PHARMACOKINETICS

Pharmacokinetics, derived from the Greek words pharmakon (drug) and kinetikos (movement).

Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement
of drug into, though, and out of the body .Think of pharmacokinetics as a drug’s journey
through the body, during which it passes through five different phases of:

1. Liberation

2. Absorption

3. Distribution

4. Metabolism

5. Excretion

The phases are abbreviated (LADME). The five steps are:

Liberation (L): is the process in which a pharmaceutical substance is released from the
formulation it is delivered in. This must occur before the drug can be absorbed into the body.
Liberation involves setting the active ingredient free from the drug formulation

Absorption: (A): Describes how the drug moves from the site of administration to into
circulation.

Distribution (D): Describes the journey of the drug through the bloodstream to various tissues of
the body.

Metabolism (M): Drug metabolism is the metabolic breakdown of drugs by living organisms,
usually through specialized enzymatic systems.

Excretion (E): Describes the removal of the drug from the body through various routes
ABSORPTION OF DRUGS

Absorption is the movement of a drug from its site of administration to the bloodstream. Drug
absorptive sites includes the skin, intestinal mucosa, mucosa membrane or oral cavity, nose, eye,
ear, vagina, rectum and lung.

It refers to the process that take place between the time drug enters into the body and the time it
gets into circulation. Ways by which drugs are absorbed into the blood includes

 Passive diffusion or Passive absorption

 Facilitated passive diffusion
 Active transport or Active absorption
 Pinocytosis

Passive diffusion
Drugs diffuse across a cell membrane from a region of high concentration (eg, gastrointestinal
fluids) to one of low concentration (eg, blood). Diffusion rate is directly proportional to the
gradient but also depends on the molecule’s lipid solubility, size, degree of ionization, and the
area of absorptive surface. Because the cell membrane is lipoid, lipid-soluble drugs diffuse
most rapidly. Small molecules tend to penetrate membranes more rapidly than larger ones.

Facilitated Passive Diffusion

This refers to the passage of certain drugs across cell membranes according to the concentration
gradient, but in association with specific substrate molecules called carrier molecule which
attach the drug molecule and diffuse across the membrane. This does not require energy to move
across the membrane

Active Transport

Active transport requires energy to facilitate the transport of drug molecules against a
concentration gradient, which usually occurs at specific sites in the small intestine. The majority
of drugs that are absorbed via active transport share a similar structure with endogenous
substances such as ions, vitamins, sugars and amino acids.

Pinocytosis

Pinocytosis involves absorption of fluid or particles following their encapsulation by a cell. The
membrane of the cells closes in around the pharmacological substance and fuses to form a
complete vesicle, which later detaches and moves into the inside of the cell. This process also
requires energy to occur.

FACTORS THAT INFLUENCE DRUG ABSORPTION

The rate and extent of drug absorption depend on multiple factors, such as:

1. Route of administration

2. The formulation and chemical properties of a drug (solid, liquid, gas)

3. Dosage of the drug

Liquid medications absorb faster than tablets and capsules. The GI membrane is composed
mostly of lipid (fat) and protein, so drugs that are lipid soluble pass rapidly through the GI
membrane. Water-soluble drugs need a carrier, either enzyme or protein, to pass through the
membrane. Large particles pass through the cell membrane if they are nonionized (have no
positive or negative charge). Weak acid drugs such as aspirin are less ionized in the stomach, and
they pass through the stomach lining easily and rapidly. An infant’s gastric secretions have a
higher pH (alkaline) than those of adults; therefore, infants can absorb more penicillin. Certain
drugs such as calcium carbonate and many of the antifungals need an acidic environment to
achieve greater drug absorption; thus food can stimulate the production of gastric acid.
Hydrochloric acid destroys some drugs such as penicillin G; therefore a large oral dosage of
penicillin is needed to offset the partial dose loss. Drugs administered by many routes do not
pass through the GI tract or liver. These include parenteral drugs, eyedrops, eardrops, nasal
sprays, respiratory inhalants, transdermal drugs, and sublingual drugs. Remember, drugs that are
lipid soluble and nonionized are absorbed faster than water-soluble and ionized drugs.

Blood flow, pain, stress, hunger, fasting, food, and pH affect drug absorption. Poor circulation to
the stomach as a result of shock, vasoconstrictor drugs, or disease hampers absorption. Pain,
stress, and foods that are solid, hot, or high in fat can slow gastric emptying time, so the drug
remains in the stomach longer. Exercise can decrease blood flow by causing more blood to flow
to the peripheral muscle, thereby decreasing blood circulation to the GI tract.

Drugs given IM are absorbed faster in muscles that have more blood vessels (e.g., deltoids) than
in those that have fewer blood vessels (e.g., gluteals). Subcutaneous tissue has fewer blood
vessels, so absorption is slower in such tissue.

Some drugs do not go directly into the systemic circulation following oral absorption but pass
from the intestinal lumen to the liver via the portal vein. In the liver, some drugs may be
metabolized to an inactive form that may then be excreted, thus reducing the amount of active
drug. Some drugs do not undergo metabolism at all in the liver, and others may be metabolized
to drug metabolite, which may be equally or more active than the original drug. The process in
which the drug passes to the liver first is called the first-pass effect, or hepatic first pass.

BIOAVAILABILITY

In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an

administered drug that reaches the systemic circulation. In other words, bioavailability is the

fraction of the administered drug that reaches the systemic circulation in the unchanged form.
By definition, when a medication is administered intravenously, its bioavailability is 100%.

However, when a medication is administered via routes other than intravenous, its bioavailability

is lower due to intestinal epithelium absorption and first-pass metabolism

DISTRIBUTION

The second stage of pharmacokinetics is the process known as drug distribution. Distribution is
the process by which medication is dispersed throughout the body via the bloodstream. Once a
drug enters into systemic circulation by absorption or direct administration, it must be distributed
into interstitial and intracellular fluids to get to the target cells. The distribution of a drug
throughout the body is dependent on common factors such as blood flow, plasma protein
binding, lipid solubility, the blood-brain barrier, and the placental barrier. Other factors include
capillary permeability, differences between blood/tissue, and volume of distribution.

FACTORS AFFECTING DISTRIBUTION

Blood Flow

The blood stream carries medications to their destinations in the body. Many factors can affect

the blood flow and delivery of medication, such as decreased flow (due to dehydration), blocked

vessels (due to atherosclerosis), constricted vessels (due to uncontrolled hypertension), or

weakened pumping by the heart muscle (due to heart failure). As an example, when

administering an antibiotic to a patient with diabetes with an infected toe, it may be difficult for

the antibiotic to move through the blood vessels all the way to the cells of the toe that is infected.
Protein-Binding

A common factor impacting distribution of medication is plasma protein in the blood. Albumin
is one of the most important proteins in the blood. Albumin levels can be decreased by several
factors such as malnutrition and liver disease. A certain percentage of almost every drug gets
bound to plasma proteins when it initially enters the bloodstream and starts to circulate. The
portion of the drug that gets “protein-bound” is inactive while it is bound, but the portion of the
drug that escapes initial protein binding becomes immediately “free” to bind to the target tissue
and exert or block an action.

Blood-Brain Barrier

Medications destined for the central nervous system (the brain and spinal cord) face an even
larger hurdle than protein-binding; they must also pass through a nearly impenetrable barricade
called the blood-brain barrier. This blockade is built from a tightly woven mesh of capillaries
that protect the brain from potentially dangerous substances, such as poisons or viruses. Only
certain medications made of lipids (fats) or have a “carrier” can get through the blood-brain
barrier.

PLACENTA BARRIER

The placenta is composed of several layers of cells acting as a barrier for the diffusion of
substances between the maternal and fetal circulatory systems.The placental barrier can limit the
delivery of drugs targeted to treat the fetus, or given to prevent maternal-to-fetal disease
transmission, such as in the case of anti-HIV-protease inhibitors
DRUG METABOLISM OR BIOTRANSFORMATION

Drug metabolism is the term used to describe the biotransformation of pharmaceutical substances
in the body so that they can be eliminated more easily. The majority of metabolic processes that
involve drugs occur in the liver by hepatic enzymes MICROSOMAL MIXED- FUNCTION
OXIDASE OR CYTOCHROME P-450. The liver is the principal site of drug metabolism
because majority of the enzymes are concentrated there. The enzyme can also be found in the
red blood cells, kidneys, lungs etc.

The purpose of metabolism in the body is usually to change the chemical structure of the
substance, to increase the ease with which it can be excreted from the body.

Drugs are metabolized through various reactions including: Oxidation, Reduction, Hydrolysis,
Hydration, Conjugation, Condensation and Isomerization.

A prodrug is a pharmacologically inactive medication or compound that, after intake, is

metabolized (i.e., converted within the body) into a pharmacologically active drug .The pass
through the body and are excreted in an unchanged form .

In some circumstances a drug may stimulate enzymes for its own metabolism by a process called
AUTO-INDUCTION or a drug may stimulate the metabolism of another drug by a process
called FOREIGN INDUCTION.
Drug excretion involves processes responsible of physically removing a drug from the body,
either unchanged or in the form of biotransformation products. The main routes for drug
excretion are the urine and the bile. Renal excretion plays an important role in eliminating
unchanged drugs or their metabolites into urine.

Drug elimination is the process by which pharmaceutical substances are removed from the body.
All drugs are eventually eliminated from the body, although there are various pathways that may
be involved in the process. Some drugs undergo metabolism before being excreted, whereas
other drugs are largely eliminated intact in the original dosage form.

The kidneys are responsible for the majority of excretion of water-soluble substances. The biliary
system can also excrete drugs that are not reabsorbed from the gastrointestinal tract.

In most cases, the amount of excreted drug in the intestine, saliva, sweat, breast milk and lungs is
negligible. However, some volatile anesthetics can be exhaled via the lungs. Also, even small
drug concentrations in breast milk of lactating women may affect a breastfeeding infant.

DRUG HALF-LIFE

Drug Half-life is defined as the amount of time required for the drug concentration to be reduced
to exactly half its initial concentration or amount in the blood. The half-life is the time required
for half of the drug to be metabolized and eliminated from the body. The half-life of the drug
is useful in determining the dosing frequency. It determines when the next dose must be
administered. Half-life can vary significantly between drugs. Some drugs have a short half-life of
only a few hours and must be given multiple times a day, whereas other drugs have half-lives
exceeding 12 hours and can be given as a single dose every 24 hours.

The major factors that affect half-life includes drug clearance, volume of distribution, age etc .
The removal of drugs from the plasma is known as clearance and distribution of drugs in the
various body tissues is known as the volume of distribution.

The half-life of a drug is an estimate of the time it takes for the concentration or amount in the
body of that drug to be reduced by exactly one-half (50%). The symbol for half-life is t½.

For example, if 100mg of a drug with a half-life of 60 minutes is taken, the following is
estimated:

 60 minutes after administration, 50mg remains

 120 minutes after administration, 25mg remains
 180 minutes after administration, 12.5mg remains
 240 minutes after administration, 6.25mg remains
 300 minutes after administration, 3.125mg remains.

STEADY STATE.

A steady state refers to the level of a drug in the body once it has reached an equilibrium
between administration and elimination. It represents the point at which the drug administration
rate equals the drug elimination rate, resulting in a relatively constant concentration in the body
over time. The dynamic equilibrium is crucial to ensure the drug's effectiveness with minimal
risk of toxicity.

Most drugs are administered in repeated doses at fixed intervals or through continuous
intravenous infusions to achieve a steady state. After each dose, the drug is absorbed, distributed,
metabolized, and eliminated from the body. As subsequent doses are administered, the drug
accumulates until the amount eliminated from the body in each dosing interval matches the
amount administered. This leads to a stable concentration being maintained within a predictable
range.

The rate at which a drug reaches a steady state depends on its half-life, which is the time it takes
for the body to eliminate half of the drug. A drug typically takes around four to five half-lives to
reach a steady state. During this time, the drug concentration gradually increases until it reaches
a plateau where the administration and elimination rates become equal.
When the rate of drug input is equal to the rate of drug elimination, steady state has been
achieved.