Basic Pharmacology 1

Kaweesa Simon Peter

Pharmacology Department, College of Health

Sciences, Kampala International University
EXCRETION OF
DRUGS
Before the end of this lecture
Students should be able to answer
 What is excretion?
 Different Mechanisms of excretion
 Factors affecting excretion
Measurement of excretion
The main routes by which drugs and their
metabolites leave the body are:

-Kidney
-Hepatobiliary system
-Lungs

 Most drugs leave the body in the urine, either

unchanged or as polar metabolites

 Some drugs are secreted into bile via the liver

 But most are reabsorbed from the intestine .
TYPES OF EXCRETION

1. RENAL EXCRETION

2. NON RENAL EXCRETION

 BILIARY EXCRETION
 EXCRETION from the LUNGS
 EXCRETION into BREAST MILK
 ARTIFICIAL EXCRETION WAYS
RENAL EXCRETION
RENAL EXCRETION

• Drugs and metabolites are excreted from the kidneys by 2 ways.

a) Glomerular filtration
b) Tubular secretion
• Tubular reabsorption is not an excretion way; however there is no doubt that it
effects the excretion of drugs from the body by the kidney.

a) Glomerular filtration:
 Glomerular filtration occurs mainly in the bowman's capsule.
 form of simple passive diffusion is the main mechanism for glomerular filtration.
 Low molecular lipid water soluble drugs are filtered from the glomerulus into proximal
tubules
 A fraction of drug molecules bound to the plasma proteins are not filtered from the
glomerulus, because the drugs cannot pass through into the proximal tubules
because of high molecular weight.
 The filtration rate is 110-130 ml/min.
RENAL EXCRETION
b) Tubular secretion of drugs:

Tubular secretion occurs mainly in the distal tubules.

Active transport is the main mechanism for tubular secretion.
The excretion by tubular secretion is higher than glomerular
filtration route.
Maximum Clearance maximum in glomerular filtration is
approximately 120 ml/min, whereas the clearance maximum of
tubular secretion is about 600 ml/min.
RENAL EXCRETION

Tubular reabsorption:

 Tubular reabsorption occurs in tubules and partially in proximal tubules.

 This mechanism works in an opposite (counter) way and it reduces the drug
excretion
 It occurs by simple passive diffusion generally
 Changing the pH value of the urine (making the urine acidic or basic) is
changes the ionization degree and the simple passive diffusion of the drug
or the metabolite and lastly affect the excretion from the kidney.
 If we make the urine acidic, the reabsorption of the weak acid drug from
the renal tubules into the blood will increase, thus the excretion will
decrease.
 In the opposite way, making the urine basic will cause an increase in the
excretion of weak acid drugs.
BILIARY EXCRETION
• These substances are generally
secreted into the biliary ducts
from the hepatocytes by active
transport and finally they are
drained into the intestines.
• Especially, highly ionized polar
compounds (conjugation
products) can be secreted into
the bile in remarkable amounts.
• The most suitable molecular
weight for the drugs to be
secreted into the bile is
approximately 500 KD.
• After biotransformation, metabolites are drained into the ENTEROHEPATIC CYCLE
small intestine by biliary duct.
• Drug metabolites in the small intestine are broken down
again in the small intestine and reabsorbed back
reaching the liver by portal vein again.
• This cycle between the liver and small intestine is called
the enterohepatic cycle.
• Especially the drugs which are metabolized by the
conjugation reactions go under enterohepatic cycle.
• This is important, because enterohepatic cycle prolongs
the duration of stay of the drugs in our body which
leads an increase in the duration of their effect.
• Drug examples that go under the enterohepatic cycle in
remarkable amounts.
 Chlorpromazine
 Digitoxin
 Indomethasin
 Chloramphenicol
EXCRETION from the LUNGS EXCRETION into BREAST MILK

Gaseous or the volatile substances  Passage of the drugs into breast milk
can pass from the blood circulation occurs generally by simple passive
into the alveoli by passing across diffusion in breast feeding women.
the endothelium and epithelium of  Drugs can be concentrated in milk
the alveolar membrane. according to the ion trapping
phenomenon.
 Because the breast milk is more acidic
Simple passive diffusion is the main than plasma, especially basic drugs tend
mechanism for this transport. to concentrate in breast milk.
 Milk / plasma ratios of a drug can be
 After passing into the alveoli, these used as an indicator of the passage of
substances can be excreted by some drugs into the breast milk.
expiration.  Milk / plasma ratios for some drugs:
 Iodide: 65
 Propyltiouracil: 12
 Aspirin: 0.6-1.0
 Penicillin: 0.1-0.25
ARTIFICIAL EXCRETION WAYS

• Hemodialysis is one of the options among the artificial excretion way for the drugs.
• It is used especially for the treatment of acute drug intoxications to eliminate the drug from
the body.
ARTIFICIAL EXCRETION WAYS

• For the achievement of this system, there are some requirements:

Plasma protein binding of the drug should be low
(bound fraction should be low).
Drug should not be stored in tissues (apparent volume
of the drug should be low)
The main elimination route of the drug should be from
kidneys in unchanged (without biotransformation) form.
PARAMETERS USED DURING DRUG ELIMINATION (CLEARANCE
& HALF LIFE)
Clearance

 Clearance is the VOLUME of plasma that can be freed of drug per unit time, i.e., gives estimate
of function of organs of elimination and rate of removal of drug from the body
• Rate of Elimination (mg/hr)
CL = -------------------------------- = vol/time
Concentration (mg/L)

2004-2005
Clearance

• A measure of the body’s ability to eliminate a drug.

• It is the rate of elimination by all routes normalized to the concentration of drug in some
biological fluid.

• CL is not the amount of drug removed, but the volume of fluid that would have to be
completely freed of drug to account for the elimination
 CLEARANCE
• It can be described as the volume of plasma cleared from the drug per unit
time (ml/min).
• Total Body Clearance: It is the plasma volume cleared from the drug per unit
time via the elimination of the drug from all biotransformation and excretion
mechanisms in the body.
• Renal Clearance: It can be described as the rate of the excretion of a drug
from kidneys. So in other words, renal clearance is the volume of plasma
cleared from the non-metabolized (unchanged) drug via the excretion by
kidneys per minute.
• There are four important factors that affect the renal clearance of the drugs:
Plasma protein binding of the drug.
Tubular reabsorption ratio of the drug.
Tubular secretion ratio of the drug.
Glomerular filtration ratio of the drug.
 V= collected urine volume
V x CU t= duration to collect the urine
Renal Clearence (CLR) =
t x CP CP= plasma concentration of the drug
CU= urine concentration of the drug

CL renal = [(Glomerular filtration rate + Tubular secretion rate) – Tubular reabsorption rate] / Cp

If the renal clearance of the drug is higher than the physiological creatinine clearance (120-130 ml/min),
that time we can say that the tubular secretion helps and contributes the elimination
of the drug additionally to filtration.

In early newborns and newborns, glomerular filtration and tubular secretion mechanisms
are immature and not sufficient.
ELIMINATION HALF-LIFE (t1/2
• It is the time it takes for the plasma concentration or the amount of drug in the
body to be reduced by 50% via different elimination mechanisms.

Half life

t1/2 = The time required for the plasma concentration of a drug to fall to half of its initial
concentration Elimination half-life is inversely (negatively) proportional with the clearance.

Half-life:
Plasma half-life: Time it takes for plasma concentration of a drug to drop to
50% of initial level.
Whole body half-life: Time it takes to eliminate half of the body content of a
drug.
 ELIMINATION HALF-LIFE (t1/2):

Vd
t1/2 = 0,693 x
Clearance

Important points to remember about Half life

1. Elimination half-life is inversely (negatively) proportional with the clearance.

2. Elimination half-life is directly proportional to volume of distribution of a drug
• The higher is the duration of stay of that drug in the body the more it becomes distributed to tissues hence, higher
volume of distribution).

3. Plasma concentration of the drug is directly proportional to the rate of metabolism

Importance of half life and drug clearance:

Half-life is used in predicting how long it takes for a periodic dosing regiment to
achieve steady-state concentrations of a drug in the plasma.

• Half life is used to establish how often the drug is administered

• To prevent drug accumulation of drugs with long t1/2

Types of half life

a)First order kinetics

A constant fraction of drug is eliminated per unit of time.

The concentration of the drug dependent of the rate of metabolism hence half life
 First Order
TIME Constant fraction
kinetics
0 x t1/2 8 1/2
1 x t1/2 4 1/2
2 x t1/2 2 1/2
3 x t1/2 1 1/2
4 x t1/2 0.5 1/2
5 x t1/2 0.25 1/2
Types of half life

a) Zero order kinetics

A constant amount of drug is eliminated per unit of time.

The concentration of the drug is independent of the rate of metabolism

 Zero Order
TIME Constant fraction
kinetics
0 x t1/2 8 2
1 x t1/2 6 2
2 x t1/2 4 2
3 x t1/2 2 2
4 x t1/2 0 2
5 x t1/2
Zero order kinetics

Rate of elimination is constant.

Rate of elimination is independent of drug concentration.

Constant amount eliminated per unit of time.

Example: Alcohol
Comparison

• First Order Elimination • Zero Order Elimination

• [drug] decreases exponentially w/ • [drug] decreases linearly with time
time • Rate of elimination is constant
• Rate of elimination is proportional • Rate of elimination is independent
to [drug] of [drug]
• Plot of log [drug] or ln[drug] vs. • No true t 1/2
time are linear
• t 1/2 is constant regardless of [drug]
Factors affecting half life
• Factors affecting half-life
• Age
• renal excretion
• liver metabolism
• protein binding