Excretion of Drugs

Prof. Hanan Hagar
Pharmacology Unit

Medical College

Excretion of Drugs

By the end of this lecture, students should be able
to

 Identify the main and minor routes of excretion
including renal elimination and biliary excretion

 Describe the enterohepatic circulation and its
consequences on duration of actions of drugs.

 Describe pharmacokinetics terms including clearance
of drugs, half-life (t ½), steady state levels,

maintenance dose and loading dose.

Routes of Excretion

Main Routes of Excretion
➢ Renal Excretion
➢ Biliary Excretion

Minor Routes of Excretion
➢ Pulmonary excretion (Exhalation).
➢ Salivary excretion.
➢ Mammary excretion via milk.
➢ Skin / Dermal excretion via sweat.
➢ Tears

Renal Excretion

Structure of kidney
The structure unit of kidney is nephron

That consists of :

 Glomerulus

 Proximal convoluted tubules

 Loop of Henle

 Distal convoluted tubules

 Collecting ducts

Nephron

Renal Excretion includes
The principle processes that determine the

urinary excretion of drugs are:

 Glomerular filtration.

 Passive tubular reabsorption.

 Active tubular secretion.

Glomerular filtration (GFR):

 Depends upon renal blood flow (600 ml/min)

 Glomerular filtration rate (GFR) is about
20% of renal blood flow = 125 ml/min.

 Glomerular filtration occurs to:

 Low molecular weight drugs

 Only free drugs (unbound to plasma proteins)

are filtered while bound drugs are not filtered.

Active tubular secretion:

 occurs mainly in proximal tubules; increases
drug concentration in tubular lumen.

 organic anionic and cationic transporters
mediate active secretion of anionic and
cationic drugs.

 can transport drugs against conc. gradients.

 Penicillin is an example of actively secreted
drug.

Transporters for acidic drugs.
➢ Salicylates
➢ Sulphonamides
➢ Penicillin
Transport of acidic drugs is blocked by
probenecid

Transporters for basic drugs
➢ Morphine
➢ Atropine
➢ Quinine
➢ Neostigmine

Passive tubular re-absorption

 In distal convoluted tubules & collecting ducts.

 Passive diffusion of unionized, lipophilic drugs

 Lipophilic drugs can be reabsorbed back from

tubular lumen to blood circulation and

excretion in urine will be low.

 Ionized drugs are poorly reabsorbed & so

urinary excretion will be high.

Polar drug= water soluble

Non polar drug = lipid soluble

Urinary pH trapping (Ion trapping)

 Changing the pH of urine by chemicals can
inhibit or enhance the renal excretion of drugs.

 Urine is normally slightly acidic and favors
excretion of basic drugs.

Urinary pH trapping (Ion trapping)

 Acidification of urine using ammonium chloride
(NH4Cl) increases excretion of basic drugs as
amphetamine.

 Alkalinization of urine using sodium bicarbonate
NaHCO3 increases excretion of acidic drugs as
aspirin.

 Ion trapping is used to enhance renal clearance
of drugs during toxicity.

Renal Excretion

Drugs excreted mainly by the kidney include:

 Aminoglycosides antibiotics (as gentamycin)

 B-lactam antibiotics as penicillin

 Lithium

These drugs should be prescribed carefully in

 patients with renal disease.

 Elderly people

Biliary Excretion

➢ Occurs to few drugs that are excreted into feces.

➢ Such drugs are secreted from the liver into bile

by active transporters, then into duodenum.

➢ Some drugs undergo enterohepatic circulation

from intestine back into systemic blood

circulation.

Enterohepatic circulation

 Drugs excreted in the bile in the form of

glucouronides will be hydrolyzed in intestine

by bacterial flora liberating free drugs that

can be reabsorbed back into blood if drugs are

lipid soluble.

 This prolongs the duration of action of drugs

e.g. digoxin, morphine, thyroxine.

Plasma half-life (t ½)
 is the time required for the plasma

concentration of a drug to fall to half of its
initial concentration.

 Is a measure of duration of action.

 Determine the dosing interval

Drugs of short plasma half life

➢ Penicillin G, tubocurarine.

Drugs of long plasma half life

➢ Digoxin, thyroxine.

Factors that may increase half-life (t ½ )

Decreased metabolism
 Liver disease.
 Microsomal inhibitors.

Decreased clearance
 Renal disease.
 Congestive heart failure.

High binding of drugs
 Plasma proteins.
 Tissue binding.

Enterohepatic recycling

Steady state level.

 A state at which the therapeutic plasma
concentration of the drug (mg/ml) remains
constant within the therapeutic window

 Therapeutic window:

the range between the effective and the toxic level

of the drug.

Therapeutic window

Steady state of a drug

Steady-state: the amount
of drug eliminated equals
the amount of drug
administered

rate of drug administration =
rate of drug elimination

How many half-lives would be necessary to
reach steady state?

Steady state concentration is attained after 3-5

half lives.

t1/2 can be used to predict how long it will take
from the start of dosing to reach steady-state
levels during multiple dosing.

No. of t1/2 Concentration achieved
(% of steady conc.)

0 100%
1 50 %
2 (50+100) 75%
3 (75+100) 87.5%
4 (87.5+100) 94%
5 (94+100) 97%

Steady state levels

Loading dose

➢ is the large initial dose that is given to achieve

rapid therapeutic plasma level.

➢ After administration of the drug, the plasma

concentration decreases due to distribution of

drug to other tissues.

➢ These doses balances the drug distribution.

➢ This is important for drugs with long halve lives.

Loading dose =Vd x required plasma drug concentration

Clinical applications of loading dose

 A loading dose may be desirable if the time
required to attain steady state of drug is long and
rapid relief is required in the condition being
treated.

 e.g. lidocaine is antiarrhythmic drug with
t1/2 of around 1-2 hours.

Clinical applications of loading dose

 Arrhythmias after myocardial infarction are life-
threatening, and one cannot wait more several hours
to achieve a therapeutic concentration.

Steady state= 3-5 X 2 hour = 6-10 hours

 Use of a loading dose of lidocaine in the coronary
care unit is standard.

Maintenance doses

 are the doses required to maintain the
therapeutic level of the drug constant or the
steady state of the drug.

 These doses balance the amount of drug lost
during metabolism and clearance.

 The patient needs to take regular doses of a
drug such as amoxicillin (500 mg)/ 8 hours to
maintain the therapeutic level.

 Maintenance dose =

Clearance x required Plasma concentration

Summary
 Polar drugs are readily excreted and poorly

reabsorbed.

 Lipid soluble drugs are reabsorbed back and
excretion will be low

 Acidic drugs are best excreted in alkaline urine
(sodium bicarbonate).

 Basic drugs are best excreted in acidic urine
(ammonium chloride).

 Enterohepatic circulation prolongs half life of the
drug.

Questions?