1. SIVANAGESWARARAO MEKALA
EXCRETION OF DRUGS
SIVANAGESWARARAO MEKALA
ASSISTANT PROFESSOR
DEPT OF CLINICAL PHARMACOLOGY

2. Drugs are eliminated from the body either unchanged by the process of excretion or converted to metabolites
Drugs are excreted in
Urine
Feces and bile
Lungs
Breast milk
Sweat ,saliva and tears .
4/3/2019

3. Renal excretion
Excretion of drugs and metabolites in the urine involves :
glomerular filtration
active tubular secretion
passive tubular reabsorption
glomerular filtration and active tubular secretion facilitates drug excretion
Where as tubular reabsorption decreases drug excretion
In neonates renal function is low compared with body mass
During adulthood, there is a slow decline in renal function, about 1% per year

4. GLOMERULAR FILTRATION:
Glomerular capillaries allow drug molecules of molecular
weight below to diffuse into the glomerular filtrate.
Unbound fraction is filtered at glomerulus but they are
reabsorbed back in the tubular lumen
The extent of filtration is directly proportional to the glomerular filtration rate
and to the fraction of the unbound drug in plasma.
If a drug binds appreciably to plasma albumin, its concentration in the filtrate will be less than the total plasma concentration Plasma albumin (68 000) is almost completely impermeable, but most drugs-with the exception of macromolecules such as heparin cross the barrier freely.

5. TUBULAR SECRETION:
Drug molecules are transferred to the tubular lumen by two
independent and relatively non-selective carrier systems.
Unlike glomerular filtration, carrier-mediated transport can
achieve maximal drug clearance even when most of the drug is
bound to plasma protein.
Up to 20% of renal plasma flow is filtered through the glomerulus, leaving at least 80% of delivered drug to pass on to the peritubular capillaries of the proximal tubule. The carriers can transport drug molecules against an electrochemical gradient

6. Active tubular secretion: proximal tubules
Efflux - transporters
P-glycoprotein
MRP2 ( multidrug-resistance-associated protein)
located in luminal membrane of PT cells.
Active transport  free drug in tubular vessels
- dissociation of Protein bound drugs
Organic base
Transporter
Organic acid

7. Organic acid transport :-
Penicillin, Salicylates, Probenecid
Organic base transport:-
Thiazides, quinine, amiloride
Both transport processes are bidirectional
Drugs & metabolites –
secretion into lumen
Endogenous substrates- e.g.- uric acid
reabsorbed into plasma

8. The carrier system is relatively non-selective and therefore drugs having similar physicochemical properties compete for the same carrier system
Eg: Probenecid & Penicillin -
 Penicillin excretion- useful in gonococal infection
Probenecid & Uric acid -
Uric acid excretion.
Tubular transport mechanisms not well developed at birth-
duration of action of many drugs in neonates e.g.-penicillin, aspirin

9. PASSIVE TUBULAR REABSORPTION :
Passive diffusion is bidirectional process
Drugs diffuse across tubules depending on:
Drug concentration
Lipid solubility
pH – alkalanization of urine in barbiturate poisoning.
If the drug is highly polar and thus low tubular permeability remains in the tubule, and its concentration rises until it is about 100 times as high in the urine as in the plasma. e.g., digoxin and aminoglycoside
pH of urine influences excretion of certain weak acids bases

10. urinary pH affects tubular reabsorption
Weakly Basic drugs better excreted in acidic urine- e.g. - morphine, amphetamine
(PH of the urine is made acidic by ascorbic acid )
Acidic drugs better excreted in alkaline urine- e.g.- barbiturates, salicylates
(PH of the urine is made alkaline by sodium bicarbonate)
This principle is utilized for facilitating elimination of drugs in poisoning
The effect of changes in urinary pH is greatest for those drugs having pKa values between 5-8.

11. Biliary and faecal excretion Faeces contain unabsorbed fraction and the drug in bile Drugs attaining high concentration in bile doxycycline cefoperazone
; only unbound drug is filtered

12. Enterohepatic circulation
Most drugs secreted from liver into bile and then into small intestines are passively reabsorbed so that the compound reenters the blood that perfuses intestines and again be carried to liver
Such recycling continues and is known as enterohepatic cycle or circulation
Examples: Morphine, Metronidazole, Estradiol
It continues till drug is metabolised in liver or excreted in kidneys or both

13. Excretion by other routes
Saliva:
Lithium, metronidazole, phenytoin
Gases and volatile liquids (general anaesthetics) are excreted by lungs
Excretion in hair and skin is of forensic importance
As, Hg

14. Basic drugs like chloramphenicol, morphine, phenytoin
Milk
Milk has an acidic pH.
Basic drugs like chloramphenicol, morphine, phenytoin
are secreted through milk and may affect the suckling
infant
Basic drugs are unionized in plasma, diffuse through mammary epithelium and gets accumulated in milk which has acidic medium