Excretion

Excretion:

is the passing out of a drug from

the body in any form, present

systemically.

Sites of Excretion

Renal: Kidney

Others:GIT

Lungs

Saliva

Sweat

Milk

Renal Excretion

Filtration:

Secretion:

Reabsorption:

Variety of Organic Acids & Bases aresecreted here.

All water soluble substances;

Total amount excreted through kidney in

the

urine is the sum of:

Total Glomerular Filtration +

Tubular Secretion +

Tubular Reabsorption

Tubular Filtration

Molecular weight for majority of the drugs is

< 20,000 so are filtered easily ( --- if free.)

Warfarin is 99% bound so only 1-2% filtered;

99% filtrate is reabsorbed,

but reabsorption depends upon

lipid-solubility & non-ionization.

Ionized drugs are trapped in the urine &

then excreted

e.g;

Digoxin,

Aminoglycosides

After 35 years of age:

↓ GFR & in renal concentrating capacity

so drugs are not so easily eliminated leading to

↑ t½

e.g., Digoxin t½ becomes > 54 h ( usual 36 h ).

In renal failure:

its t½ increases to 4 - 5 times ( 140 – 175 h )

is the most effective mechanism:

Active secretion: e.g., Penicillin.

(almost all clear in first go through renal tubules)

even plasma protein bound drugs are

completely eliminated by it.

Passive tubular reabsorption:

Non-ionized & lipid soluble drugs

Tubular Secretion

Carrier molecules (SLC, OCT 1, OCT2, OAC)

Probenecid decreases penicillin

secretion so prolonging its action.

( compete with Penicillin )

OCT2 …. Cisplatin ….. Nephrotoxicity

Cimetidine Compete … Nephrotoxicity

Carboplatin Less toxic ….. Not excreted by OCT2

Salicylates decreases secretion of

Probenecid & Sulfinpyrazone.

Role of Ionisation affect in EXCRETION

Permiation

Steady-state distribution between aqueous compartments

By Ion trapping

Aspirin ( pKa 3.5) would be concentrated

4 times in Renal tubule (pH 4.5 -…) with respect to plasma (pH 7.4 )

Actually Does not happen because:

1: Total Impermeability to charged species is not

realistic

2: Compartments rarely approach equilibrium

6000 fold in plasma (pH 7.4 ) with respect to Gastric content( pH 3.3 – 4.0 )

Urinary Acidification (by Ammonium Chloride)

(in diazepam Overdosage)

Urinary Alkalinisation (by sodium carbonate)

( In Aspirin Overdosage),

Acetazolamide???(C/I)

Why Sodium Bicarbonate is Preferred

(MUST BE) over acetazolamide for

Urinary Alkalinisaton in

Aspirin overdosage ???

More Na+ and

H2O,esp. Cl-

going down & reabsorbed leading to Hyperchloremic Metabolic Acidosis.

Acetazolamide etc.

Sodium Bicarbonate

Increase Plasma pH … (Alkaline),

Aspirin become more ionized, So can not cross BBB.

Acetazolamide

Reduce Plasma pH i.e. become acidic

so Aspirin become unionized in plasma, So can cross BBB,

Biliary Secretion & Enterohepatic Circulation

Liver cells transfer drugs from plasma to bile

Similar transport system as renal tubules

OCTs (organic Cation Transporter) …. SLC

OATs (Organic Anion Transporter) …. .SLC

P-glycoproteins (P-gp) …… ABC

Hydrophilic drug conjugates (Glucuronides) are concentrated in bile & delivered in intestine

Erythromycin,

Rifampin,

Ampicillin,

Tetracyclines,

Oral Contraceptives. (ethinylestradiol)

Morphine,

Enterohepatic Circulation

Hydrophilic drug conjugates (Glucuronides) are concentrated in bile & delivered in intestine & are hydrolyzed by intestinal flora, active drug is released once again and is reabsorbed from the intestine.

This cycle is repeated again and again

This effect create a “reservoir” of circulating drug.

Up to 20% of total drug.

Effect of antibiotic Treatment

Failure of contraception

Vecuronium ( non-depolarizing NMJ blocker)

Mainly excreted unchanged in bile

Rifampicin

Absorbs from GIT

Slowly deacetylated, retaining its biological activity

Both forms are secreted in bile

Deacetylated form is not reabsorbed

Eventually …. Drug leaves the body through faeces.

IntestineAnthracine purgatives: Senna, Cascara, etc.

Active metabolite absorbed in the small intestine, after

hydrolysis an active “principles” are liberated which

are excreted in the large gut.

( where it irritate & produce purgation )

Heavy metals: Lead, Arsenic, Iron, etc.

excreted in the feces through bile.

Rifampicin Slowly deacetylated …..in bile …… in faeces

LungsVolatile General Anesthetics: Halothane, etc. N2O

Paraldehyde: 70%-80% metabolized in the liver

which is exhaled, remaining excreted

in the urine.

(In hepatic failure ↑ed in expired air )

Alcohol: Most of it is excreted through

kidney & lungs

Skin:Mercury,

Arsenic

Saliva:Rifampin,

Lithium,

K-iodides

Breast By passive diffusion, more lipid soluble and

less protein bound drugs are better distributed

Like:

Tetracyclines, (C/I in lactation children. WHY?)

Isoniazid,

Diazepam,

Opioid,

Penicillins,

Chloramphenicol,

Anti-cancers.

Drugs sedreted in PCT by OAT &OCT

OAT

Furosemide

Penicillin

Probenacid

Methotrexate

Indomethacin

Thiazide diuretics

OCT

Morphine

Dopamine

Pethedine

Quinine

Amiloride

Triamterine

Drugs mainly excreted unchanged in urine

Up to 100-75% Furosemide

Gentacin

Methotrexate

Atenolol

Digoxin

Up to 75-50% Cimetidine

Neostigmine

Oxytetracycline

MCQ

“A three year child ingested large dose of diphenhydramine, a basic drug ( pKa 8.8). It is capable of entering most of the body tissues including brain. Which of the following statement regarding over-dosage of diphenhydramine is correct?”

1. Hemodialysis only effective therapy.

2. Absorption of the drug would be faster from stomach than from small intestine

3. More of the drug would be ionized at blood pH than at stomch pH.

4. Urinary excretion would be accelerated by giving NH4Cl

5. Urinary excretion would be accelerated by giving NaHCO3

4

Thanks