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Kiran’s Success Learning Forum ---------------

Excretion
- Dr. Kiran Vakade

 Excretion is the process by which drugs and their metabolites are eliminated from the body.
 Routes of excretion: Drugs and their metabolite are excreted through one or more of the
following pathway.
1. Kidney
2. Intestine Remember this 7 wonders
3. Lungs
4. Skin
by pneumonic MBBS KILS
5. Milk MB(B)S
6. Biliary
7. Saliva KILS MB(B)S
 Polar, ionized drugs do not undergo metabolism and excreted unchanged through kidneys and
their action is terminated. On the other hand nonpolar (lipid soluble) and unionized drugs are
undergo metabolism and then get excreted.
1. Renal:
 It is the major route of elimination of drug and its metabolites.
 It is responsible for excretion of all water soluble substances
 Three processes are important in the elimination of drug through kidneys
A. Glomerular filtration
B. Tubular reabsorption
C. Tubular secretion
 The amount of drug or its metabolite present in urine is the sum total of glomerular
filtration, tubular reabsorption and tubular secretion
 Net renal excretion: (glomerular filtration + tubular excretion) – tubular reabsorption.
A. Glomerular filtration:
 Glomerular capillaries have pores larger than usual.
 All non-protein bound drug (whether lipid soluble or insoluble) presented to glomerulus
is filtered.
 Glomerular filtration of the drug depends upon
a) Molecular weight (size):.
b) Protein binding: The protein bound drug is not filtered.
c) Renal blood flow: if renal blood flow is good then excretion is also good.
However glomerular filtration does not depend on the lipid solubility of the drug.
 Glomerular filtration rate is normally 120 ml/min. It declines progressively after the age
50 and is low in renal failure.
B. Tubular reabsorption:
 It means the absorption of the drug from renal tubules into peritubular capillaries

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 This occurs by passive diffusion.

 Majority of the reabsorption takes place in PCT.
 It depends on
a) Drug concentration gradient
b) Lipid solubility
c) Ionization of the drug at the existing urinary pH.
 Most of the lipid soluble, unionized drug filtered at glomerulus is reabsorbed by this
process, but lipid insoluble and highly ionized drugs are unable to do so.
 Rate of excretion of drugs such as aminlglycosides, quaternary ammonium compounds
parallels to g.f.r. ( or cratinine clearance)
 Changes in urinary pH affect the tubular reabsorption of drugs that are partially
ionized.
 Weak bases ionize more and are less reabsorbed in acidic urine.
 Weak acids ionize more and are less reabsorbed in alkaline urine.
 This principle is utilized for facilitating elimination of the drug in poisoning.
 Urine is alkalinized in acidic drug poisoning e.g barbiturate or salicylate poisoning.
 Though elimination of weak bases (amphetamine, morphine) can be enhanced by
acidifying urine, this is not practiced clinically, because acidosis can induce
rhabdomyolysis, cardiotoxicity and actually worsen the outcome.
C. Tubular secretions:
 This is the active transfer of the organic acids and bases by two separate classes of
relatively nonspecific transporters (OAT and OCT) which operates in the proximal
tubule.
 In addition, efflux transporters P-gp and MDR2 are located in the luminal membrane of
the tubular cells.
 If renal clearance of drug is more than 120 ml/min, additional tubular secretion can be
assumed to be occurring.
 Protein binding is a hinderance for glomerular filtration of the drug , is not so to
excretion by tubular secretion.
a) Oranic acid transport (through OATP): operates for penicillin, probenecid, uric
acid, salicylate, indomethacin, furosemide, thiazide,
b) Oragnic base transport (through OCT) operates for Amiloride, triamterene,
quinine, procainamide.
 Inherently both transport system are bidirectional, i.e. they can transport their
substrates from blood to tubular fluids and viceversa.
a) Exogenous substances like drugs and their metabolites predominately secreted into
renal tubule with help of this transport system.
b) Endogenous substances like uric acid predominantly reabsorbed with the help of
this transport system.
 Many drug interactions occur due to competition for tubular secretion, e.g.

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a) Drugs utilizing the same active transport system compete with each other. E.g.
Probenecid is an organic acid which has high affinity for the tubular OATP. It blocks
the active transport of both penicillin and uric acid. It results in decrease excretion
of penicillin and increased excretion of uric acid. This is because penicillin is
primarily secreted while uric acid is primarily reabsorbed with the help of OATP.
b) Salicylates block uricosuric action of probenicid and sulfinpyrazone and decrease
tubular secretion of methotrexate
c) Quinidine decreases renal and biliary clearance of digoxin by inhibiting efflux carrier
p-gp
 Tubular transport mechanisms are not well developed at birth. As a result duration of
action of many drugs is longer in neonates.
 .
2. Intestine:
 Orally administered drugs which are not absorbed are excreted in faeces. e.g.
aminoglycosides (streptomycin, neomycin), cholestyramine.
 Some drugs directly secreted in colon. eg. Anthraquinone purgatives, heavy metals.
 Drugs which enter in intestine through biliary also excreted through feces- such drugs are
discussed in the biliray route.
3. Lungs:
 Some drugs are expelled through exhaled air
 Volatile general anaesthetics (enter through inspiration and excrete through exhalation).
 5% of the ethyl alcohol excreted through exhaled air- the concentration of alcohol in the
exhaled air is about 2000 times less than the plasma concentration but even then it is
sufficient to indirectly measure the plasma concentration of alcohol through measuring the
concentration of alcohol in exhaled air. It is of medico – legal importance to heck the level of
alcohol in vehicle drivers. (35 μg/100 ml in exhaled air = 80 mg/100 ml in blood).
4. Skin:
 Arsenic and some heavy metals get excreted through skin
 Arsenic gets accumulated in hair follicle.
5. Milk:
 Drug enters the breast milk by passive diffusion.
 More lipid soluble and less protein bound drugs are better concentrated in milk.
 Milk has lower pH than plasma; basic drugs are somewhat more concentrated in it.
 However, the total amount of the drug reaching the infant through breast feeding is
generally small and majority of the drug can be given to lactating mother without ill effects
on the foetus.eg ACE inhibitors, Sulfonylureas, metformin, methotrexate.
6. Biliary:
 Liver cells transfer various drugs and endogenous substances like bilirubin, from plasma to
bile by means of a transport system similar to that of the renal tubule.

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 Liver actively transports into bile organic acids (especially drug glucuronides by OATP and
MRP2), organic bases (by OCT), other lipophilic drugs (by p-gp) and steroids by distinct
nonspecific active transport mechanisms.
 Relatively larger molecules (MW > 300) are eliminated in the bile.
 Certain drugs which secreted in intestine through bile are again taken up by portal
circulation resulting in increased duration of action these drugs. This phenomenon is known
as entero-hepatic circulation of the drug.
 Certain drugs are conjugated through glucuronic acid in liver and excreted in bile
conjugated drugs are hydrolysed in the intestine by intestinal bacteria free drug released
and gets absorbed through portal circulation.eg. Ethinyl estradiol
 Examples of the drugs which show enterohepatic circulation: Ethinyl estradiol,
chloramphenicol, doxycycline, rifampicin and its deacetylated metabolite.
 Enterohepatic cycling contributes to longer stay of the drug in the body.
7. Saliva:
 This is minor rout of drug excretion.
 Drugs excreted in saliva are lithium, potassium iodide, and phenytoin.
 The concentration of the lithium in saliva is twice than that of plasma and can be utilized to
indirectly measure the plasma concentration through salivary concentration and thus it may
provide noninvasive method of TDM of lithium.

Kinetics of elimination:

 Clearance (CL): the clearance of the drug is the theoretical volume of the plasma from which the
drug is completely removed in unit time.
 Drug elimination is the sumtotal of metabolic inactivation and excretion
 It can be calculated as CL = Rate of elimination/C
 Where ‘C’ is plasma concentration of the drug.
 Difference between first order and second order kinetics

First order kinetics Zero order kinetics

Defination Constant fraction of the drug Constant amount of the drug is
present in the body is eliminated eliminated in unit time.
in unit time
Rate of elimination It is directly proportional to the It remains constant irrespective
drug concentration of the drug concentration.
Clearance (CL) CL remains constant CL decreases with increase in the
concentration
Plasma t1/2, if dose is Unchanged Increased
increased
Applies to This applies to majority of the This applies to few drugs who
drugs which do not saturate the normally saturate eliminating
elimination processes mechanisms
(transporters, enzymes, blood
flow etc.) over the therapeutic

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concentration range.
Examples Most of the drug follow first Very few drugs followzero order
order kinetic kinetics e.g alcohols.
Linear kinetics Non linear kinetics.
Also called as capacity limited
elimination or Michaelis Menten
elimination

 The elimination of some drugs approaches saturation over the therapeutic range, kinetics
changes from first order to zero order. As a result plasma concentration increases
disproportionately with increase in dose. Such drug said to follow pseudo-zero order or mixed
order kinetics.
 Drugs following zero/ Pseudo zero order kinetics:

Zero
Zero order kinetics shown by

W Warfarin

A Alcohol and aspirin

T Theophyllin
T Tolbutamide
Power Phenytoin
Half-life (t1/2):

 It is the time required to reduce the plasma concentration to half (50%) of its original
concentration.
 Nearly 4-5 half-life required for complete elimination of drugs.
 To achieve steady state plasma concentration 4-5 half-life required.
 Half-life is calculated by given formula.

0.693× V
 Half-life(t1/2)= -------------------------------------
CL