EXCRETION

OF
DRUGS
Dr. M IMRAN ASHRAF
Associate Professor
MBBS. M.Phil. PhD(S).
 EXCRETION OF DRUGS
It is removal of drugs from the body
as metabolites or in unchanged form.
ROUTES OF EXCRETION
1. Kidneys
2. Hepatic (Bile & Feces)
3. Other:
• Lungs
• Saliva, sweat, tears
• Hair & Skin
• Breast milk
 KIDNEYS:
RENAL EXCRETION
 KIDNEYS: RENAL EXCRETION

The most important.

It involves:
1. Glomerular filtration
2. Active tubular section
3. Passive tubular reabsorption.
 1: GLOMERULAR FILTRATION:
The amount of drug filtered is dependent upon:

• Conc. of free drug in plasma. Only the free drug ---- Not PPB
drug.
e.g. Warfarin 98% bound to Albumin. So only 2% filtered.

• Mol. Wt (Less than 20,000)

e.g. Plasma Albumin (68,000) completely impermeable.

• GFR: (N;125 ml/min.) 20% of Renal plasma flow.

- Decreased in Cardiogenic Shock, Heart Failure & Age.
- Less in Neonates
-Declines in old age.
 2: ACTIVE PROXIMAL TUBULAR
SECRETION:
It is potentially the most effective mechanism
of renal drug elimination because:
• 80% of Renal plasma flow passes onto the
peritubular capillaries of the PRT.
• As it is active carrier mediated transport even
PPB drug can be cleared. e.g. Penicillin ----
80% PPB
• In PRT certain substances are actively
secreted by two carrier / transport
systems:
– For Acids like Penicillin, Frusemide. Also
secretes Uric acid.
– For Bases like Amiloride.
• The systems are non specific for many
compounds.
• The drug molecules are transported
against concentration / electrochemical
gradient & can ↓ plasma conc. nearly to
zero.
• Competition between drugs for the
carrier
e.g. Probenecid inhibits tubular
secretion of Penicillin.
• Transport of some substances can be
bidirectional.
e.g. Uric acid.
3: PASSIVE TUBULAR RE-ABSORPTION

• GF contains the free drug at the same conc. as in

plasma.
• As it flows down, it is concentrated producing a
gradient for lipid diffusion.

• As tubular membrane is a lipid membrane:

- Highly lipid soluble drugs are excreted slowly.
e.g. Digoxin, Aminoglycosides antibiotics
- The Ionized / lipid insoluble / polar drugs not
reabsorbed hence excreted rapidly.
e.g Drug metabolites / conjugates
• The degree of ionization of weak
electrolytes depends on urinary pH.
• In over dosage excretion can be ↑ by
manipulating urinary pH to change most
of the drug in ionized form.
pH partitioning / trapping of drug in RT
---- excretion.
• Alkalization of urine with sodium Bicarbonate
↑ excretion of Weak Acidic drugs (Aspirin).

• Acidification of urine with Ammonium chloride

↑ excretion of Weak Basic drugs
(Pyrimethamine).
 Renal excretion of drugs may decrease in
impaired renal function due to:
• Renal disease
• Old age

Some drugs are nephrotoxic i.e. Streptomycin,

Gentamicin they are not metabolized and can
produce toxicity, if dose adjustments are not
done according to creatinine clearance
 HEPATIC
(BILE & FECES)
 BILE:
Liver cell transfer drugs / metabolites
( conjugates) by active transport in to bile :
e.g. Novobiocin, Erythromycin, Estrogens & oral
contraceptives
These metabolites may be:
• Excreted in to the feces.
• Absorbed into the blood and excreted in the
urine
• May undergo Entero hepatic circulation.
 ENTERO HEPATIC CIRCULATION:

• Glucuronide conjugate is split by intestinal flora.

• Liberation of parent drug which is reabsorbed from the
jejunum and goes to liver via portal vein.
• It is again conjugated and excreted in to the bile --- in
intestine .
• This may be repeated.
• EHC prolongs the duration of action of drug.
• Broad spectrum antibiotics can inhibit EHC.
e.g. Estrogens, oral contraceptives.
 FECAL EXCRETION OF DRUGS:

The drugs excreted in feces are

• Unabsorbed drugs taken orally i.e Neomycin
• Remainder of drugs which are partially absorbed i.e
Most of the Drugs taken orally.
• Drug metabolites excreted in bile. i.e Erythromycin.
• Drugs excreted in the large intestine i.e Anthracene
Purgatives, Heavy metals.
• Drugs excreted in saliva i.e Lead ,Iodides
• Drugs diffused from blood in to the gut.
OTHER ROUTES
 • LUNGS:

– Main route for excretion of Volatile GA.

– Alcohol, Paraldehyde excreted partially ----
impart odor to breath.
 • SALIVA, SWEAT & TEARS:

– LEAD COMPOUNDS may deposit as

Lead sulphide on gums forming a blue
line.
– RIFAMPIN may impart orange color to
sweat& tears.
 • SKIN & HAIR:

• Arsenic & mercury ---- Forensic

significance.
 • BREAST MILK:

• A/E of some drugs excreted in breast milk:

• Penicillin___________ Allergy
• Isoniazid ____________ Pyridoxine deficiency
• Morphine___________ Narcotic dependence
• Radioactive Iodine____Thyroid suppression &
increased risk of thyroid cancer.
 CLEARANCE (CL)
Definition:
Clearance of a drug is defined as volume of biological
fluid that is cleared off the drug per unit time to account
for elimination.
CL predicts the rate of elimination in relation to drug
concentration (C) .
CL = Rate of elimination
C
It is expressed as L/hr/70kg.
As biological fluid may be blood , plasma or body
water so CL may be defined with respect to:
Blood (CLb)
Plasma (CLP)
Total body water (CLw)
 CLRenal = Rate of elimination Kidney
C
CLLiver = Rate of elimination Liver
C
CLOther = Rate of elimination Other (Lungs, blood, muscles)
C
CL has additive character:
CL Systemic = CLRenal + CLLiver + CL other
Significance
• CL is a measure of body’s ability to eliminate a drug.
• CL can ↓ in diseases of organs of elimination i.e. liver &
kidneys.
• CL is less at extremes of age. ---- Dose should be ↓.
Dosing interval ↑.
• CL affects plasma half life of drugs. If CL is ↓ --- t ½ prolonged.
------ So CL is important for rational long term dosage
regimens.
• CL of “high-extraction drugs” is flow limited ,
determined by:
– Cardiac Output ---- Normal blood flow : 90L/h
– Shunting of blood past hepatic sites of elimination.
e.g. Lidocaine, Morphine, Propranolol, Verapamil ,
Labetalol
• CL is usually constant for most drugs eliminated by first
order kinetics.
CL is Variable in zero order kinetics.
 FIRST ORDER KINETICS
• The rate of elimination is directly
proportional to the conc. of the drug in
plasma. Rate of elimination = CL x C
• A CONSTANT FRACTION of drug is
eliminated per unit time.
• The systems for elimination are not
saturated. e.g. Most of the drugs.
• CL can be estimated by calculating the
AUC of the time conc. profile after dose.
CL = Dose
AUC
Constant fraction of drug per unit time. ---
The elimination rate is rapid at first and
slow as the concentration ↓
 ZERO ORDER KINETICS
(SATURATION KINETICS / CAPACITY LIMITED /NON-
LINEAR / MICHAELIS MENTIN ELIMINATION)

• The rate of elimination is NOT proportional to the conc.

of the drug in plasma.
• A CONSTANT AMOUNT of drug is eliminated per unit
time.

If dosing rate exceeds the elimination, steady state can

not be achieved & plasma conc. continues to rise.
E.g. ETHANOL, PHENYTOIN, ASPIRIN (in high doses)
(Mnemonic : EPS)
 COMPARISON OF
1ST ORDER & ZERO ORDER ELIMINATION

• Constant fraction Constant amount

Elimination systems
are not saturated are saturated
• Rate of elimination = Vmax x C
Km + C
Vmax = maximum elimination capacity
Km = drug concentration at which the rate
of elimination is 50% of Vmax .
 Clearance
• CL = Rate of elimination / Cp
• CLr = Cu x Vu
Cp
• CLr varies for different drugs ---- from < 1ml/min
to 700 ml/min (=renal plasma flow)
• Unit of clearance is volume/time
• A fraction of the drug molecules present in the plasma are removed
• It requires 50 ml of plasma to account for the amount of drug being
eliminated every minute
 Specific organ clearance
• It is the capacity of an individual organ to eliminate
the drug
• Hepatic clearance (CLHepatic ) ----- Due to metabolism
• Renal clearance (CLrenal ) by elimination in urine ---
Due to excretion
• Pulmonary clearance (CLPulmonary)
 Total body clearance -- Cltotal
• Cltotal = CLrenal + CLHepatic + CLPulmonary + Clothers
• A patient in renal failure may some times benefit
from a drug that is excreted by liver
• Total clearance can be derived from the steady state
equation

• Cltotal = Ke Vd
 Flow dependent Clearance
• Flow limited clearance --------
The elimination depend primarily on rate of delivery to
the organ of elimination
• High extraction drugs ---- Drugs with “high” clearance
• A drug that is very effectively extracted by an organ, The
blood is completely cleared of the drug as it passes
through the organ
• Some drugs are eliminated on the first pass of the drug
through it
• Drugs with “low” clearance are removed slowly
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