EXCRETION OF DRUGS

Dr. Col. Azmat Ali

Sitara-e-Imtiaz (Military)
Assistant Professor
Al-Nafees Medical College & Hospital
Fate of drug
DOSE
Pharmaceutic
s
ABSORPTION
MOST TISSUES
NONSPECIFIC
BINDING
PLASMA
PROTEIN DISTRIBUTIO
FREE
BOUND N
BIOPHASE
ELIMINATION RECEPTOR
BINDING

METABOLISM RENAL
EXCRETION
EFFECT
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INTRODUCTION
 Drug elimination is the irreversible loss of drug from
the body.
 It occurs by two processes: metabolism and excretion.

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METABOLISM
 Definition
The sum total of the chemical processes that occur in
living organisms,resulting in growth, production of e
nergy, elimination of waste
material, etc.
 Metabolism consists of
 Anabolism- Build Up
 Catabolism- Breakdown of substances by enzymic
conversion of one chemical entity to another within
the body.
 Whereas excretion consists of elimination from the
body of chemically unchanged drug or its metabolites.

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 The main routes by which drugs and their metabolites
leave the body are: the kidneys
 the hepatobiliary system
 the lungs (important for volatile/gaseous
anaesthetics).

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 EXCRETION OF DRUGS
 Excretion is defined as the process where by
drugs or metabolites are irreversibly transferred
from internal to external environment through renal
or non renal route.
 Excretion of unchanged or intact drug is needed
in termination of its pharmacological action.
 The principal organ of excretion are kidneys.
 TYPES OF EXCRETION
1. RENAL EXCRETION
2. NON RENAL EXCRETION
 Biliary excretion.
 Pulmonary excretion.
 Salivary excretion.
 Mammary excretion.
 Skin / Dermal excretion.
 Gastrointestinal excretion.
 Genital excretion.

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ANATOMY OF NEPHRON

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GLOMERULAR FILTRATION
It Is non selective , 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.
GLOMERULAR FILTRATION RATE:
Out of 25% of cardiac out put 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).e.g. creatinine, insulin.

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ACTIVE TUBULAR
SECRETION
 This mainly occurs in proximal tubule.
 It is 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 base / cations
E.g. morphine, mecamylamine hexamethonium
Active secretion is Unaffected by change in pH and protein
binding.
Drug undergoes active secretion have excretion rate values
greater than normal GFR e.g. Penicillin.

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TUBULAR REABSORPTION
 It occurs after the glomerular filtration of drugs. It
takes place all along the renal tubules.
 Reabsorption of drugs indicated when the
excretion rate value are less than the GFR
130ml/min.e.g. Glucose
 TR can be active or passive processes.
 Reabsorption results in increase in the half life of
the drug.

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 Active Tubular Reabsorption:
Its commonly seen with endogenous
substances or nutrients that the body needs to
conserve e.g. 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 inorganic ions. If a drug is neither
excreted or re-absorbed its conc. In urine will be
100 times that of free drug in plasma.
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 pH OF THE URINE

• It varies between 4.5 to 7.5

• It depends upon diet, drug intake and pathophysiology of
the patient .
• Acetazolamide and antacids produce alkaline urine, while
ascorbic acid makes it acidic.
• IV infusion of sodium and ammonium chloride used in treatment
of acid base imbalance shows alteration in urine pH.
• Relative amount of ionized ,unionized drug in the urine at
particular pH & % drug ionized at this pH can be given by “
HENDERSON-HESSELBACH” equation.

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 HENDERSON-
HESSELBACH EQUATION
1)FOR WEAK ACIDS

pH= pKa +log [ ionized ]

[unionized]

% of drug ionized = 10 pH – pKa X 100

1+10pH –pKa

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 HENDERSON-HESSELBACH EQUATION

2)FOR WEAK BASE

pH=pKa +log [unionized]
[ionized]

% of drug ionized = 10 pH – pKa X 100

1+10pH –pKa

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FACTORS AFFECTING
RENAL EXCRETION
 Physicochemical properties of drug
 Urine pH
 Blood flow to the kidney
 Biological factor
 Drug interaction
 Disease state

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PHYSICOCHEMICAL
PROPERTIES OF DRUG
 Molecular size
Drugs with Mol.wt <300, water soluble are
excreted in kidney. Mol.wt 300 to 500 Dalton are excreted
both through urine and bile.
 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.

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BIOLOGICAL FACTORS
 Sex – Renal excretion is 10% lower in female than
in males.
 Age – The renal excretion 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.

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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.
 Renal clearance of a drug highly bound to plasma proteins
is increased after it is displaced with other drug e.g.
Gentamicin induced nephrotoxicity by furosemide.
 Alkalinization of urine with citrates and bicarbonates
promote excretion of acidic drugs.

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DISEASE STATE
RENAL DYSFUNCTION
Greatly impairs the elimination of drugs especially
those that are primarily excreted by kidney. Some of the
causes of renal failure are B.P, Diabetes, Pyelonephritis.
UREMIA
Characterized by Impaired GFR , accumulation of fluids &
protein metabolites, also impairs the excretion of the drugs.
Half life is increased resulting in drug accumulation and
increased toxicity.

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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 (e.g. lithium,
digoxin, warfarin).
Diseases that can decrease renal clearance
 Reduced renal blood flow
 Congestive heart failure.
 Hemorrhage

 Cardiogenic shock

 Decreased renal excretion :

 Renal disease (e.g. glomerulonephritis).

This may increase half-life (t ½ ) of drugs

So what should we do in renal
impairment?
 Dose reduction of drugs is required (when
creatinine clearance is below 60 ml/min).
 keep the usual dose but prolong the dosing
intervals (e.g. gentamicin)
 decrease the dose without changing dosing
intervals (e.g. digoxin)
 Monitor blood levels of drugs (therapeutic drug
monitoring).
 Dose reduction in renal impairment
Antibiotics:
 Penicillins, cephalosporins

 Aminoglycosides (gentamycin)

 Sulfonamides

 Non steroidal anti-inflammatory drugs

(NSAIDs)
 Lithium

 Digoxin

 Immunosuppressants (cyclosporine)

 Anticancer drugs (cisplatin - cyclophosphamide)

These drugs are contraindicated in:

Renal failure – Elderly patients
When dose reduction is not required in
renal impairment ?

 Few drugs e.g. ceftriaxone, minocycline that are

excreted into feces (biliary excretion) doesn’t
need dose adjustment in renal impairment.
Creatinine clearance and drugs excretion
 Creatinine clearance rate (CCr or CrCl) is the
volume of blood that is cleared of creatinine per
unit time.
 CrCl is a useful measure for approximating the
GFR because creatinine is produced from muscle
and freely filtered (low MW, water soluble, and is
not protein bound).
 Drugs that are primarily excreted by the kidney
(> 60%) needs dose adjustment.
Estimation of Creatinine Clearance
The Cockcroft-Gault equation for creatinine clearance
estimation

Female: CrCl = 0.85 (140 − age) X body weight

serum creatinine × 72

Male: CrCl = (140 − age) X body weight

serum creatinine × 72
NON-RENAL ROUTE OF
DRUG EXCRETION
Various routes are
 Biliary Excretion
 Pulmonary Excretion
 Salivary Excretion
 Mammary Excretion
 Skin/dermal Excretion
 Gastrointestinal Excretion
 Genital Excretion

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BILIARY EXCRETION
 Bile juice is secreted by hepatic cells of the liver.
 The flow is steady-0.5 to 1ml /min. 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.
 Compounds excreted by this route are sodium, potassium, glucose,
bilirubin, Glucuronide, sucrose, Inulin, muco-proteins e.t.c.
 Greater the polarity better the excretion.
 The metabolites are more excreted in bile than parent drugs due to
increased polarity.

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 Nature of bio transformation process:

 Phase-II reactions mainly glucuronidation and conjugation with

glutathione result in metabolites with increased tendency for biliary
excretion.
 Drugs excreted in the bile are chloromphenicol, morphine and
indomethacin.
 Glutathione conjugates have larger molecular weight and so not
observed in the urine.
For a drug to be excreted in bile must have polar groups like –
COOH, -SO3H.
 Clomiphene citrate, ovulation inducer is completely removed from
the body by BE.
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 THE ENTEROHEPATIC CIRCULATION

Some drugs which are excreted as glucuronides/ as glutathione conjugates are

hydrolyzed by intestinal/ 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

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 THE ENTEROHEPATIC CIRCULATION

EC is important in conservation of Vitamins, Folic acid and

hormones.
 This process results in prolongation of half lives of drugs
like DDT, Carbenoxolone.
 Some drugs undergoing EC are cardiac glycosides,
rifampicin and chlorpromazine.
 The principle of adsorption onto the resins in GIT is used
to treat pesticide poisoning by promoting fecal excretion.

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 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 PE.

 Intact gaseous drugs are excreted but not metabolites.

 Alcohol which has high solubility in blood and tissues are excreted
slowly by lungs.

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 SALIVARY EXCRETION
 The pH of saliva varies from 5.8 to 8.4.
 Unionized lipid soluble drugs are excreted
passively.
 The bitter after 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.

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 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.

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 MAMMARY EXCRETION
 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.

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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 like lead, mercury and arsenic are
excreted in sweat.

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 GASTROINTESTINAL EXCRETION
 Excretion of drugs through GIT usually occurs after
parenteral administration.
 Water soluble and ionized from 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.

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 EXCRETION PATHWAYS, TRANSPORT
MECHANISMS & DRUG EXCRETED.

Excretory Mechanism Drug Excreted

route
Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/
metabolites of MW< 500
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
skin
Intestine Passive diffusion Water soluble. Ionized drugs

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CONCEPT OF CLEARANCE

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 Clearance of a drug may be as low as <10 ml/min.
 Drugs like
 Chlorpropamide
 Digitoxin
 Phenobarbital
 Valprocacid
 Warfarinsodium
 Clearance may be as high as 1000 ml/min.
 Drugs like
 Hydralazine
 Imipramine
 Meperidine
 Morphine
 Verapamil
 Zidovudine
Kinetics of Clearance
1. First Oder Kinetics
 Rate of drug elimination is directly proportional to
plasma concentration.
 Properties
• The system involved in such an elimination are non-
saturable over the plasma concentration range
encountered in clinical settings.
• These drugs have a constant half-life (t1/2).
• Log plasma concentration time curve is linear.
• After a single dose near complete clearance is expected by
the end of 5 (t1/2) in trouble.
Zero Order Kinetics
 Few drugs exhibit saturable or dose dependent elimination.
 In lower plasma concentrations, clearance follows first
order kinetics, but higher concentrations, the clearance
process gets saturated, and the rate of clearance remains
fixed irrespective of plasma concentration this called zero
order kinetics.
 Properties
 Reacting enzymes is limited and gets saturated (Rate
Limiting Step).
 Half life is not constant and rises with increasing plasma
concentration.
Examples
 Alcohol
 Phenytoin
 Salicylates
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