Excretion of drugs, Pharmacokinetics

1. We are not Real Brothers
We are Renal Brothers
Furosemide Digoxin

3. ROUTES OF DRUG ELIMINATION
Drugs are eliminated from the body either unchanged or as water-
soluble metabolites. Both the processes of metabolism and excretion
are essential for the elimination of drugs from the body.
• The major routes of drug excretion are:
(a) Renal, (b) Biliary, (c) Faecal and (d) Alveolar.
• Other minor routes of drug excretion include:
(a) Milk, (b) Skin, (c) Hair, (d) Sweat and (e) Saliva.

4. Renal Excretion of Drugs
• Kidney is the most important organ for
elimination of free drugs (e.g., frusemide,
gentamicin, d-tubocurarine and digoxin) and
their metabolites.
• The three key processes that determine the
renal excretion of drugs are:
A. Glomerular filtration
B. Active tubular secretion
C. Passive tubular reabsorption

5. Glomerular Filtration
• Several factors influence the renal excretion by glomerular filtration:
(i) Molecular size: drugs having small molecular size are more readily filtered.
Usually the drugs having molecular weight above 20,000 are unable to be
filtered. Thus macromolecular substances like heparin, dextran and insulin
(irrespective of their protein binding) are unable to pass through glomerulus.
(ii) Plasma protein binding: only the free drugs can be filtered through
glomerulus, while protein binding decreases the renal excretion. For example,
a drug like warfarin which is 98% bound to albumin, is excreted to an extent
of only 2% through glomerulus.
(iii) Renal blood flow: greater the glomerular perfusion, faster is the drug removal
from the plasma.

6. Tubular Secretion
• Glomerular filtration removes at the most 20% of the drug from the blood
reaching the kidney. The rest 80% of the drug passes on to the proximal tubule
from where it is secreted into the tubular lumen. Tubular secretion is an energy-
requiring carrier-mediated active transport.
• There are two independent carrier systems operating at this level:
• One is for acidic drugs, like penicillin, salicylic acid, thiazide diuretics,
probenecid, indomethacin, methotrexate and some endogenous compound like
uric acid
• Another is for basic drugs, like morphine, quinidine, procaine, quinine,
neostigmine, quaternary ammonium compounds and for some endogenous
substances, like dopamine, choline, histamine and serotonin.

7. The competition to excrete
• Each carrier system is relatively nonselective and therefore the drugs having
similar physicochemical characteristics compete for the same carrier system.
• For example, probenecid (a weak acid) competitively inhibits the tubular
secretion of penicillin and amoxicillin, thereby increasing the plasma half-life
and effectiveness of penicillin in the treatment of certain infectious diseases.
• Similarly, weakly acidic drugs (e.g., lactic acid, salicylic acid and thiazide
diuretics) interfere with the secretion of an endogenous substance, uric acid,
with resultant rise in plasma uric acid levels sufficient to precipitate the attack of
gout in predisposed individuals.

8. Tubular Reabsorption
• The renal tubule behaves like a typical lipid barrier especially in the
distal region.
• Hence the reabsorption of drugs through the distal tubule
predominantly takes place by passive diffusion, and its extent is
dependent upon the:
i. lipid solubility,
ii. ionisation constant (pKa) of the drug and
iii. pH of the urine.

9. Modifying the Urine
• Hence as a rule, since the pH of the urine is acidic, all acidic drugs (e.g.,
salicylates, barbiturates and sulphonamides) remain predominantly non
ionised and have more chances of their reabsorption than excretion.
• On the contrary, if the pH of the urine is made alkaline by giving sodium
bicarbonate or sodium citrate, the ionisation of acidic drugs would
increase. As a result, their reabsorption would be retarded while
excretion would be facilitated.
• Alkalisation of urine, therefore, is a part of the therapeutic regimen in the
cases of salicylate or barbiturate poisoning.

10. Biliary Excretion and Enterohepatic Circulation
• Drugs that show significant elimination through bile include: quinine, colchicine,
d-tubocurarine, corticosteroids and erythromycin. These are then subsequently
eliminated through faeces.
• Some drugs are secreted through bile, but after being delivered to intestine, are
reabsorbed back and the cycle is repeated (enterohepatic circulation). Typical
such example is of Digitoxin.
• Sometimes the drugs, particularly the basic drugs, like morphine, have to be
removed by gastric lavage in order to prevent their enterohepatic circulation.
• The net result of enterohepatic circulation is the prolongation of drug action as
the drug serves as a small circulating reservoir.

11. Faecal Elimination
Substances excreted in faeces are mainly
(i) Orally ingested drugs which are not absorbed through the gut, e.g.,
magnesium sulfate, streptomycin, neomycin, bacitracin, cholestyramine and
certain purgatives, and
(ii) Certain drugs (or their metabolites) which are excreted through bile but are not
reabsorbed from the intestinal tract as described earlier, e.g., erythromycin
and corticosteroids.

12. Alveolar Excretion
• Gases and volatile liquids, e.g., general anaesthetics, nitrous oxide, ether
and alcohol are eliminated through breath, irrespective of their lipid
solubility,
• Because the excretion of drugs here depends on their partial pressure in
the blood.
• Certain essential oils like eucalyptus oil and garlic oil are eliminated
through expectoration.

13. Excretion Through Breast Milk
• Excretion of drugs in the breast milk is important, not because of the amount
excreted but because of the unwanted pharmacological effects in the nursing infant.
• Drugs are transferred to the breast milk according to pH partition principle.
• Therefore, the basic drugs, being predominantly non ionised at plasma alkaline pH
can diffuse through the mammary epithelium and get accumulated in the milk.
Once diffused into milk, these drugs cannot be reabsorbed back to plasma, because
at relatively acidic pH of milk they get substantially ionised.
• Hence, as a rule, basic drugs, e.g., chloramphenicol, tetracyclines, ergotamine,
morphine, metronidazole, carbimazole, certain immunosuppressive cytotoxic drugs,
bromocriptine, estrogen/progesterone, oral contraceptives, diazepam, antihistamines
and senna alkaloids (purgatives) are excreted more through milk as compared to acidic
drugs.

14. Severe Side effects in infants
• Sulphonamides (kernicterus and allergy),
• Penicillin's (allergy),
• ampicillin (diarrhoea),
• Dapsone (haemolytic anaemia),
• Phenobarbitone (drowsiness),
• phenytoin (methaemoglobinaemia) and
• Theophylline (restlessness).
• Infants are particularly sensitive to drug-induced haemolysis during neonatal period
(some infants may also have G6PD deficiency). Hence, the following drugs should also
be avoided

15. Excretion Through Skin, Hair, Sweat and Saliva
• Elimination of drugs through these routes is quantitatively unimportant.
• To cite a few examples, griseofulvin is secreted through keratin precursor
cells; arsenic, mercury salts and iodides are secreted through hair follicles;
iodine, potassium iodide, lithium and phenytoin are secreted through
saliva, while certain amines and urea derivatives are secreted through
sweat.

16. ThankYou