Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. Carl Rosow
Carl Rosow, M.D., Ph.D. 1 HST-151
Lecture 1 - Principles of Pharmacology: Introduction
A drug is a chemical agent which can affect living processes. For purposes of this course
we will mainly be talking about small molecules which affect cellular processes. Most of
these are Xenobiotics (Gr. xenos - stranger) chemicals that are not synthesized by the
body, but introduced into it from outside. There is inevitably a certain amount of
ambiguity in this definition: Is oxygen or water a drug? How about Vitamin C in a glass
of orange juice? How about an injection of Vitamin C to treat scurvy?
Pharmacology (Gr. pharmakon - a drug or poison, logos - word or discourse) is the
science dealing with actions of drugs on the body (pharmacodynamics) and the fate of
drugs in the body (pharmacokinetics). It overlaps with pharmacy, the science of
preparation of drugs; much of it deals with therapeutics, the treatment of disease (by
whatever means). Toxicology is the branch of pharmacology dealing with the
"undesirable" effects of drugs on biological processes (in the case of a nerve gas the bad
effect may be a desired one).
In order for a drug to work, it must enter the body and somehow be distributed in such a
way that it gets to its site of action. In most cases the site of action is a macromolecular
"receptor" located in the target tissue. Most drug effects are temporary, because the body
has systems for drug detoxification and elimination. We will consider these issues
broadly for now and go into more depth in individual lectures. As you read, refer to the
figure below:
DRUG RECEPTORS TISSUE RESERVOIRS
Effect Bound Unbound Unbound Bound
Muscle
Lung Absorption Unbound Drug Bound Drug
Skin
BLOOD Excretion
Metabolites Effect?
GI
Tract
Enterohepatic Biotransformation
Cycle
Excretion
, Carl Rosow, M.D., Ph.D. 2 HST-151
Overview of Pharmacokinetics - "What the body does to the drug"
1. The drug may enter the body in a variety of ways: as an oral liquid, pill, or capsule;
as an inhaled vapor or aerosol; absorbed through intact skin or a mucous membrane;
injected into muscle, subcutaneous tissue, spinal fluid, or directly into the
bloodstream. As we shall see, the physical properties of the drug and the specific
way it is prepared greatly influence the speed of absorption.
2. If the drug is given orally and swallowed, it must be absorbed from the GI tract into
the portal circulation. If it is absorbed from the skin, mouth, lungs or muscle it will
go directly into the systemic circulation. If drug is injected directly into the
bloodstream (e.g., intravenous injection), 100% of it is available for distribution to
tissues. This is not usually the case for other modes of administration. For example,
drug which is absorbed via the portal circulation must first pass through the liver
which is the primary site of drug metabolism (biotransformation). Some of the drug
may therefore be metabolized before it ever reaches the systemic blood. In this case,
"first-pass" metabolism reduces the bioavailability to less than 100%.
3. Once the drug is in the bloodstream a portion of it may exist as free drug, dissolved in
plasma water. Some drug will be reversibly taken up by red cells and some will be
reversibly bound to plasma proteins. For many drugs, the bound forms can account
for 95-98% of the total. This is important because it is the free drug which traverses
cell membranes and produces the effect. It is also important because protein-bound
drug can act as a reservoir which releases drug slowly and thus prolongs its action.
4. The unbound drug may then follow its concentration gradient and distribute into
peripheral tissues. In some cases, the tissue contains the target site and in others the
tissue is not affected by the drug. Sites of non-specific binding act as further
reservoirs for the drug. This total volume of distribution determines the equilibrium
concentration of drug after a specified dose.
5. Tissue-bound drug eventually reenters the bloodstream where it perfuses the liver and
kidneys. The liver metabolizes most drugs into inactive or less active compounds
which are more readily excreted. These metabolites and some of the parent
compound may be excreted in the bile and eventually may pass out of the body in the
feces. Alternatively, some of the drug may be reabsorbed again, farther down the GI
tract (the so-called enterohepatic cycle). Any biotransformed drug which is not
excreted in bile passes back into the systemic circulation.
6. Parent drug and metabolites in the bloodstream may then be excreted: most are
filtered by the kidney, where a portion undergoes reabsorption, and the remainder is
excreted in the urine. Some drugs are actively secreted into the renal tubule. Another
route of excretion is the lung: Drugs like alcohol and the anesthetic gases are
eliminated by this route. Smaller amounts of drug are eliminated in the sweat, tears
and breast milk.
HST.151: Principles of Pharmocology
Instructor: Dr. Carl Rosow
Carl Rosow, M.D., Ph.D. 1 HST-151
Lecture 1 - Principles of Pharmacology: Introduction
A drug is a chemical agent which can affect living processes. For purposes of this course
we will mainly be talking about small molecules which affect cellular processes. Most of
these are Xenobiotics (Gr. xenos - stranger) chemicals that are not synthesized by the
body, but introduced into it from outside. There is inevitably a certain amount of
ambiguity in this definition: Is oxygen or water a drug? How about Vitamin C in a glass
of orange juice? How about an injection of Vitamin C to treat scurvy?
Pharmacology (Gr. pharmakon - a drug or poison, logos - word or discourse) is the
science dealing with actions of drugs on the body (pharmacodynamics) and the fate of
drugs in the body (pharmacokinetics). It overlaps with pharmacy, the science of
preparation of drugs; much of it deals with therapeutics, the treatment of disease (by
whatever means). Toxicology is the branch of pharmacology dealing with the
"undesirable" effects of drugs on biological processes (in the case of a nerve gas the bad
effect may be a desired one).
In order for a drug to work, it must enter the body and somehow be distributed in such a
way that it gets to its site of action. In most cases the site of action is a macromolecular
"receptor" located in the target tissue. Most drug effects are temporary, because the body
has systems for drug detoxification and elimination. We will consider these issues
broadly for now and go into more depth in individual lectures. As you read, refer to the
figure below:
DRUG RECEPTORS TISSUE RESERVOIRS
Effect Bound Unbound Unbound Bound
Muscle
Lung Absorption Unbound Drug Bound Drug
Skin
BLOOD Excretion
Metabolites Effect?
GI
Tract
Enterohepatic Biotransformation
Cycle
Excretion
, Carl Rosow, M.D., Ph.D. 2 HST-151
Overview of Pharmacokinetics - "What the body does to the drug"
1. The drug may enter the body in a variety of ways: as an oral liquid, pill, or capsule;
as an inhaled vapor or aerosol; absorbed through intact skin or a mucous membrane;
injected into muscle, subcutaneous tissue, spinal fluid, or directly into the
bloodstream. As we shall see, the physical properties of the drug and the specific
way it is prepared greatly influence the speed of absorption.
2. If the drug is given orally and swallowed, it must be absorbed from the GI tract into
the portal circulation. If it is absorbed from the skin, mouth, lungs or muscle it will
go directly into the systemic circulation. If drug is injected directly into the
bloodstream (e.g., intravenous injection), 100% of it is available for distribution to
tissues. This is not usually the case for other modes of administration. For example,
drug which is absorbed via the portal circulation must first pass through the liver
which is the primary site of drug metabolism (biotransformation). Some of the drug
may therefore be metabolized before it ever reaches the systemic blood. In this case,
"first-pass" metabolism reduces the bioavailability to less than 100%.
3. Once the drug is in the bloodstream a portion of it may exist as free drug, dissolved in
plasma water. Some drug will be reversibly taken up by red cells and some will be
reversibly bound to plasma proteins. For many drugs, the bound forms can account
for 95-98% of the total. This is important because it is the free drug which traverses
cell membranes and produces the effect. It is also important because protein-bound
drug can act as a reservoir which releases drug slowly and thus prolongs its action.
4. The unbound drug may then follow its concentration gradient and distribute into
peripheral tissues. In some cases, the tissue contains the target site and in others the
tissue is not affected by the drug. Sites of non-specific binding act as further
reservoirs for the drug. This total volume of distribution determines the equilibrium
concentration of drug after a specified dose.
5. Tissue-bound drug eventually reenters the bloodstream where it perfuses the liver and
kidneys. The liver metabolizes most drugs into inactive or less active compounds
which are more readily excreted. These metabolites and some of the parent
compound may be excreted in the bile and eventually may pass out of the body in the
feces. Alternatively, some of the drug may be reabsorbed again, farther down the GI
tract (the so-called enterohepatic cycle). Any biotransformed drug which is not
excreted in bile passes back into the systemic circulation.
6. Parent drug and metabolites in the bloodstream may then be excreted: most are
filtered by the kidney, where a portion undergoes reabsorption, and the remainder is
excreted in the urine. Some drugs are actively secreted into the renal tubule. Another
route of excretion is the lung: Drugs like alcohol and the anesthetic gases are
eliminated by this route. Smaller amounts of drug are eliminated in the sweat, tears
and breast milk.
