EXCRETION OF DRUGS

MALLA REDDY PHARMACY COLLEGE

By
Dr. G.SAILAJA,M.Pharm.Ph.D.,
Assoc. Professor,
Dept. of Pharmaceutics
 “ Excretion is defined as the process where by drugs or
metabolites are irreversibly transferred from internal to
external environment through renal or non renal routes.”
 Excretion of unchanged or intact drug is needed in
termination of its pharmacological action.
 The principal organ of excretion are kidneys.
 Agent that excreted in urine are :
1. water soluble 2.non volatile
3. small in molecular size(< 500 daltons.)
4. which are metabolized slowly 2
 TYPES OF EXCRETION
 RENAL EXCRETION : By Kidneys
 NON RENAL EXCRETION
 Biliary excretion.
 Pulmonary excretion.
 Salivary excretion.
 Mammary excretion.
 Skin / Dermal excretion.
 Gastrointestinal excretion.
 Genital excretion.

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•Functional unit of kidney in excretion is the
nephron
•Each kidney comprises of one million nephrons
•Each nephron is made up of
1. Glomerulus
2. Proximal tubule
3. Henle loop
4. Distal tubule
5. collecting tubule
 URINARY EXCRETION PROCESS

•It includes

 Glomerular filtration

Active Tubular Secretion

 Active / Passive Tubular Reabsorption

 GLOMERULAR FILTRATION

 It Is nonselective, unidirectional process

 Ionized or unionized drugs are filtered, except those that

are bound to plasma proteins.

 Driving force for GF is hydrostatic pressure of blood

flowing in capillaries.

 Acts as negative charged barrier so, retention of anionic

compounds
 It depends on renal blood flow
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 GLOMERULAR FILTRATION RATE:
• Out of 25% of cardiac output or 1.2 liters of blood/min that
goes to the kidney via renal artery, only 10% or 120 to
130ml/min is filtered through glomeruli. The rate being
called as glomerular filtration rate.

• GFR can be determined by an agent which are excreted by

filtration and is neither reabsorbed nor secreted in tubules.
Ex. Creatinine, inulin, mannitol etc.

• The normal GFR rate is 120-130 ml/min.

• It depends on renal blood flow

 ACTIVE TUBULAR SECRETION
Occurs in proximal tubule.
It is a carrier mediated process which requires energy for transportation
of compounds against conc. Gradient.

Two secretion mechanisms are identified.

System for secretion of organic acids/anions
E.g. Penicillin, salicylates etc (uric acid secreted)

System for organic bases / cations

E.g. morphine, mecamylamine, hexamethonium

Both the systems are nonselective and independent of each other.

But both can be bidirectional i.e., agents may be secreted and reabsorbed
eg., uric acid
It is unaffected by changes in PH and protein binding
Excretion rate values > GFR (130ml/min)
Eg., Penicillin has renal clearance of 500ml/min (AS+ GF)
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•Two structurally similar drugs compete if they have
•Similar ionic charge
•Carrier mediated transport process for excretion
•Drug > Clr will retard the excretion of other drug and results in
•Increased Half life of drug
•Causing accumulation of drug
•Eg., Probenocid inhibits AS of Penicillin's, PAS, PAH ( reduction
in dose is suggested)
•Probenocid is a lipophilic drug and well reabsorbed
•Probenocid suppress the carrier mediated Reabsorption of uric
acid ( used in treatment of gout)
•Agents used are : Para amino hippuric acid (highly polar agent)
and Iodopyracet
 TUBULAR REABSORPTION
 It occurs after the glomerular filtration of drugs.
 It takes place all along the renal tubules.
 Excretion rate values are less than the GFR 130ml/min.
(Reabsorption of drugs are indicated) e.g. Glucose
 TR can be active or passive processes.
 It results in increase in the half life of the drug.
 Active Tubular Reabsorption:
It is commonly seen with endogenous substances or
nutrients that the body needs to conserve e.g.
electrolytes, glucose, vitamins, amino acids.
Very few drugs are reabsorbed actively eg., oxopurinol
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 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 inorganic ions).

 If a drug is neither secreted nor re-absorbed its conc.

in urine will be 100 times that of free drug in plasma.

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•Lipophilic drugs are reabsorbed
•Reabsorption of weak acids / weak bases
depends upon degree of ionisation
--------- Ph of the urine
--------Pka of drug
-------- urine flow rate
NEPHRON
 FACTORS AFFECTING RENAL EXCRETION

1) Urine pH and pKa.

2) Urine flow rate.
3) Physicochemical properties of drug.
4) Distribution and Binding characteristic of drug.
5) Blood flow to the kidneys.
6) Biological factors.
7) Drug interactions.
8) Disease states.

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 pH and pKa OF THE URINE :
 It varies between 4.5 to 7.5
 diet - carbohydrate – high alkaline pH
 Protein - lower alkaline Ph
 drug intake – sodium bicarbonate- alkaline ph
 Ascorbic acid – acidic ph
 Patho physiology of the patient- alkalosis – alkalization of urine
acidosis- acidification of urine
• IV infusion of sodium bicarbonate and ammonium chloride used in
treatment of acid base imbalance.
• Relative amount of ionized, unionized drug in the urine at
particular pH can be given by
“ HENDERSON-HESSELBACH” equation
 HENDERSON-HESSELBACH EQUATION
 For weak acids :
pH= pKa +log [ ionized ]
[unionized]
% of drug ionized = 10 (pH – pKa) X 100
1+10 (pH – pKa)
 For weak base :
pH=pKa +log [unionized]/ionized

% of drug ionized = 10(pKa - pH) X 100

1+10 (pKa - pH)

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• If R : concentration ratio of the drug in urine to
that in plasma then
• Ra= U = 1+ 10 ( ph urine- pka)
P 1+10 (ph plasma- pka)

• Rb= U = 1+ 10 (pka- ph urine)

P 1+10 (pka - ph plasma)
With increased urinary PH- Renal clearance increases
Increased pka, decreased ionised and increased renal clearance
 The significance of pH-dependant excretion for any particular
compound is greatly depends upon its pKa & lipid solubility.

 A characteristic of drugs, pKa value govern the degree of ionization

at a particular pH.
 A polar & ionized drug will be poorly reabsorbed passively &
excreted rapidly.

 Reabsorption is also affected by the lipid solubility of drug

 Ionized but lipophilic drug will be reabsorbed while an unionized but
polar one will be excreted.
 The toxicity due to overdose of the drug whose excretion is sensitive
to pH change can be treated by acidification or alkalinisation of the
urine.
 Drug if Polar and in unionised form is not reabsorbed – excretion
is independent of ph of urine and its flow rate.
• Excretion= rate of filtration+ rate of secretion
• Ex: penicillin, gentamycin

 Very weakly acidic drugs, non polardrugs (pka>8) and very weak
bases , non polar ( pka <6) are mostly unionised throughout the
entire range of urine ph – reabsorbed passively at all values of
urine ph.
• Rate of excretion is low and insensitive to urinary ph.
• Ex: phenytoin, propoxyphylline
 A strongly acidic drug (pka<2.0) or a strongly basic drug
(pka>12.0) is completely ionized at all values of urine ph and
therefore not reabsorbed
• Rate of excretion is always high and insensitive to ph of urine
• Ex: cromoglycic acid, guanethidine

 Acidic drugs in the pka range of 3 to 8 (several NSAIDS) and for

basic drugs in the pka range of 6 to 12 ( morphine analogs) the
extent of re absorption greatly depends on urine ph .
 Ex: dexamphetamine 3 to 55% of the dose excreted in urine at
urinary ph of 8 to 5.
 Toxicity / over dose of medicines -- treated by acidification/
alkalization of urine.
 PHYSICOCHEMICAL PROPERTIES OF DRUG
Like molecular size, pKa , lipid solubility
• Molecular size
 Drugs with Mol.wt <300 are excreted in kidney.

Mol.wt 300 to 500 Dalton are excreted both through urine
and bile.

Stereoselctivity was seen

Ex: chloroquine,terbutaline

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 BINDING CHARACTERISTICS OF THEDRUGS
• Clearance is inversely proportional to apparent vd
• Large vd drug is poorly excreted in urine
• Drugs that are bound to plasma proteins behave as
macromolecules and cannot be filtered through glomerulus
• Cl R = urine drug concentration urine flow rate
• plasma drug concentration

• Free drug will be excreted in the urine the fraction of bound

drugh too plasma proteins can be given by
• Fu= Cu/C
• Cl R = fu* urine flow rate
• Protein bound drug has long half lives.
 Plasma concentration of drug

• Glomerular filtration and re absorption depends on it.( both

are passive process).
• A unbound drug excreted by filtration – Exists a linear
relationship between KE and Plasma conc.
• Drugs which are reabsorbed or secreted actively, the rate
process increases with an increase in plasma concentration
until saturation of carriers occurs.
• Incase of actively reabsorbed drugs excretion is negligible at
low plasma conc. ex: glucose.
 1.drug excreted by filtration
2. Drug filtered and reabsorbed actively
3. Drug filtered and actively secreted

3
1

2
excretion
• Rate of

plasma concentration
 BIOLOGICAL FACTORS :
• Age, sex, species, strain difference etc., alter the excretion
of the drug.
• Sex – Renal excretion is 10% lower in female than in males.
• Age – The renal function in newborn is 30-40 % less in
comparison to adults.
• Old age – The GFR is reduced and tubular function is
altered which results in slow excretion of drugs and
prolonged half lives.
 BLOOD FLOW TO THE KIDNEY :
• Important in case of drug excreted by glomerular filteration
and those are actively secreted (more contact with the drug)
only.
• Increase the perfusion enhance the elimination.
 URINE FLOW RATE :
 Polar drug are not affected by urine pH hence not get
reabsorbed so unaffected by urine flow rate.
 Only those drugs whose re absorption is pH sensitive Ex.
Weak acids and bases depend on urine flow rate.
 Urine flow rate can be increased by forced diuresis by large
fluid intake or other diuretics.
 Both urine ph control and forced diuresis used to treat
toxicity.
 When drug was excreted by renal route only
 Drug is absorbed passively from the renal tubules
 Reabsorption is sensitive to ph
 DRUG INTERACTIONS :

 Any drug interaction that result in alteration of binding

characteristics, renal blood flow, active secretion, urine pH,
and forced diuresis would alter renal clearance of drug.

 Alteration in PBD: renal clearance increases after

displacement with other drug
 Ex: gentamycin induced nephrotoxicity by furosemide.
 Alteration in urinary ph:
 Alkalinization of urine with citrates and bicarbonates
promote excretion of acidic drugs.
 Acidification of urine with ascorbic acid enhances excretion
of basic drugs.
 All diuretics increase elimination of drugs
 DISEASE STATE :

 RENAL DYSFUNCTION

 Greatly cause the elimination of drugs those are primarily

excreted by kidneys.

 Some of the causes of renal failure are hypertention,

Diabetes, hypovolemiya (low blood supply to kidney),
heavy metals, inflammation of kidneys(pyelonephritis)
 UREMIA
 Characterized by Impaired GF , accumulation of fluids &
protein metabolites, Impaired renal clearance. Half life
increased resulting in drug accumulation and increased
toxicity.
CONCEPT OF CLEARANCE
 Renal Clearance

• Clearance is defined as hypothetical volume of fluid

containing drug from which the drug is removed or cleared
completely in a specific period of time.
• Clearance [CL]=Elimination rate/plasma drug conc.
• The sum of individual clearance by all eliminating organs
(kidney, liver, lungs, biliary systems) called as ‘Total body
clearance’.
• Renal Clearance : The volume of blood or plasma which is
completely cleared of the unchanged drug by the kidney per unit
time’
 RC = UV/P RC = rf+rs-rr/P

RC = renal clearance rate

U = drug concentration in urine
V = flow rate of urine (ml/min) rf = rate of filtration
P = plasma drug concentration rs = rate of secretion
rr = rate of
reabsorption
• Renal clearance tests are used to:
– Determine the GFR
– Detect glomerular damage
– Follow the progress of diagnosed renal disease
NON-RENAL ROUTE OF DRUG EXCRETION
Various routes are ;
1) Biliary Excretion
2) Pulmonary Excretion
3) Salivary Excretion
4) Mammary Excretion
5) Skin/dermal Excretion
6) Gastrointestinal Excretion
7) Genital Excretion
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1 ) BILIARY EXCRETION :
 Bile juice is secreted by hepatic cells of the liver. Its
 important in the digestion and absorption of fats.

90% of bile acid is reabsorbed from intestine and transported



back to the liver for resecretion.

The metabolites are more excreted in bile than parent drugs

due to increased polarity.

Several factor influence secretion of drug in bile are;
1) Molecular weight.
2) Polarity.
3) Nature of biotransformation.
4) Other factor like sex,spices, disease state, drug interation.
 Nature of bio-transformation process:
 Phase-II reactions mainly glucuronidation and conjugation
with glutathione result in metabolites with increased polarity
and molecular weight for biliary excretion.
 Ex. of drugs excreted in the bile are chloromphenicol,
morphine and indomethacin.
 Fora drug to be excreted in bile must have polar groups like –
COOH, -SO3H.

 Conjugation with amino acids ,acetylation ,methylation

do not result in metabolites with high molecular weight and
polarity hence little influence on biliary excretion.
 Efficacy of drug excretion by biliary system can be tested by
an agent that is completely eliminated in bile, Ex.
sulfobromophthalein.
• This marker is excreted in half an hour in intestine when
hepatic function is normal. Delay in its excretion indicates
hepatic and biliary malfunction.
 Some drugs which are excreted as glucuronides or as
glutathione conjugates are hydrolyzed by intestinal or
bacterial enzymes to the parent drugs which are
reabsorbed.
• The reabsorbed drugs are again carried to the liver for
resecretion via bile into the intestine.
This phenomenon of drug cycling between the intestine & the
liver is called Enterohepatic circulation
Enterohepatic Circulation is important in conservation of
vitamins, folic acid and hormones.
This process results in prolongation of half lives of drugs like
DDT, oral contraceptives.

2 ) PULMONARY EXCRETION :
Gaseous and volatile substances such as general anesthetics
(Halothane) are absorbed through lungs by simple diffusion.

Pulmonary blood flow, rate of respiration and solubility of

substance effect pulmonary excretion.
Intact gaseous drugs are excreted but not metabolites.
Alcohol which has high solubility in blood and tissues
are excreted slowly by lungs.
3 ) SALIVARY EXCRETION :
The pH of saliva varies from 5.8 to 8.4. Unionized lipid
soluble drugs are excreted passively.
The bitter taste in the mouth of a patient is indication of drug
excreted. Some basic drugs inhibit saliva secretion and are
responsible for mouth dryness. Compounds excreted in saliva
are Caffeine, Phenytoin, Theophylline.
4 ) MAMMARY EXCRETION :
Milk consists of lactic secretions which is rich in fats and
proteins. 0.5 to one litre of milk is secreted per day in lactating
mothers.
Excretion of drug in milk is important as it gains entry in
breast feeding infants.
pH of milk varies from 6.4 to 7.6.Free un-ionized and lipid
soluble drugs diffuse passively.
Highly plasma bound drug like Diazepam is less secreted in
milk.
Since milk contains proteins. Drugs excreted can bind to
it.
Amount of drug excreted in milk is less than 1% and fraction
consumed by infant is too less to produce toxic effects. Some
potent drugs like barbiturates and morphine may induce toxicity.
ADVERSE EFFECTS :
Discoloration of teeth with tetracycline and jaundice due to
interaction of bilirubin with sulfonamides.
Nicotine is secreted in the milk of mothers who smoke.
5 ) SKIN EXCRETION :
Drugs excreted through skin via sweat follows pH partition
hypothesis.
Excretion of drugs through skin may lead to urticaria and dermatitis.
Compounds like benzoic acid, salicylic acid, alcohol and heavy
metals are excreted in sweat.

6 ) GASTROINTESTINAL EXCRETION :
Excretion of drugs through GIT usually occurs after parenteral
administration.
Water soluble and ionized form of weakly acidic and basic drugs are
excreted in GIT.
Example are nicotine and quinine are excreted in stomach.
Drugs excreted in GIT are reabsorbed into systemic circulation &
undergo recycling.
EXCRETION PATHWAYS, TRANSPORT
MECHANISMS & DRUG EXCRETED.
Excretory Mechanism Drug Excreted
route
Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/
metabolites of MW< 300
Bile Active secretion Hydrophilic, unchanged drugs/
metabolites/ conjugates of MW >500
Lung Passive diffusion Gaseous &volatile, blood & tissue
insoluble drugs
saliva Passive diffusion Free, unionized, lipophilic drugs. Some
Active transport polar drugs
Milk Passive diffusion Free, unionized, lipophilic drugs (basic)
Sweat Passive diffusion Free, unionized lipophilic drugs
Intestine Passive diffusion Water soluble. Ionized drugs
 REFERENCES
 Brahmankar M D., Jaiswal S B., Biopharmaceutics and
Pharmacokinetics A Treatise vallabh prakasan I edition 2002,
p.no;178-192.
 Shrgel L., Wu-Pong S., Yu A B C., Applied Biopharmaceutics
& Pharmacokinetics V edition 2005,Mc Graw Hill
publication house p.no;131-159.
 Venkateswarlu V., Biopharmaceutics and Pharmacokinetics II
edition 2008, PharmaMed Press, p.no;103-145.
 Gibaldi M., Biopharmaceutics and Clinical Pharmacokinetics
IV edition 2006, PharmaMed Press,p.no; 203
 Ali J., Khar R K., Ahuja A., A Text Book of
Biopharmaceutics and Pharmacokinetics , II edition 2005,
Birla Publication Pvt.Ltd, p.no;121-131.
THANK YOU …