Pharmacokinetics

Contents
1. Pharmacokinetics
2. Absorption
3. Distribution
4. Factors affecting distribution of drugs
5. Metabolism
6. Necessity of metabolism
7. Production of toxic metabolites
8. Excretion
9. Factors affecting renal excretion
 Pharmacokinetics
 In practical therapeutics, a drug should be able to reach its intended site of
action after administration by some convenient route.
 In only a few situations is it possible to apply a drug directly to its target
tissue, e.g., by topical application of an anti-inflammatory agent to inflamed skin
or mucous membrane.
 Most often, a drug is administered into one body compartment, e.g., the GIT,
and must move to its site of action in another compartment, e.g., the brain in the
case of an antiseizure medication.
 This requires that the drug be absorbed into the blood from its site of
administration and distributed to its site of action, permeating through the
various barriers that separate these compartments.
Pharmacokinetics
 Pharmacokinetics
 For a drug given orally to produce an effect in the central nervous
system it needs to pass through several barriers. These barriers
include the tissues that make up the wall of the intestine, the walls of
the capillaries that perfuse the gut, and the blood-brain barrier, the
walls of the capillaries that perfuse the brain.

 Finally, after bringing about its effect, a drug should be eliminated

at a reasonable rate by metabolic inactivation, by excretion from
the body or by a combination of these processes.
 Absorption
Absorption: Rate and extent to which drug molecules cross cell
membrane to enter into systemic circulation is called
absorption.

Objective of absorption: A drug must be absorbed from its site

of administration before entering into site of action or plasma.
 Absorption
 Absorption depends on the following three types of factors-

1. Mechanisms by which drugs cross membranes

2. Physicochemical properties of drug molecules &

3. Membrane’s physicochemical properties

Mechanisms by which drugs cross membranes

(1) Aqueous Diffusion
(2) Lipid Diffusion
(3) Special Carriers
(4) Endocytosis and Exocytosis
Absorption
 Absorption
1. Aqueous diffusion: Aqueous diffusion occurs within the larger aqueous
compartments of the body (interstitial space, cytosol, etc) and across
epithelial membranes through aqueous pores which permit the passage of
molecules as large as 20,000–30,000 Da. Aqueous diffusion of drug
molecules is usually driven by the concentration gradient of the permeating
drug. Drug molecules that are bound to large plasma proteins (eg, albumin) do
not permeate most vascular aqueous pores.
2. Lipid diffusion: Lipid diffusion is important because of the large number of
lipid barriers that separate the compartments of the body.
 Absorption

3. Special carriers: Special carrier molecules exist for many substances that
are important for cell function and too large or too insoluble in lipid to
diffuse passively through membranes, eg, peptides, amino acids, and
glucose. These carriers bring about movement by active transport or
facilitated diffusion and, unlike passive diffusion, are selective, saturable,
and inhibitable. Because many drugs are or resemble such naturally
occurring peptides, amino acids, or sugars, they can use these carriers to
cross membranes.
Absorption
Absorption
Absorption
 Absorption
4. Endocytosis and exocytosis: A few substances are so large or impermeant that
they can enter cells only by endocytosis, the process by which the substance is
bound at a cell-surface receptor, engulfed by the cell membrane, and carried into
the cell by pinching off of the newly formed vesicle inside the membrane. The
substance can then be released inside the cytosol by breakdown of the vesicle
membrane. This process is responsible for the transport of vitamin B12.
The reverse process (exocytosis) is responsible for the secretion of many
substances from cells. For example, many neurotransmitter substances are stored
in membrane-bound vesicles in nerve endings to protect them from metabolic
destruction in the cytoplasm. Appropriate activation of the nerve ending causes
fusion of the storage vesicle with the cell membrane and expulsion of its contents
into the extracellular space.
Absorption
Absorption
 Distribution
 Distribution in pharmacology is a branch of pharmacokinetics which
describes the transfer of a drug from one location to another within the body.

 It is defined as a process whereby an absorbed chemical moves away from

the site of absorption to other areas of the body.

 Following absorption or systemic administration into the bloodstream, a drug

distributes into interstitial and intracellular fluids and plasma.

 Interstitial fluid represents about 15% of the total body weight.

Intracellular fluid (fluid inside cells) - 40% of the total body weight. Blood
plasma - 8% of the body weight.
Factors Affecting Distribution of Drugs
1. Binding of drug to plasma protein- Some drugs have the capacity to bind
with certain types of proteins that are carried in blood plasma. This is
important as only drugs that are present in the plasma in their free form can be
transported to the tissues. The binding between a drug and plasma protein is
rarely specific and is usually labile and reversible. The binding generally
involves ionic bonds, hydrogen bonds, Van der Waals forces and, less
often, covalent bonds.

2. Rate of blood flow to various organs- Well-perfused organs (liver, kidney,

brain) initially receive most of the drug. For lesser perfused ones- muscle,
skin, fat etc., distribution is slower.
Factors Affecting Distribution of Drugs

3. Physicochemical Properties of Drugs-

i) Molecular Weight- Drugs with low molecular weight (<500 to 600 Da) can
be easily distributed.

ii) Lipophilicity– Lipid soluble drugs (non-ionized) can cross the membranes
easily whereas, water soluble drugs (ionized) can’t cross the cell membrane, and
so remains in mostly ECF.

So, we can say that uncharged, non-polar, low molecular weight and highly
lipid soluble drugs are transported across membranes easily.
Factors Affecting Distribution of Drugs

4. pH of the Distribution Media

Most of the drugs are available as weak acids or weak bases. The
weak base is absorbed and distributed at a faster rate from the
intestine (pH 7.50 – 8), this is because the basic substances can’t be
ionized in basic medium. So the uncharged substances can be
passed easily due to its lipid solubility. Similarly, weak acid is
absorbed and distributed at a faster rate from stomach (pH 1.4 – 2).
 Factors Affecting Distribution of Drugs

5. Tissue Binding- This refers to the situation in which some drugs attain higher
concentration in certain tissue compared to the other drugs depending upon—
a. The affinity of the drug for the tissue
b. Selectivity of the drug binding

Some drugs readily distribute in those specific tissues & remain accumulated
there. For e.g. Tetracycline to bone, Phenobarbitone to brain, Chlorpromazine to
eye, Chloroquine to kidneys etc.
 Metabolism

 Drug metabolism is the process by which the body breaks down drugs,

usually through specialized enzymatic systems.

 Although every tissue has some ability to metabolize drugs, the liver is the
principal organ of drug metabolism. Other tissues that display considerable
activity include the gastrointestinal tract, the lungs, the skin, the kidneys,
and the brain.

 Within a given cell, most drug metabolizing activity is found in the

endoplasmic reticulum and cytosol; although biotransformation also can
occur in the mitochondria, nuclear envelope and plasma membrane.
 Necessity of Metabolism
 Renal excretion plays a pivotal role in terminating the biological activity of
some drugs, particularly those that possess polar characteristics, such as
functional groups that are fully ionized at physiologic pH.
 However, many drugs do not possess such physicochemical properties.
Pharmacologically active organic molecules tend to be lipophilic and remain
unionized or only partially ionized at physiologic pH; these are readily
reabsorbed from the glomerular filtrate in the nephron. Certain lipophilic
compounds are often strongly bound to plasma proteins and may not be readily
filtered at the glomerulus.
 Consequently, most drugs would have a prolonged duration of action if
termination of their action depended solely on renal excretion.
 Lipophilic non polar drugs

Lipophilic non polar drugs

 Necessity of Metabolism

 In metabolism drugs are converted from lipid soluble compounds to more

polar hydrophilic compounds which is essential for the elimination of

these compounds from the body and termination of their biological activity.

 In general, biotransformation reaction generates more polar inactive

metabolites that are readily excreted from the body. However, in some
cases metabolites with potent biological activity, or toxic properties are
generated.
 Necessity of Metabolism

 Most metabolic biotransformation occur at some point between

absorption of the drug into the general circulation and its renal
elimination. A few transformations occur in the intestinal lumen or
intestinal wall. In general, all of these reactions can be assigned to one
of two major categories called phase I and phase II Reactions.
 Phase I reactions usually convert the parent drug to a more polar
metabolite by introducing or unmasking a functional group (−OH,
−NH2 etc). Often these metabolites are inactive, although in some
instances activity is only modified or even enhanced.
 Necessity of Metabolism
 If phase I metabolites are sufficiently polar, they may be readily excreted.

However, many phase I products are not eliminated rapidly and undergo a

subsequent reaction in which an endogenous substrate such as glucuronic acid,

sulfuric acid, acetic acid, or an amino acid combines with the newly incorporated

functional group to form a highly polar conjugate. Such conjugation or synthetic

reactions are the hallmarks of phase II metabolism.

 Production of Toxic Metabolites
 Virtually all drug molecules are metabolized by the liver and/or other tissues to
inactive metabolites. Sometimes, metabolism produces a pharmacologically active
metabolite, as with the angiotensin receptor antagonist losartan and the
antihistamine ebastine, which are converted from inactive prodrugs to the active
drugs.
 However, a drug metabolite can have a toxic effect. A significant example is that
of acetaminophen, a commonly used analgesic and antipyretic. In its therapeutic
dose range (generally 500 mg 4 times a day), acetaminophen is metabolized to N-
acetyl-parabenzoquinoneimine. However, when the level of acetaminophen
exceeds the therapeutic range (greater than 4g), it results in excessive accumulation
of N-acetyl-para benzoquinoneimine, that reacts with proteins to produce protein
complexes.
 Production of Toxic Metabolites
 Although the biological mechanisms are still not well understood, some of
these complexes between the drug metabolite and cellular proteins are highly
toxic to the liver and, in the case of acetaminophen overdose, can cause
hepatotoxicity and death.
 An antidote for acetaminophen overdose is N-acetylcysteine, which reacts
directly with (and thereby detoxifies) the metabolite. Administered within 8 to 16
hours of an overdose of acetaminophen, N-acetylcysteine can be lifesaving. This
example demonstrates the importance of dose. Although acetaminophen is used
safely by millions of individuals every day, the same drug is responsible for
roughly 50% of the cases of acute liver failure in the United States.
 Excretion

 Excretion

 Elimination of drugs and its metabolites from body through urinary system

is called excretion.

 Drugs eliminated from the body either unchanged or converted to

metabolites by excretion.

 Excretory organs excluding lungs, eliminate polar compounds more

efficiently than substance with high lipid solubility.

 Lipid soluble drugs thus are not readily eliminated until they are

metabolized to more polar compounds.

 Excretion

Possible routes/pathways of drug excretion-

 Renal

 Hepatic

 Fecal

 Pulmonary

 Breast Milk

 Saliva, Sweat and Tears

 Factors Modifying Renal Excretion
1. Ionization of drug:

Unionized drug-well reabsorbed from tubules

Ionized drug - poorly reabsorbed

2. pH of drug:

Acidic drug - In alkaline urine,

Alkaline drug- In acidic urine,

3. Rate of metabolism:

Directly proportional to excretion

4. Extent of plasma protein binding:

High plasma protein binding

Less plasma protein binding

 Factors Modifying Renal Excretion
5. GFR:

More GFR through the kidney

7. Tubular secretion: More secretion

8. Tubular reabsorption: More reabsorption

9. Impaired renal function:

10. Renal blood flow:

Increase in renal blood flow