EXCRETION OF DRUGS

Sarita Sharma Assistant professor Department of pharmacology Mumbai

• Excretion is a process whereby drugs/metabolites are irreversibly transferred from the internal to the external environment. OR

• Excretion is the passage out of systemically absorbed drug.

• Principal organs involved – Kidneys, – Lungs, – Biliary system– Intestines– Saliva– Milk.

Types of excretion:

RENAL excretion NON-RENAL excretion

1. Biliary excretion2. Pulmonary excretion

3. Salivary excretion4. Mammary excretion

5. Dermal excretion

RENAL EXCRETION

Kidney is the primary organ of removal for most drugs especially for those that are water soluble and not volatile.

The three principal processes that determine the urinary excretion of a drug

1.glomerular filtration,2. tubular secretion, and 3.tubular reabsorption (mostly passive back-

diffusion)

a) Glomerular Filtration• The ultrastructure of the glomerular capillary wall

is such that it permits a high degree of fluid filtration while restricting the passage of compounds having relatively large molecular weights.

• This selective filtration is important in that it prevents the filtration of plasma proteins (e.g., albumin) that are important for maintaining the plasma volume.

• Several factors, including molecular size, charge, and shape, influence the glomerular filtration of large molecules.

• As the ultrafiltrate is formed, any drug that is free in the plasma water, that is, not bound to plasma proteins or the formed elements in the blood (e.g., red blood cells), will be filtered as a result of the driving force provided by cardiac pumping.

• All unbound drugs will be filtered as long as their molecular size, charge, and shape are not excessively large.

• Compounds with 20 Å to 42Å may undergo glomerular filtration.

• GFR normally is 120ml/min.

• GFR declines progressively after the age of 50 and also low in renal failure.

b) Active Tubular Secretion

• Many drugs which do not enter into GF but do so by tubule secretion which maily occurs in proximal tubules.

• It is carrier mediated process which require energy for transportation of compounds against the conc. Gradient.

• Mainly 2 secretion mechanism are identified:• 1) system for secretion of organic acids/anions—eg. Penicilline,

salicylates etc.• 2) system for secretion of organic base/cations– eg. Morphine,

hexamethonium etc.

• These active secretory systems are important in drug excretion because charged anions and cations are often strongly bound to plasma proteins and therefore are not readily available for excretion by filtration.

• Active secretory systems can rapidly and efficiently remove many protein-bound drugs from the blood and transport them into tubular fluid. • Any drug known to be largely excreted by the kidney that

has a body half-life of less than 2 hours is probably eliminated, at least in part, by tubular secretion.

• Some drugs can be secreted and have long half-lives, however, because of extensive passive reabsorption in distal segments of the nephron.

Organic Anion Transport Organic Cation Transport

Acetazolamide Acetylcholine

Bile salts Atropine

Hydrochlorothiazide Cimetidine

Furosemide Dopamine

Indomethacin Epinephrine

Penicillin G Morphine

Prostaglandins Neostigmine

Salicylate Quinine

c) Active Tubular Reabsorption• Some substances filtered at the glomerulus are

reabsorbed by passive diffusion and depends on the lipid solubility and ionization of drug at the existing urinary pH.• So lipid soluble drugs filtered from GF but 99% of the

drug is reabsorbed but non-lipid soluble and highly ionized drugs are unable to do so.

• Active reabsorption is particularly important for endogenous substances, such as ions, glucose, and amino acids, although a small number of drugs also may be actively reabsorbed.• Reabsorption result in increase in half life of the drugs.

Clinical Implications of Renal Excretion

• The rate of urinary drug excretion will depend on the drug’s volume of distribution, its degree of protein binding, and the following renal factors:

1. Glomerular filtration rate2. Extent of active tubular secretion of the

compound5. Possibly, extent of active tubular reabsorption

Changes in any of these factors may result in clinically important alterations in drug action.

1)Biliary Excretion/Faeces:

• Bile juice is secreted by the hepatic cells of the liver(steady flow—0.5 to 1 ml/min) is important for the digestion and absorption of fats.• Greater the polarity better the excretion so metabolites are

more excreted than parent compound.• Generally larger molecules (MW>300) are eliminated by bile.• Some drugs which are excreted as glucuronides are

hydrolysed by intestinal/bacterial enzymes to the parent drug which are reabsorbed(enterohepatic cycling) and ultimate excretion occures in urine. Only the remaining is excreted in faeces.• Enterohepatic cycling causes longer stay of drug in body.• Eg. Erythromycine, rifampine, ampicilline etc.

Drugs that Undergo Enterohepatic Recirculation

Adriamycin Methadone

Amphetamine Metronidazole

Chlordecone Morphine

1,25-Dihydroxyvitamin D3 Phenytoin

Estradiol Polar Glucuronic Acid Conjugates

Indomethacin Polar Sulfate Conjugates

Mestranol Sulindac

• Extensive enterohepatic cycling may be partly responsible for a drug’s long persistence in the body.

• Orally administered activated charcoal and/or anion exchange resins have been used clinically to interrupt enterohepatic cycling and trap drugs in the gastrointestinal tract.

PULMONARY EXCRETION

• Gases and other volatile substances are eliminated by lungs, irrespective to their lipid solubility.

• Alveolar transfer of the gas/vapour depends on its partial pressure in the blood.

• Eg: Alcohol, general anaesthetics

EXCRETION IN OTHER BODY FLUIDSSweat and Saliva• Minor importance for most drugs.• Saliva:• un-ionized lipid-soluble form of the drugs are excreted

passively.• Thus, the bitter after taste in the mouth of a patient is an

indication of drug excretion.• Substances excreted into saliva are usually swallowed, and

therefore their fate is the same as that of orally administered.• Eg:caffeine, metronidazole, alcohol etc.• Sweat:• Drugs or their metabolites that are excreted into sweat may

be partially responsible for the dermatitis and other skin reactions.• Eg: Alcohol, heavy metals like lead, mercury etc

Milk:• Milk consists of lactic secretions which is rich in fats and proteins

with pH 7.0• 0.5 to 1 litre of the milk is secreted in lactating mothers.• Low-molecular weight un-ionized water-soluble drugs will diffuse

passively across the mammary epithelium and transfer into milk • However, the total amount of the drug reaching to the infant

through breast feeding is generally small and majority of the drugs can be given to lactating mother without ill effects on infant• but some are contraindicated that should be avoided.• Eg. Insulin, digoxin, diclofenac etc can be given(safe)

• Acyclovir, alcohol, amino glycosides etc (contraindicated/conditional)

Clearance(CL)• It’s a theoritical volume of plasma from which

the drug is completely removed in unit time.• CL = rate of elimination/ C

• C = plasma concentration

• Eg: creatinine Clearance

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