Introduction to pharmacokinetics

1. Pharmacokinetic
Overview
The intensity of the
drug's effect, and the
duration of the drug
action are controlled by
four fundamental
pathways of drug
movement and
modification in the body.
Figure: Schematic representation of
drug absorption, distribution,
metabolism and elimination.

2. First, drug absorption from the site of administration
permits entry of the therapeutic agent (either directly or
indirectly) into plasma (input). Absorption is defined as
the passage of a drug from its site of administration
into the plasma.
Second, the drug may then reversibly leave the blood
stream and distribute into the interstitial and
intracellular fluids (distribution).
Third, the drug may be metabolized by the liver,
kidney, or other tissues.
Finally, the drug and its metabolites are eliminated
from the body (output) in urine, bile, or feces.

3. Routes of drug administration
The route of administration is determined primarily
- by the properties of the drug (such as water or lipid
solubility, ionization, etc.) and
- by the therapeutic objectives (for example, the
desirability of a rapid onset of action or the need for
long-term administration or restriction to a local site).
The route of administration (ROA) that is chosen may
have a profound effect upon the speed and efficiency
with which the drug acts.

4. Enteral: oral, sublingual,
rectal
Parenteral: intravascular
(intravenous), intramuscular,
subcutaneous
Other: inhalation, intranasal,
intrathecal (in CSF), topical,
transdermal
The main routes of drug administration are:
Figure: Commonly used routes of drug
administration.

6. Enteral routes:
Drug placed directly in the GI tract:
Oral- swallowing
Sublingual- placed under the tongue
Rectum- absorption through the rectum

7. Oral
Giving a drug by mouth is the most common route of
administration but it is also the most variable, and
requires the most complicated pathway to the tissues.
Little absorption occurs until the drug enters the small
intestine.
Drug absorption from the intestine:
The drug absorbed by passive transport mechanism in
intestine at a rate determined by the ionization and
lipid solubility of the drug molecules.
Strong bases of pKa 10 or higher are poorly absorbed,
as are strong acids of pKa less than 3, because they
are fully ionized.

8. Figure: Absorption of drugs from the intestine, as a function of pKa,
for acids and bases.
Weak acids and bases are well absorbed; strong acids and bases
are poorly absorbed.

9. There are a few instances where intestinal absorption
depends on carrier-mediated transport mechanism
rather than simple lipid diffusion.
For example levodopa, iron, calcium.
Advantages:
Convenient- can be self-administered, pain free, easy
to take
Absorption- takes place along the whole length of the
GI tract
Cheap- compared to most other parenteral routes

10. Disadvantages:
- Unpleasant taste of some drugs
- Irritation to gastric mucosa - nausea and vomiting
- Destruction of drugs by gastric acid and digestive
juices
- Sometimes inefficient- only part of the drug may be
absorbed
- Effect too slow for emergencies
- First-pass effect - drugs absorbed orally are initially
transported to the liver via the portal vein
- Unable to use in unconscious patient or who have
had GI surgery

11. Most of the drug is absorbed in the small intestine,
Why?
1. Small intestine has a much larger surface area for
absorption (~200 m2) as compared to the stomach
(~1-3 m2).
2. Drug spends more time in the small intestine (~4
hrs) than the stomach (~0.5-1 hrs).
Food in the stomach can decrease absorption
- Food may delays gastric emptying time so that drugs
may destroyed by acid.
- Interactions between drug and food particles.
- Exception: propranolol- due to  blood flow.

12. First-pass effect
When a drug is absorbed across the GI tract, it enters
the portal circulation before entering the systemic
circulation.
A drug can be metabolized in the gut wall or even in
the portal blood, but most commonly it is the liver that
is responsible for metabolism before the drug reaches
the systemic circulation (plasma). In addition, the liver
can excrete the drug into the bile (fluid secreted by
liver).
Any of these sites can contribute to this reduction in
bioavailability, and the overall process is known as
first-pass effect or first-pass elimination.

13. Portal circulation
Figure: First-pass effect

14. The greater the first-pass effect, the less the agent will
reach the systemic circulation when the agent is
administered orally. (imp)
Lidocaine (anesthetic agent) is a drug with a first-pass
effect that is so great that oral administration is not
practical.
In the case of propranolol, a significant portion of the
orally administered dose is metabolized through a first-
pass effect.
More than 90% of nitroglycerin is cleared during a
single passage through the liver.
Therefore, a much larger oral dose is required to
achieve the same therapeutic response as that
obtained from a dose administered intravenously.

15. Sublingual/Buccal
Placement under the tongue allows the drug to diffuse
into the capillary network and therefore to enter the
systemic circulation directly.
When only small amounts of drugs are required to gain
access to the blood, the sublingual route may be very
satisfactory.
For example, nitroglycerin in angina pectoris.
Because the stomach is bypassed, acid-liability and
gut-permeability is not important.
Drugs are absorbed from the mouth straight into the
systemic circulation without entering the portal system
and so escape first-pass metabolism by the liver.

16. Advantages
-rapid absorption
-drug stability
-avoid first-pass effect
Disadvantages
-inconvenient
-small doses
-unpleasant taste of some drugs
Rectal
50% of the drainage of the rectal region bypasses the
portal circulation; thus the biotransformation of drugs
by the liver is minimized.
Drug’s property:
- Non-polar
- Lipid soluble

17. - Devoid of destruction of the drug by intestinal
enzymes or by low pH in the stomach
- Unconscious patients (postoperative) and children
- If patient is nauseous or vomiting
- Absorption may vary
- Good for drugs affecting the bowel such as laxatives
- Irritating drugs contraindicated
- Can be used for both local effects and systemic
effects

18. Parenteral routes:
Parenteral administration is used for drugs that are
poorly absorbed from the gastrointestinal (GI) tract,
and for agents such as insulin that are unstable in the
GI tract.
Parenteral administration is also used for treatment of
unconscious patients and under circumstances that
require a rapid onset of action.
The three major parenteral routes are
- Intravascular (intravenous or intra-arterial)
- Intramuscular
- Subcutaneous

20. Intravascular:
Intravenous (IV) injection is the most common
parenteral route. For drugs that are not absorbed
orally, there is often no other choice.
- Rapid onset of action because the drug is injected
directly into the bloodstream
- Useful in emergencies and in patients that are
unconscious
- The drug avoids the GI tract and first-pass
metabolism by the liver
- Smaller doses generally are required than the other
routes but cost is high

21. Greater risk of adverse effects as:
a. High concentration attained rapidly
b. That are injected cannot be recalled by
strategies such as emesis or binding to activated
charcoal
c. Risk of embolism (obstruction of blood vessel)
d. May introduce bacteria through contamination,
induce hemolysis
e. Pain at application site
f. No self administration facility
Capillary: brings the blood into intimate relationship with the tissue cell
Artery Arterioles Capillary VenulesVeins

22. Intra-artery
Similar properties, advantages and disadvantages of
intravascular route. Intra-artery route is specially used
when high drug concentration in specific tissue is
required than other tissue:
- diagnostic purpose and
- for chemotherapy
Intramuscular
Drugs administered intramuscularly can be aqueous
solutions or specialized depot preparations- often a
suspension of drug in a non-aqueous vehicle, such as
ethylene glycol or peanut oil.

23. Absorption of drugs in aqueous solution is fast,
whereas that from depot preparations is slow. Drug
passes through capillary walls to enter the blood
stream.
- Pain at injection sites for certain drugs
- This parenteral route may be used when an
immediate effect is not required but a prompt effect is
desirable
- Absorption from an intramuscular depot is more
predictable and uniform than from a subcutaneous site

24. Subcutaneous
Drug is injected beneath the skin and permeates
capillary walls to enter blood stream.
Absorption from the site of injection is dependent on
local blood flow. Concurrent administration of
vasoconstrictor will slow absorption.
For example, minute amount of epinephrine is
sometime used in combination with a drug to restrict
its area of action. Epinephrine acts as a local
vasoconstrictor and decreases removal of a drug,
such as lidocaine (local anesthetic), from the site of
administration.

25. Examples of drugs given by this route are insulin and
sodium heparin, neither of which is absorbed orally,
and both of which should be absorbed slowly over
many hours.
Inhalation
Inhalation provides the rapid delivery of a drug across
the large surface area of the mucous membranes of
the respiratory tract and pulmonary epithelium,
producing an effect almost as rapidly as by
intravenous injection.

26. This route of administration is used for drugs that are
gases and volatile agents (for example, some
anesthetics), or those that can be dispersed in an
aerosol.
The route is particularly effective and convenient for
patients with respiratory complaints (for example,
asthma or chronic obstructive pulmonary disease) as
drug is delivered directly to the site of action and
systemic side effects are minimized.

27. Topical
Topical application is used when a local effect of the
drug is desired.
Used for most dermatologic and ophthalmologic
preparations.
Clotrimazole is applied as a cream to the skin in the
treatment of dermatophytosis.
Atropine is instilled directly into the eye to dilate the
pupil and permit measurement of refractive errors.
Intra-articular
Injected into bone joints

28. Intrathecal/lntraventricular
It is sometimes necessary to introduce drugs directly
into the cerebrospinal fluid (CSF): some anesthetics.
Transdermal
This route of administration achieves systemic effects
by application of drugs to the skin, usually via a
transdermal patch.
The rate of absorption can vary markedly depending
upon the physical characteristics of the skin at the site
of application. Small lipid soluble molecule.
This route is most often used for the sustained delivery
of drugs, such as the antianginal drug, nitroglycerin.