing
through the capillaries and the dialysate is circulated outside the
capillaries.
 The permeability characteristics of the membrane and the
membrane surface area are determinants of drug diffusion and
ultrafiltration.
39

40. Extracorporeal Removal of drugs
 Hemodialysis
40
Characteristics of the Dialysis Machine
Blood flow rate Higher blood flows give higher
clearance rates.
Dialysate Composition of the dialysate and
flow rate.
Dialysis membrane Permeability characteristics and
surface area.
Trans membrane
pressure
Ultrafiltration increases with
increase in transmembrane
pressure.
Duration and
frequency of dialysis

41. Extracorporeal Removal of drugs
 Hemoperfusion
 Process of removing drug by passing the blood from the patient
through an adsorbent material and back to the patient.
 Useful procedure for rapid drug removal in accidental poisoning and
drug overdosage.
 The drug molecules in the blood are in direct contact with the
adsorbent material, any molecule that has great affinity for the
adsorbent material will be removed.
 The two main adsorbents used in hemoperfusion include
 activated charcoal, which adsorbs both polar and nonpolar drugs,
 Amberlite resins are available as insoluble polymeric beads, each bead containing
an agglomerate of cross-linked polystyrene microspheres. The Amberlite resins
have a greater affinity for nonpolar organic molecules .
 Factors for drug removal by hemoperfusion
 Affinity of the drug for the adsorbent, surface area of the adsorbent, absorptive
capacity of the adsorbent, rate of blood flow through the adsorbent, and the
equilibration rate of the drug from the peripheral tissue into the blood.
41

42. Extracorporeal Removal of drugs
 Hemofiltration
 Hemofiltration is a process by which fluids, electrolytes, and small-
molecular-weight substances are removed from the blood by means of
low-pressure flow through hollow artificial fibers or flat-plate
membranes.
 Fluid is filtered out of the plasma during hemofiltration, replacement
fluid is administered to the patient for volume replacement.
 Hemofiltration is a slow, continuous filtration process that removes
nonprotein bound, small molecules (<10,000 Da) from the blood by
convective mass transport.
 The clearance of the drug depends on the sieving coefficient and
ultrafiltration rate.
 Hemofiltration provides a creatinine clearance of approximately 10
mL/min and may have limited use for drugs that are widely distributed
in the body, such as aminoglycosides, cephalosporins, and acyclovir.
 A major problem with this method is the formation of blood clots
within the hollow filter fibers.
42

43. Biliary Excretion
 Hepatic cells lining the bile canaliculi produce bile.
 Production and secretion is active process.
 Secreted from liver & stored in gall bladder- secreted in
duodenum.
 Bile flow- 0.5 to 1 ml/min
 Digestion and absorption of fats.
 90% absorbed back and transported to liver for resecretion.
 10% excreted in faeces.
 Process is capacity limited and gets saturated.
 Drug clearance value 500ml/min
43

44. Biliary Excretion
 Hepatic cells lining the bile canaliculi produce bile.
 Production and secretion is active process.
 Secreted from liver & stored in gall bladder- secreted in
duodenum.
 Bile flow- 0.5 to 1 ml/min
 Digestion and absorption of fats.
 90% absorbed back and transported to liver for resecretion.
 10% excreted in faeces.
 Process is capacity limited and gets saturated.
 Drug clearance value 500ml/min
44

45. Bibliography
 D. M. Bramhankar and S. B. Jaiswal. Biopharmaceutics and
Pharmacokinetics A Treatise. Delhi;Vallabh Prakashan. 2010
 Jambhekar SS, Breen PJ. Basic Pharmacokinetics. London;
Pharmaceutical Press. 2009.
 Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics and
Pharmacokinetics. McGraw Hill. 2007
45