Pharmacokinetics

Alfred Kasongo
School of Nursing Sciences
2023
 Introduction

Pharmacokinetics refers to what the body does to a drug.

Pharmacodynamics describes what the drug does to the body
 ADME
• Absorption: First, drug absorption from the site of administration
permits entry of the therapeutic agent (either directly or indirectly) into
plasma.
• Distribution: Second, the drug may then reversibly leave the
bloodstream and distribute into the interstitial and intra cellular fluids.
• Metabolism: Third, the drug may be bio transformed by metabolism
by the liver, or other tissues.
• Elimination: Finally, the drug and its metabolites are eliminated from
the body in urine, bile, or feces.
quiz
• Pharmacokinetics is:
a) The study of biological and therapeutic effects of drugs
b) The study of absorption, distribution, metabolism and excretion of
drugs
c) The study of mechanisms of drug action
d) The study of methods of new drug development
• What does “pharmacokinetics” include?
a) Pharmacological effects of drugs
b) Unwanted effects of drugs
c) Chemical structure of a medicinal agent
d) Distribution of drugs in the organism
• Absorption is the transfer of a drug from its site of
administration to the bloodstream via one of several
mechanisms.
• For IV delivery, absorption is complete. That is, the total dose
of drug administered reaches the systemic circulation (100%
bioavailability).
• Drug delivery by other routes may result in only partial
absorption and, thus, lower bioavailability.
 Mechanism of absorption of drugs from the
GIT
• Passive diffusion
The drug moves from a region of high concentration to one of
lower concentration. Passive diffusion does not involve a
carrier, is not saturable, and shows a low structural specificity.
• Active transport
This mode of drug entry also involves specific carrier proteins
that span the membrane. Energy-dependent active transport
is driven by the hydrolysis of adenosine triphosphate. It is
capable of moving drugs against a concentration gradient.
• Endocytosis and exocytosis
Endocytosis involves engulfment of a drug molecule by the cell
membrane and transport into the cell by pinching off the drugs filled
vesicles.
• Facilitated diffusion
Other agents can enter the cell through specialized transmembrane
carrier proteins that facilitate the passage of large molecules from a
region of high concentration to a region a region of low concentration.
Does not require energy
quiz
The main mechanism of most drugs absorption in GI tract is:

• a) Active transport (carrier-mediated diffusion)

• b) Filtration (aqueous diffusion)
• c) Endocytosis and exocytosis
• d) Passive diffusion (lipid diffusion)
• What kind of substances can’t permeate membranes by passive
diffusion?
a) Lipid-soluble
b) Non-ionized substances
c) Hydrophobic substances
d) Hydrophilic substances
 Factors affecting absorption
• Blood flow to absorption site
Blood flow to the intestines is greater than flow in the
stomach (absorption is greater in the intestines than the
stomach)
• Total surface area available for absorption:
With a surface rich in brush borders containing microvilli, the
intestine has a surface area about 1000-fold that of the
stomach, making absorption of the drug across the intestine
more efficient
Contact time at the absorption surface:
If a drug moves through the GI tract very quickly, as can
happen with severe diarrhea, it is not well absorbed.
Conversely, anything that delays the transport of the drug
from the stomach to the intestine delays the rate of
absorption of the drug
Effect of pH on drug absorption:
A drug passes through membranes more readily if it is
uncharged.
Thus, for a weak acid, the uncharged, protonated HA can
permeate through membranes, and A– cannot. For a weak
base, the uncharged form, B, penetrates through the cell
membrane, but BH+, the protonated form, does not.
Acidic drugs (HA) release a proton (H+), causing a charged
anion (A–) to form:2 HA ←→ H+ + A–
Weak bases (BH+) can also release an H+. However, the
protonated form of basic drugs is usually charged, and loss of a
proton produces the uncharged base (B): BH+ ←→ B + H
BIOAVAILABILITY
Bioavailability is the fraction of administered drug that
reaches the systemic circulation.
For example, if 100 mg of a drug are administered orally, and
70 mg of this drug are absorbed unchanged, the bioavailability
is 0.7, or 70%
 FACTORS INFLUENCING BIOAVAILABILITY
• These are some of the factors that affect BA
• First-pass hepatic metabolism:
When a drug is absorbed across the GI tract, it first enters the
portal circulation before entering the systemic circulation. If
the drug is rapidly metabolized in the liver or gut wall during
this initial passage, the amount of unchanged drug that gains
access to the systemic circulation is decreased
• Solubility of the drug:
Very hydrophilic drugs are poorly absorbed because of their inability to
cross the lipid-rich cell membranes. . For a drug to be readily absorbed,
it must be largely hydrophobic, yet have some solubility in aqueous
solutions. This is one reason why many drugs are either weak acids or
weak base
• Chemical instability:
Some drugs, such as penicillin G, are unstable in the pH of the
gastric contents. Others, such as insulin, are destroyed in the
GI tract by degradative enzymes.
• Nature of the drug formulation:
Drug absorption may be altered by factors unrelated to the
chemistry of the drug. For example, particle size, salt form,
crystal polymorphism, enteric coatings, and the presence of
excipients (such as binders and dispersing agents) can
influence the ease of dissolution and, therefore, alter the rate
of absorption
• What does the term “bioavailability” mean?
a) Plasma protein binding degree of substance
b) Permeability through the brain-blood barrier
c) Fraction of an uncharged drug reaching the systemic circulation
following any route administration
d) Amount of a substance in urine relative to the initial doze
• What does the term “bioavailability” mean?
a) Plasma protein binding degree of substance
b) Permeability through the brain-blood barrier
c) Fraction of an uncharged drug reaching the systemic circulation
following any route administration
d) Amount of a substance in urine relative to the initial doze
 DISTRIBUTION
Drug distribution is the process by which a drug reversibly leaves the
blood stream and enters the interstitium (extracellular fluid) and then
the cells of the tissues
Factors affecting distribution.
• Blood flow
The rate of blood flow to the tissue capillaries varies widely, Blood flow
to the brain, liver, and kidney is greater than that to the skeletal
muscles. s. Adipose tissue, skin, and viscera have still lower rates of
blood flow
• Capillary permeability
Capillary permeability is determined by capillary structure and by the
chemical nature of the drug.
Capillary structure varies widely in terms of the fraction of the basement
membrane that is exposed by slit junctions between endothelial cells.
In the liver and spleen, a large part of the basement membrane is
exposed due to large, discontinuous capillaries through which large
plasma proteins can pass.
In the brain, where the capillary structure is continuous, and there are
no slit junctions
DRUG BINDING
• Drugs bind to proteins in the blood plasma
Plasma albumin is the major drug-binding protein and may act as a
drug reservoir.
as the concentration of the free drug decreases due to elimination by
metabolism or excretion, the bound drug dissociates from the protein
• Binding to tissue proteins:
Numerous drugs accumulate in tissues, leading to higher
concentrations of the drug in tissues than in the extracellular fl uids
and blood
• Hydrophobicity:
The chemical nature of a drug strongly influences its ability to
cross cell membranes.
Hydrophobic drugs readily move across most biologic
membranes.
By contrast, hydrophilic drugs do not readily penetrate cell
membranes and must pass through the slit junctions.
• D. Volume of distribution
The apparent volume of distribution(Vd)can be thought of as the fluid
volume that is required to contain the entire drug in the body at the
same concentration measured in the plasma. I
• 6. A hydrophilic medicinal agent has the following property:
a) Low ability to penetrate through the cell membrane lipids
b) Penetrate through membranes by means of endocytosis
c) Easy permeation through the blood-brain barrier
d) High reabsorption in renal tubules
 DRUG CLEARANCE
Once a drug enters the body, the process of elimination
begins. The three major routes involved are:
1) hepatic metabolism
2) elimination in bile
3) elimination in urine
Most drugs are eliminated according to first-order kinetics,
although some, such as aspirin in high doses, are eliminated
according to zero-order or non-linear kinetics.
Most drugs are eliminated according to first-order kinetics, although
some, such as aspirin in high doses, are eliminated according to zero-
order or non-linear kinetics

KINETICS OF METABOLISM
First-order kinetics:
• That is, the rate of drug metabolism and elimination is directly
proportional to the concentration of free drug, and first-order kinetics
are observed. First-order kinetics is sometimes referred to clinically as
linear kinetics
• Zero-order kinetics:
The rate of metabolism remains constant over time.
This is called zero order kinetics .
sometimes referred to clinically as nonlinear kinetics
A constant amount of drug is metabolized per unit of
time, and the rate of elimination is constant and does
not depend on the drug concentration
 Reactions of drug metabolism
The kidneys cannot easily or effectively eliminate lipophilic
drugs because they may be reabsorbed in the collecting duct.
Thus the drugs need to changed to their hydrophilic state so
that they can be excreted.
That takes place through phase 1 and two reactions.
Phase I:
Phase I reactions convert lipophilic molecules into more polar
molecules by introducing or unmasking a polar functional
group, such as –OH or –NH2. Phase I metabolism may
increase, decrease, or leave unaltered the drug’s
pharmacologic activity.
The P450 system is important for the metabolism of many
endogenous compounds (such as steroids, lipids, etc)
Cytochrome P450, designated as CYP, is a superfamily of heme
containing isozymes that are located in most cells but are
primarily found in the liver and GI tract.
The cytochrome enzymes can inhibited or induced.
• Phase II:
This phase consists of conjugation reactions. If the
metabolite from Phase I metabolism is sufficiently
polar, it can be excreted by the kidneys .
A conjugation reaction with an endogenous substrate,
such as glucuronic acid, sulfuric acid, acetic acid, or an
amino acid, results in polar
 DRUG CLEARANCE BY THE KIDNEY
Renal elimination of a drug Elimination of drugs via the
kidneys into urine involves the three processes of
• Glomerular filtration,
• Active tubular secretion, and
• Passive tubular reabsorption.