3. Elimination:
• Once a drug enters the body, it starts getting eliminated irreversibly. This
process reduces the plasma concentration of the drug per unit time.
• When drugs dissolved in body fluids, they exist in the both ionized form
(water soluble that can’t pass BBB) and nonionized form (lipid soluble, can
pass BBB).
• Drug mainly eliminated through the kidney, and it involves three
physiological processes: glomerular filtration, proximal tubular secretion,
and distal tubular reabsorption. Glomerular filtration: Free drug flows out
of the body and into the urine-to-be as part of the glomerular filtrate.
4. Route of drug elimination:
1- Drug elimination in the urine
To be extensively excreted in urine, a drug or metabolite must be water soluble
and must not be bound too tightly to proteins in the bloodstream. The acidity of
urine, which is affected by diet, drugs, and kidney disorders, can affect the rate at
which the kidneys excrete some drugs.
2- Drug elimination in the bile
Some drugs pass through the liver unchanged and are excreted in the bile.
Other drugs are converted to metabolites in the liver before they are excreted
in the bile. In both scenarios, the bile then enters the digestive tract. From
there, drugs are either eliminated in feces or reabsorbed into the bloodstream
and thus recycled.
5. 3- Others forms of elimination:
Some drugs are excreted in saliva, sweat, breast milk, and even exhaled air. Most
are excreted in small amounts. The excretion of drugs in breast milk is significant
only because the drug may affect the breastfeeding infant (drugs that
contraindicated with breastfeeding). Excretion in exhaled air is the main way that
inhaled anesthetics are eliminated.
I: Water-soluble, non-volatile, small molecular size (less than 500 daltons)
drugs are mostly eliminated through the renal route.
II: Drugs having the size greater than 500 daltons are majorly excreted in
bile.
III: Drugs having the size between 300–500 daltons are excreted both in
urine, as well as bile.
6. Zero order elimination
• The plasma concentration – time profile
during the elimination phase is linear
• Zero Order elimination is rather rare, mostly
occurring when the elimination system is
saturated
• Example on zero order elimination: Ethanol,
Phenytoin, Salicylates, Cisplatin, Fluoxetine and
Omeprazol.
• Zero-order kinetics is elimination of a constant quantity per time unit of the
drug quantity present in the organism
• The rate of elimination is independent of the concentration of the drug.
8. First-order elimination kinetics :
Occur when a constant proportion of the drug is eliminated per unit time.
Rate of elimination is proportional to the amount of drug in the body. The
higher the concentration, the greater the amount of drug eliminated per unit
time.
For every half life that passes the drug concentration is halved. For
example: a drug concentration of 100 and a half life of one hour will reduce
to 50 in the first hour, 25 in the second hour and 12.5 in the 3rd hour and so
on. Elimination mechanisms are NOT saturable
9. • The plasma concentration – time
profile during the elimination phase
shows an exponential decrease in
the plot with linear axes and is
linear if plotted on a semi
logarithmic plot (plasma
concentration on logarithmic axis
and time on linear axis
• For example, 1% of the drug
quantity is eliminated per minute.
Many drugs are eliminated by first
order kinetics.
10. The time course of the decrease of the drug concentration in the plasma can be
described by an exponential equation of the form:
11. Clinical Implications
In clinical pharmacology, first order kinetics are considered as a « linear
process », because the rate of elimination is proportional to the drug
concentration. This means that the higher the drug concentration, the higher its
elimination rate. In other words, the elimination processes are not saturated and
can adapt to the needs of the body, to reduce accumulation of the drug.
95% of the drugs in use at therapeutic concentrations are eliminated by first
order elimination kinetics.
Because in a saturated process the elimination rate is no longer proportional
to the drug concentration but decreasing at higher concentrations, zero-order
kinetics are also called “non-linear kinetics” in clinical pharmacology.
12. Clearance
• Clearance is variable in zero-order kinetics because a constant amount of
the drug is eliminated per unit time, but it is constant in first-order kinetics,
because the amount of drug eliminated per unit time changes with the
concentration of drug in the blood
• Drug clearance is concerned with the rate at which the active drug is
removed from the body; and for most drugs at steady state, clearance
remains constant so that drug input equals drug output. Clearance is
defined as the rate of drug elimination divided by the plasma
13. Importance of clearance:
• Most drugs are given continuously. Clearance, the parameter which relates
rate of elimination to drug concentration, is important because it defines the
rate of administration required to maintain a plateau drug concentration
14. The difference between clearance and elimination:
Applied Biopharmaceutics & Pharmacokinetics defines elimination as the
"irreversible removal of the drug from the body" and clearance as "volume
of fluid cleared of drug per unit time".
The factors that affect drug clearance:
Inherent ability of the clearing organ to eliminate the drug. Any disease
process might interfere. Blood flow to the organ- which sometimes is
dependent on cardiac output. In severe cases functions of excretory organs
might be affected
15. Drug Elimination Monitoring:
• When taking care of patients with hepatic or renal disease or conditions
affecting those organs, we must consider the fact that drug elimination may be
affected.
• Drug doses may require reduction (and/or dosing frequency), and some drugs
may require discontinuation. If the administration of a particular drug is
absolutely necessary, careful monitoring for adverse effects is of the essence.
• In patients unaffected by liver or kidney pathology, the plasma concentration
of drugs such as vancomycin or phenytoin still needs monitoring to ensure
they remain in the therapeutic window.
