The document discusses drug elimination, focusing on the processes of biotransformation and excretion, particularly renal excretion, which includes glomerular filtration, tubular secretion, and reabsorption. It details factors affecting drug excretion such as molecular size, urine pH, and blood flow to the kidneys, and emphasizes the importance of understanding renal clearance in drug dosage adjustments in renal failure. Additionally, it covers the role of dialysis in treating patients with severe renal impairment.

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Introduction
• Elimination is defined as the process th t tends to irreversible loss of drug from the
body & terminate its action
• Elimination process involves two differen processesi.e.
Biotransformation - The conversion from one chemical form to another chemical form
i.e. Metabolism (activation/ inactivation).
Excretion - The process whereby drugs/ their metabolites are irreversibly transferred
from internal to external environment.

3. Introduction
a
n
• Excretion
The process where by drugs or met bolites are irreversibly transferred from
internal to external environment through renal or non renal route.
• Excretion of unchanged or intact drug is eeded in termination of its pharmacological
action.
• The principal organ of excretion are kidneys.

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Types of Excretion
RENAL EXCRETION
NON REN L EXCRETION
- Biliary excretion.
- Pulmonary excretion.
- Salivary ex retion.
- Mammary excretion.
- Skin / Dermal excretion.
- Gastrointestinalexcretion.
- Genital excretion

6. Renal Excretion of Drugs
Agents that are excreted in the urine are
• Water soluble
• Non-volatile
• Small in molecular size (less than 500 Daltons)
• The ones that are metabolized slowly

7. Renal Excretion of Drugs
• The basic functional unit of excretion in the kidney is the nephron
Parts of the nephron
• Glomerulus
• The proximal tubule
• The loop of Henle
• The distal tubule
• Collecting tubule

10. 1. Glomerular filtration
2. Active tubular secretion
3. Active or passive tubular reabsorption
Rate of excretion = Rate of Filtration +
a
R
Renal Excretion of Drugs
The principal processes that determine the urinary excretion of a drug are
Increase the concentration of drugs
in lumen and f cilitate excretion
Prevents excretion
ate of Secretion – Rate of reabsorption

11. Glomerular Filtration
• Non-selective , unidirectional process
• Ionized or unionized drugs are filtered,
except those that are bound to plasma
proteins or blood cells
• Driving force for GF is hydrostatic
pressure of blood flowing in capillaries

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filtered through glomeruli
The rate being called
filtration rate (GFR)
Glomerular filtration
Out of 25% of cardiac out put or 1.2 liters of
blood/min that goes to the kidney via re al
artery only 10% or 120 to 130ml/min is
as glomerular
Out of 180 liters of ultrafiltrate filtred daily,
only 1.5 liters is excreted. The remainder is
reabsorbed from the tubules

13. Glomerular filtration
• GFR: The rate at which filtration of blood/min takes place through glomeruli
• Normal GFR:-120-130ml/min
• GFR is measured by an agent which is excreted exclusively by filtration e.g. Inulin,
Mannitol, Creatinine

14. Summary
• Factors affecting tubular reabsorption – p
• Drug elimination – biotransformation and excretion
• Excretion – renal and non-renal routes
• Steps in urinary excretion – glomerular filtration, tubular secretion and tubular
reabsorption
H, pKa and urine flow rate

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LH-17
Learning bjectives
By the end of this session, students will be able to:
• Explain the concept of drug elimination
• Describe the process involved in renal excretion of drugs
• Analyze the factors affecting active tub lar secretion,tubular reabsorption

16. Active Tubular Secretion
• A carrier-mediated process (active transport)
• Drug diffuses against conc. Gradient
• Requires energy
• Two mechanisms:-
 System for secretion of organic acids/anions
-penicillin's & endogenous acids like uric acid
 System for secretion of organic bases/ cations
-morphine, & amines like histamine

17. Active Tubular Secretion
 Both systems are nonselective & independent of each other, but bidirectional
 Unaffected by changes in pH & protein binding
 Dependent on renal blood flow
 Drugs undergoing active secretion have excretion values greater than the normal GFR
(>130ml/min). Ex. Penicilllin – Renal clearance – 500 ml/min
 Exhibit some degree of structural specificity
 ATS is saturable & competitive process
 Secretion occurs in proximal tubules

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Active Tubular Secretion
 Agents that are used to measure active t bular secretion – those that are filtered as
well as secreted
 Removed from the blood in a single pass through the kidneys
 Their clearance reflects the renal plasma flow rate
 i.e., 600 to 700 ml/min
 Measured by agents like:- PAH its renal plasma flow is: 600-700 ml/min

19. Active Tubular Secretion
 Competitive process
 A drug with greater rate of clearance will retard the excretion of the other drug with
which it competes
 The half life of both the drugs is increased
 May result in accumulation and toxicity
Exploited therapeutically
 Example: half life of penicillin G is increased by inhibiting its excretion by agents like
probenecid
 Undesirable in case of nitrofurantoin (urinary antiseptic)

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Tubular Reabsorption
• Occurs after glomerular filtration of dru s.
• What will be the excretion rate of drugs undergoing reabsorption?
• Reabsorption indicated when the excretion rate values are less than the GFR of
130ml/min
• Agent that is completely reabsorbed after filtration has a clearance value of zero
Example glucose
• Tubular reabsorption – increases the half life of the drugs

21. Active Tubular
Reabsorption
endogenous substances
Its commonly seen with
or
nutrients that the body needs to
conserve
Ex. electrolytes, glucose, vitamins.
Passive
Tubular
Reabsorption
It is common for many exogenous
substances including drugs. The
driving force is Conc. Gradient
which is due to re-absorption of
water, sodium and inorganicions.
If a drug is neither excreted or re-
absorbed its conc. In urine will be
100 times that of free drug in
plasma.

22. • Dependent on lipophillicity
• Majority of drugs are weak electrolyte , i.e, weak acids or weak bases
• Diffusion of these drugs depends on their ionization
• Ionization depends on
1. pH of the urine
2. pKa of the drug
3. Urine flow rate
Passive tubular reabsorption

23. Urine pH
• Urine pH is not constant like the plasma pH
• Varies between 4.5 to 7.5
• Depends upon:
• Diet : carbohydrates ↑; Proteins ↓
• Drugs : Antacids ↑; Ascorbic acid ↓
• Respiratory and metabolic acidosis and alkalosis
• i.v infusion of solutions of sod. Bicarbonate and ammonium chloride

24. Penicillin (acidic), gentamycin (basic)
Polar in unionised form
a
Phenytoin – weakly acidic non polar
Propoxyphene – weakly basic, non
polar
Cromoglycic acid – strongly acidic
Guanethedine– strongly basic
Effect of urine pH, pKa and lipid solubility - summarized
Drugs Re bsorption? Excretion?
No
Independent of urine pH
and flow rate
Extensively
reabsorbed
Low. Independent to
urine pH
No High

25. Effect of urine pH, pKa and lipid solubility - summarized
Drug Acidic filtrate
Weak acid
HA
Negligible ionisation
HA
Pka 3.8 to 8.0
Weak Base
BOH
pKa 6.0 to 12.0
Significant ionisation
BOH B+ + OH-
Excreted in
urine
Plasma Alkaline filtrate
HA H+ + A-
Significant ionisation
HA H+ + A-
BOH
Excreted in
urine
Negligible ionization
BOH
B+ + OH-

26. Passive reabsorption
• Therapeutic activity of hexamine (urinary antiseptic)dependent on urinary pH
• It is converted to active form, formaldehyde only at acidic pH
• Toxicity of drugs whose excretion is sensitive to pH can be treated with acidification
(with ammonium chloride) or alkalinisation (with sod. Bicarbonate)
Example: Sulphonamides (acidic) ????

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Urine Fl w Rate
of urine pH are no reabsorbed
• Normal urine flow rate 1 to 2ml/min
• Pola drug whose excretio i indep nden
unaffected by UFR
• Drugs whose reabsorption is pH-sensitive
dependent on urine flow rate
for such agents re-absorption are
• Urine flow rate can be increased by forced diuresis
• Forced diuresis is the increase in urine flow induced by large fluid uptake or
administration of mannitol or other diuretics

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Urine Fl w Rate
• Forced diuresis is used to remove exc ssive drugs by promoting its excretion and
decreasing the time for reabsorption
• Examples of agents that can cause increase in urine flow rate???
Urine pH control and forced diuresis can be used to treat toxicity in the following cases
1. Urinary excretion is the major route for drug excretion
2. Extensively passively reabsorbed
3. Renal reabsorption is sensitive to urine pH

29. Summary
• Factors affecting tubular reabsorption – p
• Drug elimination – biotransformation and excretion
• Excretion – renal and non-renal routes
• Steps in urinary excretion – glomerular filtration, tubular secretion and tubular
reabsorption
H, pKa and urine flow rate

30. LH-18
Session objectives
n
By the end of this session, students will be able to:
• Discuss on the importance of cleara ce in the overall drug elimination
process
• Analyze the factors affecting renal clearance
• Explain the concept of creatinine clearance and renal function

31. Concept of Clearance
• Total body clearance/ total systemic clearance is the sum of individual clearances by
all eliminating organs
• i.e. Renal, hepatic, pulmonary, biliary……
Or
• Total body clearance = Renal clearance + Non renal clearance
Clearance is defined as the hypothetical volume of body fluids containing drug from
which the drug is removed or cleared completely in a specific period of time

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Concept of Clearance
• The body is regarded as a space that contains a definite volume of body fluid in
which the drug is dissolved
• ???
• Vd
• Drug clearance is defined as the fixed v lume of fluid (containing the drug) cleared
of drug per unit time
• Example penicillin : Vd = 12L and Clearance 15ml/min

33. Concept of Clearance
Renal Clearance is defined as the volume of blood or plasma which is completely
cleared of the drug by the kidney per unit time

34. Factors Affecting Renal Excretion/ Renal Clearance
1. Physicochemical properties of the drug
2. Plasma concentration of drug
3. Distribution & binding of drugs
4. Urine pH
5. Blood flow to the kidneys
6. Biological factors
7. Drug interactions
8. Disease states

35. 1. Molecular size
2. pKa
3. Lipid solubility
Below 300 Daltons
Above 500 Daltons
Between 300 to 500 Daltons
Physicochemical properties of drug
Molecular size & Route of excretion
Molecular weight of drug/metabolite Excretion pattern
Excreted mainly in urine; less than 5% in
bile
Excreted mainly in bile; less than 5% in
urine
Excreted both in urine and bile

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Physicochemical properties of drug
• pKa
Polar and ionized excreted
• Lipophilicity
Urinary excretion of unchanged drug is inversely related to lipophilicity of drug
because it is passively reabsorbed to lar e extent

37. Plasma concentration of the Drug
• Glomerular filtration & Reabsorption Passive process  Affected by plasma drug
concentration
• Renal clearance and rate of excretion of a drug in relation to its plasma concentration
is affected by the physiological process – filtration, active reabsorption and active
secretion

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Distribution and binding characteristics of the drug

39. Distribution and binding characteristics of the drug
Clr = fu X Urine flow rate
• Drugs extensively bound to plasma have long half life
Example
• Oxytetracycline (66% unbound)  99 ml/min
• Doxycycline (7% Unbound)  16 ml/min

40. Blood flow to the Kidneys
• Blood flow is important for drugs excreted by glomerular filtration and active
secretion
• In case of active secretion, perfusion increases the contact drug with the secretory
sites and enhances their elimination
• Renal clearance of such drugs is called perfusion rate-limited

41. Biological factors
• Age – renal function of newborns is 30 to 40% less in comparison to adults
• Sex
– Renal excretion is approx 10% lower in females than in males
– In old age, the GFR is reduced and tubular function is altered, the excretion of
drugs is thus slowed down and half-life is prolonged

42. Drug interaction
• Any drug interaction that result in alteration of binding characteristics, renal
blood flow, active secretion, urine pH, intrinsic clearance and forced diuresis
would alter renal clearance of drug
Alteration in P-D binding
• Renal clearance of a drug highly bound to plasma proteins is increased after it is
displaced with other drug
Ex. Furosemide displaces gentamicin from its binding sites  increases free
antibiotic concentration accelerates its renal clearance

43. Drug interaction
Alteration of urine pH
• Acidification of urine with ammonium chloride or ascorbic acid enhances excretion of
basic drugs
• Alkalinisation of urine with citrates, tartarates, bicarbonates and carbonic anhydrase
inhibitiors promote excretion of acidic drugs

44. Drug interaction
x
Competition for active secretion
• Acetohexamide  metabolised to hydro yhexamide (active metabolite)
• Phenylbutazone competes with hydroxyhexamide for active secretion and prolongs its
action

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Dise se state
Renal Dysfunction
Greatly impairs the elimination of drugs e pecially those that are primarily excreted
by kidney
Uremia (impaired GF and accumulation of fluids and protein metabolites)
Half life is increased resulting in drug accumulation
Results in drug accumulation and toxicity

46. • Renal function  Determined by measuring GFR
Markers used for determination of GFR
• Should be entirely excreted in unchanged form by glomerular filtration only
• Should be physiologically and pharmacologically inert
Markers used…
• Exogenous – Inulin  tedious method
• Endogenous - Creatinine
Renal function and renal failure

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Renal function and renal failure
Creatinine
• Endogenous amine produced as a result of muscle catabolism
• Creatinine clearance can be measured by determining the steady state plasma conc.
of creatinine
• Creatinine production varies with age, weight and gender
• Different formulae are used to calculate creatinine clearance in diff age groups

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49. LH-19
Session objectives
By the end of this session, students will be able to:
• Discuss dosage adjustment in renal failure
• Explain the concept of dialysis and hemodialysis
• Discuss on non renal routes of drug excretion

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Dosage adjustment in renal failure
• Drugs have altered PK profile
• Renal clearance and elimination rate is reduced
• Elimination half-life is increased
• Apparent volume of distribution is alter d
• Dose must be altered depending upon the renal function in such patients

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Dosage adjustment in renal failure
Dosage regimen need not be changed wh n
 Fraction of drug excreted unchanged, fu is less than or equal to 0.3
 The renal function RF is greater than or qual to 0.7 of normal
Based on the assumption that
 Metabolites are inactive
 Binding and drug availability is unaltered
• When fu value approaches unity and RF approaches zero, elimination is extremely
slow and dosing should be drastically re uced

52. Dialysis and Hemoperfusion
• Patients with severe renal failure are put on dialysis to remove toxic wastes from
their blood
• Dialysis is a process where, easily diffusible substances are separated from poorly
diffusible ones by the use of semipermeable membrane
The two procedures of dialysis are
1. Peritoneal dialysis
2. Haemoperfusion

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Peritoneal dialysis

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Haemodi lysis