Clearance of drugs. Elimination of drugs - sites Review of renal physiology. Nature of drugs & factors affecting elimination. Drug half life Steady state concentration & Maintenance dose. Clearance: Volume of plasma that is cleared of drug per unit time. Elimination rate: is mass/amount of drug that is cleared from the body. Clearance is related with elimination by a constant proportion factor.

1. ELIMINATION OF
DRUGS
DR AWAIS IRSHAD
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2. OBJECTIVES
• CLEARANCE OF DRUGS.
• ELIMINATION OF DRUGS - SITES
• REVIEW OF RENAL PHYSIOLOGY.
• NATURE OF DRUGS & FACTORS AFFECTING
ELIMINATION.
• DRUG HALF LIFE
• STEADY STATE CONCENTRATION & MAINTENANCE
DOSE.
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3. EXCRETION OF DRUGS
• Excretion is the removal of waste substances from body fluids and predominantly occurs
via kidneys.
• The process by which drugs or metabolites are irreversibly transferred from internal to
external environment through renal or non renal route.
• Most drugs are excreted in urine either as unchanged drugs or drug metabolites
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4. Routes of Excretion
Non Renal
Excretion
Pulmonary
Excretion
Salivary
Excretion
Dermal
excretion
Biliary
Excretion
Mammary
Excretion
Renal
excretion
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5. PHYSIOLOGY
• The two kidneys constitute less than 1% of the total
body weight, but receive about 25% of the cardiac
output.
• Afferent arterioles from the renal artery supply blood to
the glomerulus at arterial pressure.
• About 20% of this is converted to glomerular ultra
filtrate.
• Further reabsorption & secretion takes place at various
points along the nephron.
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6. PHYSIOLOGY
• The final product (urine) is only about 1% of the
volume of the original glomerular filtrate.
• Most drugs are metabolized first prior to being
excreted. However, some drugs, such as
aminoglycoside antibiotics are polar compounds and
are excreted by the kidneys without being
metabolized first.
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7. RENAL EXCRETION OF
DRUGS
 THE MOST IMPORTANT ORGAN FOR DRUG
EXCRETION IS THE KIDNEY.
THE PRINCIPLE PROCESSES
THAT DETERMINE URINARY
EXCRETION OF DRUGS ARE:
• GLOMERULAR
FILTRATION.
• ACTIVE TUBULAR
SECRETION.
• PASSIVE OR ACTIVE
TUBULAR RE-
ABSORPTION.
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8. Pharmacology
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↑
Excretio
n of
dugs
↑ renal blood flow
↑Glomerular
filtration
↓ Plasma protein binding
Because of ↑
glomerular
filtration

9. GLOMERULAR
FILTRATION
The amount of blood filtered
by the glomeruli in a given
time (GFR = 120-130 ml/min)
Glomerular
capillaries allow
drug molecules of
molecular weight
below about 20 000
to pass into the
glomerular filtrate
Plasma albumin
molecular weight
approx 68 000 is
almost completely
impermeant
Most drugs molecules cross
the barrier freely.
If a drug binds to
plasma albumin,
only free drug is
filtered
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Warfarin, a drug is 98% bound to albumin, concentration in
filtrate is only 2% of that in plasma, and clearance by filtration is
correspondingly reduced.
Glomerular filtration occurs to:
• Low molecular weight drugs
• Free form of the drugs (not bound to plasma proteins).
• Water soluble drugs , Aminoglycosides.
• Drugs with low volume of distribution (Vd)

10. TUBULAR
SECRETION
Up to 20% of
renal plasma
flow is filtered
through
glomerulus,
leaving at least
80% of delivered
drug to pass on
to the
peritubular
capillaries of the
proximal tubule.
Because at least
80% of the drug
delivered to the
kidney is
presented to the
carrier, tubular
secretion is
potentially the
most effective
mechanism of
renal drug
elimination.
Unlike
glomerular
filtration,
carrier-mediated
transport can
achieve maximal
drug clearance
even when most
of the drug is
bound to plasma
protein.
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Penicillin, although about 80% protein bound and therefore cleared only slowly by filtration, is
almost completely removed by proximal tubular secretion, and is therefore rapidly eliminated

11. acidic drugs
endogenous
acids, such
as uric acid
OAT
organic
bases
OCT
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The OAT carrier
can transport
drug molecules
against an
electrochemical
gradient, and
can therefore
reduce the
plasma
concentration
nearly to zero.
OCT facilitates
transport down
electrochemical
gradient
TUBULAR SECRETION
Drug molecules are transferred to the tubular
lumen by two independent and relatively non-
selective carrier systems
Many drugs compete for the same
transport system, leading to drug
interactions. Like, probenecid was
developed originally to prolong action
of penicillin by retarding its tubular
secretion.

12. DIFFUSION ACROSS THE RENAL TUBULE
Lipid-soluble drugs
are therefore excreted
poorly, whereas polar
drugs of low tubular
permeability remain
in the lumen and
become progressively
concentrated as water
is reabsorbed
volume of
urine being
only about 1%
of glomerular
filtrate
Water is
reabsorbed as
fluid
traverses the
tubule
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if the tubule is freely permeable to drug
molecules, some 99% of the filtered drug will
be reabsorbed passively down the resulting
concentration gradient
The degree of
ionization of many
drugs—weak acids or
weak bases—is pH
dependent.
Ion-trapping effect
means that a basic
drug is more rapidly
excreted in an acid
urine which favors
the charged form
and thus inhibits
reabsorption.
Conversely, acidic
drugs are most
rapidly excreted if
the urine is alkaline

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• Group of drugs that are not affected by
metabolism.
• Only renal elimination determines their duration
of action

14. Polar drug= water soluble
Non polar drug = lipid soluble
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15. ELIMINATION - CLEARANCE
• Clearance: Volume of plasma that is
cleared of drug per unit time.
• Elimination rate: is
mass/amount of drug that is
cleared from the body.
• Clearance is related with
elimination by a constant
proportion factor.
• If the clearance is low then less drug lost
in urine and more in body.
• If the clearance is high then more drug in
urine and less in body.
• Inverse relationship – decreased GFR –
increased plasma concentration.
• Units are in L/hr or L/hr/kg
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16. CLEARANCE
VOLUME OF PLASMA THAT IS CLEARED OF DRUG PER UNIT
TIME
VOLUME PER UNIT TIME = ML/MIN
• CLEARANCE = ELIMINATION RATE
VOLUME PLASMA DRUG CONC
• RATE OF DRUG ELIMINATION = CL X CONC
AMOUNT OF DRUG MASS
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Cl = 40 mg/hr in urine = 2 ml/hr
20 mg/ ml (remaining)
Cl = 120 mg/hr in urine = 6 ml/hr
20 mg/ ml (remaining)
Clearance is related with
elimination by a constant
proportionate factor

17. TO CALCULATE DOSE & FREQUENCY OF
DRUGS
TWO VITAL THINGS OF DRUGS WHICH DETERMINE THEIR
BEHAVIOR
VOLUME OF DISTRIBUTION
INVERSE RELATIONSHIP
• LOW VD – HIGH CONC IN PLASMA,
DISTRIBUTED IN BLOOD LARGE
CHARGED MOLECULES, HYDROPHILIC
& HIGH CLEARANCE.
• HIGH VD – LOW CONC IN PLASMA,
HYDROPHOBIC, LIPOPHILIC, BOUND
TO PROTEINS & FAT TISSUES
CLEARANCE
INVERSE RELATIONSHIP
• LOW = LESS DRUG IS LOST IN URINE,
MORE IN THE BODY.
• HIGH = MORE DRUG IS LOST IN URINE,
LESS IN THE BODY.
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24. DRUG HALF-
LIFE
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31. KINETICS OF METABOLISM:
FIRST ORDER
KINETICS
• THE RATE OF DRUG
METABOLISM IS DIRECTLY
PROPORTIONAL TO THE
CONCENTRATION OF THE
DRUG.
• A CONSTANT FRACTION OF
DRUG IS METABOLIZED PER
UNIT OF TIME.
ZERO ORDER
KINETICS
• THE RATE OF DRUG
METABOLISM IS CONSTANT
AND INDEPENDENT OF THE
DRUG DOSE.
• A CONSTANT AMOUNT OF
DRUG IS METABOLIZED PER
UNIT OF TIME.
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FACTORS AFFECTING RENAL EXCRETION OF DRUG
Physiochemical properties of drugs
• Molecular weight
• Lipid solubility
• Volume of distribution
• Binding character
• Degree of ionization
 Blood flow to the kidney - CCF
 Urine pH
 Biological factor - Age
 Disease states

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FACTORS AFFECTING RENAL EXCRETION
Drug MW: larger MW drugs are difficult to be excreted than smaller MW especially
by glomerular filtration.
Drug lipid solubility: urinary excretion is inversely related to lipophilicity,
increased lipid solubility increase volume of distribution of drug and decrease renal
excretion.
Volume of distribution: clearance is inversely related to volume of
distribution of drugs (Vd). A drug with large Vd is poorly
excreted in urine. Drugs restricted to blood (low Vd) have
higher excretion rates.

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FACTORS AFFECTING RENAL EXCRETION
Renal blood flow: increased perfusion leads to increased excretion; important for drugs
excreted by glomerular filtration.
Binding characteristics of the drugs: Drugs that are bound to plasma proteins behave as
macromolecules and cannot be filtered through glomerulus. Only unbound or free drug appear
in glomerular filtrate. Protein bound drug has long half lives.
Biological factor: age can affect renal clearance. Renal clearance is reduced in neonates and
elderly.
Disease states impairs the elimination of drugs e.G. Hypertension, diabetes, pyelonephritis

36. URINE pH
• Urine pH is a great influence on whether a drug is excreted quickly or
slowly and in some clinical situations is manipulated to control the
excretion of certain drugs from the body.
• Urine is normally slightly acidic and favors excretion of basic drugs.
• Most drugs are either weak acids or weak bases. In alkaline urine, acidic
drugs are more readily ionized. In acidic urine, alkaline drugs are more
readily ionized. Ionized substances (also referred to as polar) are more
soluble in water so dissolve in the body fluids more readily for excretion.
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37. URINARY pH TRAPPING
• IT IS USED TO ENHANCE RENAL CLEARANCE OF DRUGS DURING
TOXICITY.
• URINE ACIDIFICATION: BY AMMONIUM CHLORIDE
(NH4CL) INCREASES EXCRETION OF BASIC DRUGS (AMPHETAMINE).
• URINE ALKALIZATION: BY SODIUM BICARBONATE
NAHCO3 INCREASES EXCRETION OF ACIDIC DRUGS (ASPIRIN).
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ION TRAPPING
Consider a barbiturate (weak acidic drug) overdose.
Urine Blood
pH 5.3 pH 7.4
Non-ionised weak acid drug
+
Ionized
Urine
Most of acidic drug will be reabsorbed back into body.

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ION TRAPPING
Urine Blood
pH 8.0 pH 7.4
Less Non-ionised weak acid drug
+
More Ionized
Urine
In presence of sodium bicarbonate, urine is alkaline
and more excretion of acidic drug into urine
Most of acidic drug will be eliminated into urine.

40. Effect of Lipid solubility and pH
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Glomerular blood flow; filtrate 99% of GF is re-absorbed;
concentration of drug rises in
tubule
If lipid soluble drug moves
down concentration gradient back
into blood
Re-absorption
ionised drug is less lipid soluble

41. DRUG RENAL CLEARANCE:
 If renal clearance is impaired, this may increase
T ½ of drugs and toxic levels of drugs may remain in the body.
Renal clearance is especially important for some drugs which
are:
 Mainly excreted by the kidney
 Have narrow therapeutic index (eg. Lithium, digoxin,
warfarin).
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42. SO WHAT SHOULD WE DO IN
RENAL IMPAIRMENT?
DISEASES THAT CAN DECREASE
RENAL CLEARANCE
• Reduced renal blood flow
• Congestive heart failure.
• Hemorrhage
• Cardiogenic shock
• Decreased renal excretion :
• renal disease (eg.
Glomerulonephritis).
This may increase half-life (t ½ ) of
drugs
• Dose reduction of drugs is required
(when creatinine clearance is below 60
ml/min).
• Keep the usual dose but prolong the
dosing intervals (eg. Gentamicin)
• Decrease the dose without changing
dosing intervals (eg Digoxin)
• Monitor blood levels of drugs
(therapeutic drug monitoring).
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43. DOSE REDUCTION IN RENAL
IMPAIRMENT
Antibiotics:
• Penicillins, cephalosporins
• Aminoglycosides (gentamycin)
• Sulfonamides
 Non steroidal anti-inflammatory drugs (NSAID’s)
 Lithium
 Digoxin
 Immunosuppressants (cyclosporine)
 Anticancer drugs (cisplatin - cyclophosphamide)
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WHEN DOSE REDUCTION IS NOT REQUIRED IN RENAL IMPAIRMENT ?
Drugs like Ceftriaxone, minocycline that are excreted into feces (biliary excretion) doesn’t need
dose adjustment in renal impairment.

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45. THANK YOU
REFERENCES
• Basic & clinical Pharmacology Katzung
14th edition
• Lippincott’s Pharmacology 6th edition.
• Rang & Dale 9th edition
• Clinical pharmacology 11th edition
peter Bennett
• Principles of pharmacology: the
pathophysiologic basis of drug therapy,
By Golan 2nd edition
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