Module 1 1/25/2013 2:22:00 PM
What is Pharmacology?
o Derived from the Greek words “pharmakon” meaning remedy
and logos meaning study.
o Generally pharmacology is considered the study of drugs.
o The study of drugs can include various aspects, some of
1) How a drug is delivered (it‟s route of administration).
2) How a drug works (it‟s mechanism of action).
3) The therapeutic effect of drugs on patients.
4) The adverse effects of drugs on patients.
Classification of Therapeutics
o 1) Drugs – Traditional drugs (i.e. chemical agents).
o 2) Biologics – antibodies, hormones.
o 3) Natural Health Products – herbals, vitamins, minerals.
Canadian Drug Legislation
o 1. Food and Drugs Act/Regulations
o 2. Health Canada
o 3. Health Canada Products and Food Branch
o 4. Therapeutic Products Directorate, Biologics and Genetic
Therapies Directorate and Natural Health Products Directorate
Approval of typical drugs
Approval of hormones/antibodies
Approval of natural source medicine products
What is a Drug?
o Drugs are actually chemicals.
o Within every pill are many molecules of a chemical. It is the
chemical that actually produces the pharmacological effect.
Naming of Drugs
o Drugs have three types of names:
1. Chemical Name – Describes the chemical structure of
the molecule. 2. Generic Name – A unique name that identifies a
Most often used in Pharmacology.
3. Trade name – The name assigned by a drug
Major problem with trade names is many
companies may make the same drug, therefore it
may have many different trade names.
Approval of Marketed Drugs in Canada
BASIC PHYSIOLOGY AND THE CELL MEMBRANE
Physiological Barriers to Drug Transport
o Intestinal villi form a barrier against ingested drugs, toxins
o Some cells have tight junctions which prevent molecules from
passing between cells.
i.e. brain cells
o In order to exert its effect, a drug must have the right
chemical properties to pass through these barriers.
Components of the Cell
o Nucleus – Contains genetic material.
o Smooth Endoplasmic Reticulum – Metabolizes drugs,
carbohydrates and steroids.
o Rough Endoplasmic Reticulum – Synthesizes proteins.
o Golgi Apparatus – Processes and packages proteins and lipids.
o Mitochondria – Produces ATP.
o Cell membrane – Separates the intracellular and extracellular
environments. o The Cell Membrane
Composed of phospholipids which have a polar (water
soluble), phosphate containing head and two fatty acid
(lipid soluble) tails.
The cell membrane is often called a lipid bilayer
because of the arrangement of the phospholipids.
“Fluid” because the phospholipids are flexible allowing
them to undulate back and forth.
Contains proteins embedded in the phospholipids.
HOW DO DRUGS CROSS THE CELL MEMBRANE
1) Direct penetration of the cell membrane.
o To directly penetrate cell membranes, drugs must be lipid
o Cell membranes are composed of primarily lipid
Therefore drugs must be able to dissolve into the lipids
of the cell membrane in order to pass through it.
o Molecules that are not lipophilic cannot pass through cell
2) Through ion channels and pores.
o The channels and pores in cell membranes are very small.
Only very small compounds (molecular weight < 200)
can pass through channels and pores.
o Channels are selective meaning only certain small compounds
can fit through them.
Charge can also be a factor
o Examples of compounds that cross membranes through
channels include ions like sodium, potassium and lithium
3) Specific transport proteins (drug transporters).
o Are carrier proteins that move drugs from one side of the cell
membrane to the other.
o Two types:
Uptake transporters move drugs from outside the cell to
inside. Important in mediating intestinal absorption,
renal excretion and reaching target sites of action
Efflux transporters move drugs from inside the cell to
Important for protecting cells and are present in
the intestine, placenta, kidney and at the blood
THE CHEMISTRY OF PHARMACOLOGY
Types of Drug Molecules
o 1) Polar Molecules
Have an uneven distribution of electrical charge and
have no net charge.
Examples of polar molecules include water, glucose and
o 2) Ions
Atoms or molecules where the total number of electrons
is not equal to the total number of protons.
Have a net charge.
Due to their charge, ions cannot directly pass through
the cell membrane.
Very small ions pass through ion channels or
o 3) Quaternary Ammonium Compounds
Have at least one nitrogen atom that has a positive
charge at all times.
Due to the positive charge, these molecules are unable
to cross cell membranes.
o 4) Ionizable Molecules
Can exist in charged or uncharged form. Weak acids or weak bases.
Determination of whether a weak acid or a weak base
carries a charge depends on the pH of the surrounding
The Impact of pH on Drug Movement
o Only non‐ionized drugs can directly penetrate the cell
o Most drugs are weak bases and therefore cross membranes
more easily in an alkaline medium (intestines)
o Example: Medium = stomach (acidic)
The acidic drug is unionized and can therefore cross the
The basic drug is ionized and therefore can‟t cross the
o Acidic Medium (stomach)
+ weak acid = non ionized
+ weak base = ionized
o Alkaline Medium (small intestine)
+ weak acid = ionized
+ weak base = non ionized
o Occurs when there is a difference in pH on different sides of a
o Drugs accumulate on the side of the membrane where they
o Ion trapping can be put into use clinically in some cases of
o Example: an acidic drug is placed into an acidic environment.
Since acidic drugs are unionized in acidic environments,
the drug is able to cross the membrane.
The other side of the membrane is basic, therefore
when the drug crosses the membrane is becomes
ionized. Since ionized drugs are unable to cross cell membranes,
the drug is now “trapped” on the basic side of the
DRUG MOVEMENT OUT OF CAPILLARIES
o The smallest blood vessels in the body.
o Blood supply from the heart travels through the arteries into
narrower arterioles which narrow further into capillaries.
o Capillary beds supply tissue with oxygenated blood and allow
the drugs and other molecules to move from the blood to the
o Capillaries have large gaps between them called
o Hydrophilic drugs can pass between fenestrations to leave the
o Lipophilic drugs can either pass between fenestrations or
directly through capillary endothelial cells.
o Capillaries at the blood brain barrier have tight junctions.
They do not have fenestrations.
In order to penetrate the brain, drugs must either be
lipophilic or have a specific transport protein that carries
them into the brain. Module 2 1/25/2013 2:22:00 PM
o The study of drug movement in the body.
o It‟s what the body does to the drug.
o Composed of four basic processes:
The movement of the drug from the site of
administration into the blood.
Rate determines how quickly the drug effect will
The amount of absorption determines how intense
the effect will be
FACTORS AFFECTING ABSORPTION
1) Rate of Dissolution
o Dissolution means dissolving in solution.
o Drugs must dissolve before they can be absorbed.
o Drugs with a fast rate of dissolution will have a faster onset of
action than drugs with slow dissolution.
o When we swallow a medication, the tablet undergoes
disintegration and the medication dissolves in our stomach
2) Surface Area
o Surface area is a major determinant of drug absorption.
o The larger the surface area, the faster drug absorption is.
o Which has the greater surface, the stomach or the small
While the stomach has folds called rugae, the intestine
has thousands of finger like projections called villi.
The villi that line the intestine make the surface area
very large. 3) Blood Flow
o Drug absorption is fastest in areas with high blood flow.
o Areas with a high blood flow maintain a concentration
gradient which drives absorption.
o Areas with low blood flow do not maintain as great of a
o Exercise increases blood flow and can increase drug
o Blood flow is decreased in heart failure, severe hypotension,
hypothermia and circulatory shock.
4) Lipid Solubility
o Drugs with high lipid solubility (i.e. lipophilic drugs) are
absorbed more rapidly than water soluble (i.e. hydrophilic)
o Lipophilic drugs are able to cross the cell membrane whereas
hydrophilic drugs can‟t.
5) pH Partitioning
o Drug absorption is greater when there‟s a difference between
the pH at the site of administration and the blood such that
the drug is ionized in the blood.
Remember the effect of pH dependent ionization*
If the drug becomes ionized, it will become „trapped‟ in
6) Activity of Drug Transport Proteins
o The rate and extent of drug absorption can be significantly
impacted by drug transporters.
o Uptake drug transporters increase the absorption of drugs.
o Efflux drug transporters decrease the absorption of drugs.
ROUTES OF ADMINISTRATION
8 major routes of drug administration
o 1) Oral (PO = per os which is latin for by mouth)
o 2) Sublingual o 3) Transdermal
o 4) Rectal
o 5) Intravenous (IV)
o 6) Subcutaneous (SubQ or SC)
o 7) Intramuscular (IM)
o 8) Pulmonary
Routes of administration are often referred to as enteral or
o Enteral – Routes of administration that involve the
o Parenteral – Routes of administration that do not involve the
o Intestine vs. Stomach
Drug absorption would be greater in the intestine than
What about drugs that are weak acids, wouldn‟t they be
better absorbed in the stomach?
Based on the pH effects weakly acidic drugs
should be better absorbed in the acidic
environment of the stomach because they would
unionized. However, the surface area of the stomach is small
and the stomach is covered with a thick layer of
Therefore the rate of drug absorption in the
intestine will be greater than the stomach, even if
the drug is ionized!
o Pharmaceutical Phase
Occurs after the patient swallows a tablet.
It involves the disintegration of the tablet and the
dissolution of the drug.
If the drug does not completely disintegrate or does not
go into solution, absorption is reduced.
o Gastric Emptying
The movement of the stomach contents into the
Since the rate of drug absorption is greater in the
intestine, things that increase gastric emptying also
increase the rate of drug absorption.
Factors Affecting Gastric Emptying
Drugs with enteric coating are covered with
a special coating that prevents their
dissolution in the acidic environment of the
Once the drug passes into the more alkaline
duodenum, the enteric coating dissolves.
The fraction of a dose of drug that reaches
the systemic circulation unchanged.
Can be influenced by:
o 1) Drug formulation
o 2) Route of Administration
o 3) Degree of Metabolism Aqueous solutions have high bioavailability
while tablets have low bioavailability
o Involves placing a drug under the tongue.
o The drug dissolves and is absorbed across the oral mucosa.
o Venous drainage from the oral mucosa is to the superior vena
Superior vena cava takes blood to the heart.
o Drugs administered sublingually avoid first pass metabolism
through the liver.
o In order to be absorbed drugs must be lipophilic and
o Not all drugs penetrate the skin.
o The epidermis provides a lipid barrier, therefore drugs must
be lipophilic enough to penetrate the skin.
o Drugs must also be relatively hydrophilic in order to dissolve
in the extracellular fluid.
Ideal transdermal preparations have some degree of
lipophilicity and some degree of hydrophilicity and are
usually small (< 600 Da) molecules.
o Transdermal drugs are typically administered as patches,
ointments, sprays or lotions.
o Transdermal administration provides constant plasma drug
levels with minimal peaks and troughs.
o Tolerance may develop unless drug‐free period‟s are
Typically patches are removed for 6 – 10 hours per day
to avoid tolerance.
o Factors Affecting Transdermal Absorption
1) Thickness of the skin – Transdermal absorption is
inversely proportional to skin thickness.
Increasing thickness = decreased absorption 2) Hydration – Transdermal absorption is increased
when the skin is well hydrated.
3) Hair follicles – Provide routes for drugs to bypass the
barrier function of the epidermis.
In general the greater the number of hair follicles,
the greater the transdermal absorption is.
4) Application Area – The greater the application area,
the greater the transdermal absorption.
5) Integrity of the barrier – In conditions such as
psoriasis, burned or abraded skin, transdermal
absorption is increased.
o Useful when the patient is unconscious or vomiting.
o Approximately 50% of rectally administered drugs bypass the
liver (an important site for drug metabolism).
The drug is inserted into the rectum as a suppository.
The suppository dissolves and the drug crosses the
rectal mucosa into the blood.
Some drugs may irritate the rectal mucosa
5) Intravenous (IV)
o Drug is injected directly into a peripheral vein.
o Most commonly used veins are those on the back of the hand
or the median cubital vein at the elbow although any visible
vein may be used.
o Intravenous drugs can be given as a bolus or by an IV drip.
In IV bolus a single dose is administered over a short
time period. In an IV drip a drug is administered under continuous
infusion over a prolonged period.
Drugs are typically diluted in a “vehicle” such as saline
in an IV bag.
No barriers to absorption, bioavailability is 100%.
Allows precise control of the drug dosage and duration
Allows administration of poorly soluble drugs that must
be diluted in a large volume.
Allows the injection of drugs that are irritants (i.e. many
chemotherapeutic drugs) as they can be injected slowly
so they are diluted in the blood.
Expensive, invasive and inconvenient.
Drug cannot be removed once injected.
Risk of infection and fluid overload.
Risk of injecting wrong formulation (IM formulation
sometimes injected IV by accident).
o Drug is injected beneath the skin into the subcutaneous
o The only barrier to absorption is the capillary wall.
o Irritant drugs must not be injected subcutaneously as this will
cause severe pain and/or tissue sloughing.
o The primary determinants of rate of absorption are blood flow
and water solubility.
7) Intramuscular (IM)
o Drug is injected directly into muscle tissue.
o Absorption is determined by the ability of the drug to pass
through fenestrations in the capillary wall. o The primary determinants of rate of absorption are blood flow
and water solubility.
1. Can be used for poorly soluble drugs.
2. Can use it to administer depot preparations
Preparations in which the drug is absorbed slowly
2. May cause local tissue and/or nerve damage if the
injection is done improperly.
o Factors Affecting Intramuscular Absorption
Blood flow is different depending on which muscle is
used for injection.
In general blood flow is deltoid > vastus lateralis>
Exercise increases blood flow and may therefore
increase absorption for IM drugs.
Blood flow may be decreased in heart failure, severe
hypotension and hypothermia.
o Gaseous and volatile drugs can be inhaled and absorbed into
the blood through the pulmonary epithelium.
o Absorption is very rapid (almost instantaneous) due to the
large surface area of the lung.
o In the case of pulmonary disease (i.e. asthma), the drug is
delivered to its site of action which is a major advantage.
o Drugs such as general anesthetics used in surgery are also
often administered by the pulmonary route of administration. Module 3 1/25/2013 2:22:00 PM
Drugs distribute into compartments in the body where they may be
stored, metabolized, excreted or exert their pharmacological effect.
The bodies compartments include:
o 1. Interstitial Space – The extracellular fluid that surrounds
Low molecular weight, water soluble drugs distribute in
the interstitial space.
o 2. Total body water – Includes the interstitial space,
intracellular fluid and the plasma.
o 3. Plasma – The non‐cell containing component of blood.
Drugs strongly bound to plasma protein and high
molecular weight drugs typically distribute in plasma.
o 4. Adipose Tissue – The bodies fat.
Lipid soluble (lipophilic) drugs distribute into adipose
o 5. Muscle – Some drugs bind tightly to muscle tissue.
o 6. Bone – Some drugs adsorb onto the crystal surface of bone
with eventual incorporation into the crystal lattice.
Bone can be a reservoir for the slow release of some
o 7. Other tissues
o 1. Blood flow to tissues.
The more drug that distributes out of the blood, the
lower the concentration of drug in the blood.
Blood flow to tissues is a key determinant of drug
distribution. In well perfused tissues such as the liver, kidney and
brain, drug distribution is rapid.
Distribution to tissues with lower blood flow such as
skin, fat and bone is much slower.
Implications for Altered Blood Flow
Neonates have limited blow flow and therefore
may have limited drug distribution.
Poor blood flow rarely limits drug distribution in
adult patients however some exceptions do exist.
Patients with heart failure or shock may
have reduced blood flow and therefore
altered drug distribution.
Solid tumors have low regional blood flow.
The outer portion of tumors has a high
blood flow but the blood flow progressively
decreases towards the middle.
Therefore it is difficult to attain high drug
concentrations within solid tumors.
Abscesses (infection filled with pus) have no blood
supply and are therefore difficult to treat with
antibiotics. They are often drained prior to drug
o 2. Ability of drug to move out of capillaries.
With the exception of the brain, drug movement out of
the capillaries into the interstitial space occurs rapidly
due to the permeable nature of the capillary wall.
Drugs move out of the capillary through fenestrations.
o 3. Ability of drug to move into cells.
Once drugs leave the vasculature they must enter their
target organ to have an effect.
The cell membrane is a significant barrier to drugs
reaching their targets. In order for drugs to enter cells they must be
sufficiently lipophilic to cross the cell membrane or be
carried by an uptake transporter into the cell.
Some drugs are extruded (removed) from cells by efflux
The most widely studied efflux transporter.
Plays an important role in the distribution of drugs.
Although the “P” in P‐gp stands for permeability, it is helpful to
remember the word Protective when you think of P‐gp.
Protective because it facilitates drug efflux from cells, promotes
drug excretion and protects the body from exposure to drugs and
An active transporter which means that it requires energy (ATP) in
order to transport drugs against a concentration gradient.
In the liver pumps drugs into the bile to facilitate excretion.
In the intestine, P‐gp pumps drug into the lumen preventing
absorption into the blood.
In the kidney P‐gp pumps drugs into the lumen facilitating
In the brain P‐gp pumps drugs into the blood limiting exposure in
PLASMA PROTEIN BINDING
In plasma drugs can be bound to plasma proteins or free
Only free drug is available to elicit a pharmacological response.
Proteins are large and therefore drugs that are bound to plasma
proteins are unable to pass through capillary fenestrations.
There are two major plasma proteins that bind drugs in plasma:
o 1. Albumin – Has a high affinity for lipophilic and anionic (i.e.
weakly acidic) drugs.
Responsible for the majority of protein binding. o 2. Alpha 1 acid glycoprotein – Binds primarily cationic (i.e.
weakly basic) and very hydrophilic drugs.
Plasma Protein Binding is Reversible
o The binding of drugs to plasma proteins is reversible.
o If some of the free drug is removed, some of the protein
bound drug will dissociate from the protein and become free.
Conditions Affecting Plasma Protein Binding
o The following decrease plasma albumin concentration
Liver and kidney disease
This results in an increase in free drug concentration
which may result in toxicity.
o The following increase alpha-1-acidic glycoprotein
Hepatic inflammation (i.e. in hepatitis)
This results in decreased free drug concentration which
may lead to ineffective therapy.
VOLUME OF DISTRIBUTION (Vd)
Represents the APPARENT volume that a drug distributes into.
Vd is the ratio of the total amount of drug in the body (D) to the
plasma concentration of the drug (C), therefore:
o Vd = D/C
It is important to note that Vd is NOT a physical, anatomical space,
rather it is a calculated volume that helps determine the relative
distribution of a drug within the body.
Some drugs have a Vd much larger than the volume of the body
due to extensive binding to tissue. Water Compartments in the Body
o Plasma – The liquid portion of blood. (~4 L)
o Interstitial Fluid – The fluid that surround the cells of the
body. (~10 L)
o Intracellular Fluid – The fluid inside cells. (~28 L)
Drugs with a Small VD
o Have the following characteristics:
Highly protein bound (retained in plasma).
Large molecular weight (unable to pass through
o Unable to leave the vascular space (plasma).
o When displaced from plasma proteins, free drug concentration
o Distribute into the plasma volume which is approximately
0.057 L/kg or 5.7% of total body weight (~4 L in a 70 kg
Drugs with an Intermediate VD
o Have the following characteristics:
Low molecular weight (able to pass through capillary
Very hydrophilic (can‟t cross cell membranes).
Intermediate protein binding.
o Able to leave the vascular space and enter the interstitial
Unable to enter cells.
o Distribute into the extracellular fluid (plasma + interstitial
The extracellular space is ~0.2 L/kg or 20% of total
body weight (~14 L in a 70 kg person).
Drug with a Large VD
o Have the following characteristics:
Low molecular weight (able to pass through capillary
fenestrations). Lipophilic (able to cross cell membranes).
Minimal protein binding.
o Able to leave the vascular space and the interstitial space.
o When displaced from plasma proteins, drug moves into the
tissue, decreasing drug concentration in the blood and further
o Distribute into body compartments such as fat, bone, muscle
and other tissues.
o Distribute into greater than 0.2 L/kg.
o Keep in mind that these drugs may have a Vd larger than
total body water!
How is this possible?
Remember that Vd is mathematically derived and is
NOT an actual physical volume.
Drug Displacement from Protein
o Drug binding to protein is reversible.
o If two drugs are present in the blood, one drug may displace
the other drug from plasma protein.
o The fate of the displaced drug depends on its volume of
o Small Vd
When the Vd of the displaced drug is small, displaced
drug does NOT distribute into tissues, it stays in the
This means the free drug concentration increases.
o Large Vd
When the Vd of the displaced drug is large, displaced
drug leaves the plasma and distributes into the tissues.
This causes the total plasma drug concentration to
decrease, and the apparent Vd to increase even further.
BODY COMPOSITION AND DRUG DISTRIBUTION
As we age our body composition changes.
o Total body water decrease with age o Muscle mass increases and then decreases
Elderly people have an increased proportion of body mass as fat.
o Similarly, obese people have a larger proportion of body mass
o Drugs that distribute in fat will have a larger Vd in obese or
elderly people than young healthy adults.
As people age they have a decreased percentage of muscle per
total body mass.
o Therefore drugs that distribute into muscle will have a lower
Vd. Module 4 1/25/2013 2:22:00 PM
Metabolism is the enzyme mediated alteration of a drug‟s structure.
o Also referred to as biotransformation.
Sites of drug metabolism include:
o Liver – primary site
o Intestines – enterocytes that line the gut are responsible
Bacterial flora play an important role
o Stomach – alcohol metabolism
Drug metabolism evolved in humans to protect us from a number of
environmental toxins as well as synthesize essential endogenous
o Exogenous – substances that are not naturally in our body to
i.e. wine, cigarettes, steak, coffee, vegetables and
They have the potential to be toxic and drug
metabolism helps prevent this
o Essential endogenous molecules synthesized by drug
i.e. vitamin D synthesis, bile acid synthesis, cholesterol
metabolism, synthesis and metabolism of hormones,
Therapeutic Consequences of Drug Metabolism
o 1) Increase water solubility of drugs to promote their
Most important consequence because this allows
o 2) Inactivate drugs.
Metabolite does not have activity
o 3) Increase drug effectiveness Active More active
o 4) Activate prodrugs (inactive until metabolized)
Prodrug (inactive) Active drug
o 5) Increase drug toxicity
Less favorable consequence
KINETICS OF DRUG METABOLISM
o In most clinical situations the concentration of drug is much
lower than the metabolic capacity of the body
Concentration of drug < drug metabolizing enzymes
In these situations drug metabolism displays 1st order
o Drug metabolism is directly proportional to the concentration
of free drug.
This means a constant fraction of drug is metabolized
per unit time.
o The concentration decreases faster when there are higher
drug concentrations than at the end when the drug
concentrations are low.
High concentration = high metabolism
Low concentration = low concentration
o The plasma drug concentration is much higher than the
metabolic capacity of the body.
Drug concentration > drug metabolizing enzymes
o Drug metabolism is constant over time.
This means a constant amount of drug is metabolized
per unit time.
Rate of drug metabolism is same throughout
o One of the best examples of zero order kinetics is ethanol.
o A constant amount of drug is eliminated over time.
Metabolism is independent of drug concentration FIRST PASS METABOLISM
PO (orally administered) drugs may undergo significant metabolism
prior to entering the systemic circulation.
o This is called 1st pass metabolism.
First pass metabolism can occur via:
o 1. Hepatocytes in the liver
o 2. Intestinal enterocytes
o 3. Stomach
o 4. Intestinal bacteria
The result of 1st pass metabolism is a decrease amount of parent
drug that enters systemic circulation.
Example: Oral administration of alcohol
o Stomach = first site
Alcohol dehydrogenase metabolizes alcohol
o Moves into the intestines
CYP enzymes metabolize into metabolites
o Moves into the liver
CYP enzymes + many others
o The amount of metabolism on the first pass through the liver
can greatly determine a drugs bioavailability.
o Drugs are characterized as having high or low extraction ratio
Depending on how much metabolism occurs on the first
pass through the liver.
Almost none of the drug will reach the systemic
circulation and act in our body if extensively
metabolized in the liver
o High ER Drugs
Have low oral bioavailability (1‐ 20%)
PO doses are usually much higher than IV doses
To compensate for high first pass metabolism
Small changes in hepatic enzyme activity produce large
changes in bioavailability. Very susceptible to drug‐drug interactions
Will be extensively metabolized in its first pass through
o Low ER Drugs
Have high oral bioavailability ( > 80%)
PO doses are usually similar to IV doses.
Small changes in hepatic enzyme activity have little
effect on bioavailability.
Not very susceptible to drug‐drug interactions.
Take many passes through the liver via the systemic
circulation before they are completely metabolized.
Will be minimally metabolized in its first pass through
TYPES OF DRUG METABOLISM
Drug metabolism is broadly divided into 2 phases:
o Phase I metabolism
Convert lipophilic drugs to more polar molecules by
introducing or unmasking polar functional groups such
as hydroxyl (‐OH) or amine (‐NH2).
Making a drug more hydrophilic/water soluble in
order to facilitate excretion
Involves oxidation, reduction and hydrolysis reactions.
Mediated by cytochrome P450 enzymes, esterases and
Metabolites formed can be more active, less active or
equally active as the parent drug.
o Phase II Metabolism
Increase the polarity of lipophilic drugs by conjugation
reactions (addition of large water soluble molecule to
drug). Making a drug more hydrophilic/water soluble n
order to facilitate excretion
Conjugates include glucuronic acid (a sugar), sulfate (‐
SO4), acetate or amino acids (i.e. glycine).
Metabolites are less active than the parent drug.
Exception: Morphine 6‐glucuronide (metabolite) is
a more potent analgesic (pain reliever) than
o Intracellular Site of Drug Metabolizing Enzymes
Phase I – enzymes are localized to the smooth
Phase II –enzymes are localized predominantly in the
cytosol of the cell
Exception of glucuronidation which is localized to
the smooth endoplasmic reticulum.
CYTOCHROME P‐450 DRUG METABOLIZING ENZYMES
CYPs are a large family of drug metabolizing enzymes.
CYPs are the predominant phase I drug metabolizing enzyme
The majority drug metabolism in the body is performed by hepatic
CYPs oxidize drugs by inserting one atom of oxygen into the drug
molecule producing water as a by product.
o Drug + O2 + NADPH + H+ → Drug (oxidized) + H20 +
There are 12 families of CYPs with 3 accounting for the majority of
Malnutrition can decrease CYP activity as these enzymes require
dietary protein, iron, folic acid and zinc for full activity.
o Example: CYP3A4 where 3 = family, A = subfamily and 4 =
CYP3A4 metabolizes the largest fraction of currently marketed
drugs. PHASE II DRUG METABOLIZING ENZYMES
1. UDP‐glucoronosyltransferases (UGTs)
o Are localized in the smooth endoplasmic reticulum
o Catalyze the transfer of a glucuronic acid (sugar) to a drug.
o Glucuronidated drugs are more polar and therefore more
o There are 19 human UGT enzymes.
o Drug + UDP‐glucuronic acid → drug‐glucuronide + UDP
2. Sulfotransferases (SULTs)
o Are cytosolic phase II drug metabolizing enzymes.
o Catalyze the transfer of a sulfate group to a hydroxyl group of
o Sulfated drugs are more polar and therefore more easily
o There are 11 human SULT enzymes.
o Drug + sulfate → drug‐sulfate
3. Glutathione S Transfreases (GSTs)
o May be cytosolic or microsomal.
o Catalyze the transfer of a glutathione molecule to a drug.
Glutathione (GSH) is an intracellular anti‐oxidant.
Transfer of a glutathione molecule onto a reactive (i.e.
toxic) drug renders the metabolite less toxic.
o There are over 20 human GST enzymes.
o Reactive Drug + GSH → drug‐GSH
4. N‐acteyltransferases (NATs)
o Are cytosolic metabolizing enzymes.
o Catalyze the transfer of an acetyl group from acetyl CoA to a
o Subject to genetic polymorphisms which is a major cause in
variability to drug response.
o There are 2 human NAT enzymes: NAT 1 and NAT2.
o Drug + Acetyl CoA → Acetylated Drug + CoA 5. Thiopurine Methytransferase (TPMT)
o Are cytosolic metabolizing enzymes.
o Catalyze the transfer of a methyl group from S‐
adenosylmethionine to a drug.
o Subject to genetic polymorphisms.
Although rare, these polymorphisms have dramatic
effect on drug safety.
o Drug + S‐adenosylmethionine → Drug‐CH3 + Methionine
The fraction of drugs metabolized by phase II enzymes is relatively
equally split between UGTs, SULTs, GSTs and NATs.
FACTORS AFFECTING DRUG METABOLISM
o The expression and activity of drug metabolizing enzymes
changes as we age.
For example, infants have almost no CYP activity. It
takes babies approximately 1 year after birth until they
have a reasonable level of drug metabolizing enzymes.
By age 2, babies have the same amount of drug
metabolizing enzymes as adults do.
2. Drug interactions (enzyme inducers and enzyme inhibitors).
o Enzyme Induction
Induction is a process where a cell synthesizes an
enzyme in response to a drug or other chemical.
Certain CYP isozymes are susceptible to induction by
The consequence of CYP induction is increased
Enzyme induction plays an important role in drug
Consequences of increased drug metabolism may
1. Decreased plasma drug concentration. 2. Decreased drug activity (if metabolite is
3. Increased drug activity (if metabol