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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