General Pharmacology:

Pharmacokinetics-
Excretion & Elimination Kinetics
Dr. Sahil Kumar Nautiyal
MBBS, MD Pharmacology (MAMC)
Assistant Professor and Head
Department of Pharmacology
Definition:
Pharmacokinetics is the quantitative study of drug
movement in, through and out of the body.
 Excretion

Definition:
Excretion is the passage out of systemically absorbed drug.
Drugs are excreted in:
 Enterohepatic circulation
Refers to the process whereby a drug/ metabolite in the liver is secreted
into the bile, stored in the gall bladder, and subsequently released into the
small intestine, where the drug can be reabsorbed back into circulation
and subsequently returned to the liver.

An bio cs ↓ bacteria in small intes ne (which perform hydrolysis of estrogen metabolite found in bile
to free drug) metabolite excretedlower circulating conc. of ethinylestradiol.
 Renal
Excretion

Glomerular Tubular Tubular

Filtration Reabsorption Secretion

Net renal excretion =

(Glomerular filtr. + Tubular secretion) – Tubular reabs.
 1) Glomerular Filtration
• Depends on the plasma protein binding and renal blood
flow.
• Does not depend on the lipid solubility because all
substances can cross the fenestrated glomerular
membrane.
 2) Tubular reabsorption
• Depends on lipid solubility & ionization.
• As lipid solubility depends on ionization,
ionized drug will be excreted by kidney.
• In acidic drug poisoning urine should be alkalinized with
sodium bicarbonate.
• In basic drug poisoning urine should be acidified using
ammonium chloride.
 3) Tubular secretion
• Does not depend on lipid solubility/ PPB.
• Active transfer of organic acids and bases by nonspecific
transporters (OATP and OCT)
• Drugs utilizing the same transporter may show drug
interactions.
Probenecid ↓ penicillin excretion, ↑ uric acid excretion.
Remember, exogenous substances e.g. penicillins are
removed whereas
endogenous substances like uric acid are retained by these
pumps (OATP/ OCT).
 Tubular transport mechanisms are not well
developed at birth  duration of action of many
drugs is longer in neonates.
 Kinetics of Elimination

• Drug elimination is the sum total of metabolic

inactivation and excretion.

• Two important parameters are discussed in elimination

which help in rational dosage regimens:
Clearance (CL)
Plasma Half-life (t1/2)
 Clearance (CL)
Definition:
It is the theoretical volume of plasma from which the drug
is completely removed in unit time.
• CL = Rate of Elimination/ Plasma Concentration
 Plasma Half-life (t1/2)
Definition:
The plasma half-life (t½) of a drug is the time taken for its
plasma concentration to be reduced to half of its original
value.
 distribution t½ and
elimination t½ (half-life)

 One compartment
distribution
 First order
elimination,
 Given i.v.
ln2 is the natural logarithm of 2 (or 0.693) and k is the elimination rate constant of the drug-
The fraction of the total amount of drug in the body which is removed per unit time.
1 t½ – 50% drug is eliminated.
2 t½ – 75% (50 + 25) drug is eliminated.
3 t½ – 87.5% (50 + 25 + 12.5) drug is eliminated.
4 t½ – 93.75% (50 + 25 + 12.5 + 6.25) drug is eliminated.
 Thus, nearly complete drug
elimination occurs in 4–5 half-lives.
 Order of Kinetics

Depending on whether the elimination processes

involved are saturated or not (over the clinically
obtained concentrations), elimination may follow:

First order/ linear kinetics (majority of drugs)

Zero order/ non-linear/ exponential kinetics
First  Zero order kinetics
 Rate of Elimination = k X {Plasma Concentration}order
Rate of Elimination
= k (Constant)
{Plasma Concentration} order

For Zero order kinetics, this means:

Rate of Elimination
= k (Constant)
1
Rate of Elimination = k (Constant)
Amount of drug eliminated
= k (Constant)
Time
Constant amount of drug is eliminated per unit time
 Rate of Elimination = Some constant X {Plasma Concentration}order
Rate of Elimination
= Constant
{Plasma Concentration} order

For 1st order kinetics, this means:

Rate of Elimination
= Constant
Plasma Concentration
Clearance (CL) = (Constant)
Amount of drug eliminated
= Constant
Plasma Concentration X Time
Drug Fraction eliminated
= Constant
Time
Constant fraction of drug is eliminated per unit time
Elimination of some drugs approaches saturation, kinetics changes from first order to zero
order at higher doses. Plasma concentration increases disproportionately with increase in dose.
• First order kinetics—t½ remains constant because V and CL
do not change with dose.
• Zero order kinetics—t½ increases with dose because CL
progressively decreases as dose is increased. (saturation)
Repeated drug administration
Plateau principle
Steady State is the state at which
Rate of Administration = Rate of Elimination
 Repeated drug administration

• Time to reach steady state = 4-5 t½

• Cpss achieved is directly dependent to the amount of
drug given i.e. dose given per unit time
(dosing rate)
• Variation b/w peak and trough depends on dosing
interval
• If t½ is very high, we give loading dose f/b maintenance
dose (can’t wait for 4-5 t½ as it will be a very long time!)
 Repeated drug administration
Drug is repeated at relatively short intervals accumulates in the body 
elimination (CL) balances administration (dose rate) 
steady-state plasma concentration (Cpss)

From this equation it is implied that doubling the dose rate

would double the average Cpss and so on.
After oral administration, often only a fraction (F) of the
dose reaches systemic circulation in the active form.
In such a case—
Zero order kinetics:
• Increase in dose beyond saturation levels causes an
increase in Cpss which is out of proportion to the
change in dose rate.

• That is why it’s called “non-linear”!

• Dosage intervals ( दन म कतनी बार दवाई लेनी है ) –

a compromise between:

कतनी fluctuations clinically acceptable (loss of

efficacy at troughs and side effects at peaks) ह and

कतनी frequency of dosing convenient है.

 Target Level Strategy
Drug Type Example Strategy
For drugs whose effects are Anticonvulsants, Achieving a certain plasma
not easily measurable and Antidepressants, Lithium concentration which has
narrow safety margin. been defined to be in the
therapeutic range (such
data are now available)

Drugs with short t½ Penicillin, ampicillin, Administered at

(up to 2–3 hr) chloramphenicol, conventional intervals (6–12
erythromycin, propranolol hr); achieve the target levels
only intermittently
and fluctuations in plasma
concentration are
marked but therapeutically
acceptable.

Drugs with longer t½ Chloroquine, Digoxin, Loading dose strategy/

Doxycycline Two phase dosing strategy
Maintenance dose:
 Prolongation of Drug Action
• By prolonging absorption
Oral - Sustained release tablets, spansule, capsules. Drugs with t½ < 4 hr are suitable for
controlled release formulations.
Parenteral - s.c. & i.m. injection of drug in insoluble form (benzathine penicillin, lente
insulin) or as oily solution (depot progestins); adrenaline with LA)
Transdermal drug delivery systems
• By increased plasma protein binding e.g. Sulfadoxine.
• By retarding renal excretion eg. Probenecid-Penicillin
• By retarding rate of metabolism
 Prolongation of Drug Action
Retarding rate of metabolism
Addition of functional groups Inhibition of specific enzyme

Addition of Ethinyl group to Estradiol makes it • Ritonavir - Indinavir,

longer acting (Oral Contraceptive) • Imipenem – Cilastatin
• Amoxicillin - Clavulanic Acid
 Thank you
For making it through!