Download As we know, there are two main areas of pharmacology, they are

As we know, there are two main areas of pharmacology, they are pharmacodynamics and
pharmacokinetics.
The actions of drug on body are termed pharmacodynamics.
The actions of the body on drug are called pharmacokinetics.
When a drug enters the body, the body begins immediately to work on the drug: absorption,
distribution, metabolism (biotransformation), and elimination. These are the processes of
pharmacokinetics.
ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution,
metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an
organism. The four criteria all influence the drug levels and kinetics of drug exposure to the
tissues and hence influence the performance and pharmacological activity of the compound as a
drug.
The absorption, distribution, metabolism, and excretion of a drug all involve its passage across
cell membranes. What’s cell membrane? How is the membrane structured? Let’s recall something
you have learned in physiology.
How did you talk about the plasma membrane in physiology? The fluid mosaic model? Or the
lipid bilayer with embedded proteins? As you see from this picture, the plasma membrane consists
of a bilayer of amphipathic lipids. The hydrophilic head, or we say the polar heads oriented
outward, and the hydrocarbon chains or we say the nonpolar tails oriented inward to form a
continuous sheet. Membrane proteins embedded in the bilayer serve as receptors, ion channels, or
transporters and provide selective targets for drug actions.
I think these are something you have learned in physiology. But the structure is beside the point.
It’s not our point. Our point is how does the drug cross the membrane.
As you have known in physiology, there are three ways that substances come inside or go
outside the cell: passive (simple) diffusion, filtration, and specialized transport.
Or in simple terms, we say drugs cross membranes by passive diffusion or active transport. This
statement is somewhat simplified, but it provides a useful starting point.
First of all, let’s talk about passive diffusion.
Passive Membrane Transport
The vast majority of drugs gain access to their site of action by this method. This is the most
important mechanism for majority of drugs.
What would be the easiest substance of diffusing across the membrane? Due to the cell
membrane's hydrophobic nature, lipid bilayers are generally impermeable to ions and polar
molecules, but lipid soluble drugs can diffuse by dissolving in the lipoidal matrix of the membrane,
and the drug diffuses across the membrane in the direction of its concentration gradient.
What’s the concentration gradient? The difference of concentration between the two areas is
often termed as the concentration gradient. Simple diffusion is the movement of drug from a high
concentration to a lower concentration until the concentration of the drug is uniform throughout
and reaches equilibrium. Also, greater the difference in the concentration of the drug on the two
sides of the membrane, faster of its diffusion.
Weak Electrolytes and Influence of pH
Most drugs are weak acids or bases. Do you remember what’s a weak acid? We have known in
chemistry a strong acid (such as hydrochloric acid (HCl)) is an acid that ionizes completely, in
other words, one mole of a strong acid HA dissolves in water yielding one mole of H+ and one
mole of the conjugate base, A−. Essentially none of the non-ionized acid HA remains.
In contrast a weak acid is an acid that dissociates incompletely, that is, in aqueous solution a
significant amount of undissociated HA still remains. In other words, at equilibrium both the
nonionized and ionized species are present in solution. The nonionized molecules usually are more
lipid-soluble, so according to what we have learned we know that the nonionized molecules can
diffuse readily across the cell membrane. In contrast, the ionized molecules usually are unable to
penetrate the lipid membrane because of their low lipid solubility.
So remember that a drug tends to pass through membranes if it is nonionized or we say it is
uncharged.
But herein lies another problem. The ratio of nonionized to ionized molecules is different at
each pH, and the ratio is pH dependent. The ratio of non-ionized to ionized drug at each pH is
readily calculated from the Henderson-Hasselbalch equation: but we can understand this ratio in
another simple way.
Let’s look at that figure. This figure presents the relationship between the pH and the degree of
ionization of a weak acid. As you can see, for a weak acid, when the pH is lower than the pKa, the
nonionized form predominates. When the pH is higher than the pKa, the ionized form
predominates.
Remember the pKa? That is the equilibrium constant (of course, the p means we’ve taken the
negative logarithm of the equilibrium constant). The pKa is the pH at which half (50%) the drug
(weak acid or base electrolyte) is in its ionized form. In other words, when the pH is equal to the
pKa，the preceding equation (HA=H++A-)is balanced. There are equal amounts of weak acid in the
ionized and nonionized forms.
If we decrease the pH by adding more H+, we will drive the equilibrium for the weak acid more
to the left, which is the nonionized (uncharged) form. If we take away H+ making the pH higher,
we will drive the equilibrium toward the right. This increases the concentration of the ionized
form of the weak acid.
OK, what about weak bases? Weak bases are the opposite of weak acids. Let’s look at the graph.
In this graph, the effects of pH on the degree of ionization of both a weak acid and a weak base are
presented. As you can see, in contrast to weak acid, for a weak base, when the pH is lower than the
pKa, the ionized form predominates. When the pH is higher than the pKa, the nonionized form
predominates.
Now I'm sure you will say it seems that I understand, but it seems difficult to remember. If you
have trouble remembering when weak acid become charged or uncharged after changing the pH,
let’s think of it in a easy way. I will give you a key, that is, acid meets acid, or base meets base,
noncharged; acid meets base, or base meets acid, charged. Let me explain, acid meets acid, that is,
weak acid is in a acid environment,
That is a definition or a phenomenon termed ion trapping: at steady state, an acidic drug will
accumulate on the more basic side of the membrane and a basic drug on the more acidic side.
Let’s explain this phenomenon. For example, this is a bilayer membrane, as we have talked
before, only nonionized form (lipid soluble form) can cross the membrane, but ionized form can
not. On the left side of the membrane, the pH is 5, and on the right side, the pH is 7. A weak acid,
pKa is 6. On which side the concentration of the weak acid increase? Yes, the right side. Let’s
explain it.
Once a non-charged molecule of a weak acid crosses the cell membrane to enter the right side,
it becomes charged because of the higher pH inside the right side, and thus becomes unable to
cross back. Because transmembrane equilibrium must be maintained, another unionized molecule
must diffuse into the right side to repeat the process. Thus its concentration on the right side
increases many times that of the left side. The non-charged molecules of the drug remain in equal
concentration on either side of the cell membrane.
To test your understanding of this, try out these questions.
1. In the stomach (pH 2.0)，which will be better absorbed, a weak acid (pK 6.8) or a weak base
(pK 7.1)?
The answer is a weak acid will be better absorbed in the stomach. In the stomach (pH 2.0),
weak acids are uncharged and will be absorbed into the bloodstream, whereas weak bases are
charged and will remain in the GI tract.
Ok, that is the main idea about the passive diffusion. Remember that only lipid soluble drugs
can cross membrane by passive diffusion. What about the water soluble drugs? How can they
cross the membrane? And then, we will talk about another transmembrane way: filtration.
Filtration
Filtration is passage of drugs through aqueous pores in the membrane or through paracellular
spaces.
Firstly, let’s talk about the passage of drugs through aqueous pores. Water is special, as you
know, water is a polar molecule, but its molecular weight is so small that water can cross cell
membranes through aqueous pores. And bulk flow of water can carry with it drug molecules.
Whether a drug can cross the pores or not, it depends on the size of the membrane pores, only
drugs of a certain size may pass through it. Lipid-insoluble drugs cross the membranes by
filtration if their molecular size is smaller than the diameter of the pores.
Majority of cells(intestinal mucosa, RBC, etc.) have very small pores (4 A) and drug with MW
exceeds 100 to 200 daltons are not able to penetrate.
However, capillaries (except those in brain) have large paracellular space (40 A) and most drug
(even albumin) can filter through these. Hereon, I mentioned the paracellular transport.
Paracellular transport refers to passing through the intercellular space between the cells. It is in
contrast to transcellular transport, where the substances travel through the cell.
Although capillaries usually have large paracellular space, drug molecules with protein bound
are too large and polar for paracellular transport to occur; thus, paracellular movement generally is
limited to unbound drug. As described later，this type of transport is an important factor in
filtration across glomerular membranes in the kidney.
However, there is an important exception to this type of transport in specific tissues, such as
capillaries of the central nervous system (CNS). The capillary endothelial cells in brain have tight
junctions and lack large intercellular pores, so paracellular transport in them is limited. This is
so-called blood-barrier, and we will discuss it later in distribution.
Ok, let's pass on to the next topic, carrier-mediated membrane transport.
Carrier-Mediated Membrane Transport
While passive diffusion through the bilayer is dominant in the disposition of most drugs,
carrier- mediated mechanisms also play an important role. As you know in physiology, all cell
membranes express a host of transmembrane proteins in which serve as carriers or transporters for
physiologically important ions, nutrients, metabolites and of course, including drugs and their
metabolites. Let us recall something about carrier-mediated transport in physiology. Carrier
transport is specific for the drug, it’s saturable, and it’s competitively inhibited by analogues which
utilize the same transporters.
Depending on requirement of energy, carrier transport is of two types: active transport and
facilitated diffusion.
Let’s talk about active transport firstly. Active transport requires energy, and this is its most
distinguishing characteristic. Active transport is the movement of a substance across a cell
membrane against its concentration gradient (from low to high concentration). In all cells, this is
usually concerned with accumulating high concentrations of molecules that the cell needs, such as
ions, glucose and amino acids. The action of the sodium-potassium pump is an example of active
transport, you’ll discuss it in 24 chapter, in drugs used heart failure.
As to facilitated diffusion, it is a process of passive transport without needing energy. In
facilitated diffusion, the solutes move down the concentration gradient and are aided by specific
transmembrane integral proteins. What types of substance use facilitated diffusion? Polar
molecules and charged ions.
Polar molecules and charged ions are dissolved in water but they cannot diffuse freely across
the plasma membrane due to the fact that they are polar and charged. We have talked that only
lipid or nonpolar, noncharged molecular can diffuse freely. Polar molecules are transported across
membranes by proteins that form transmembrane channels. These channels are gated so they can
open and close, thus regulating the flow of ions or small polar molecules. Larger molecules, such
as glucose or amino acids, are transported by transmembrane carrier proteins, such as permeases
that change their conformation as the molecules are carried through.
For a compound to reach a tissue, it usually must be taken into the bloodstream - often via
mucous surfaces like the digestive tract (intestinal absorption) - before being taken up by the target
cells.
DRUG ABSORPTION, BIOAVAILABILITY； AND ROUTES OF ADMINISTRATION
Absorption is movement of the drug from its site of administration into the circulation.
Absorption is a primary focus in drug development and medicinal chemistry, since the drug
must be absorbed before any medicinal effects can take place and not only the extent (fraction) of
absorption but also the rate of absorption is important. The fraction of absorption and the rate of
absorption is bioavailability, and we will discuss it later.
In pharmacology (and more specifically pharmacokinetics), absorption is the movement of a
drug into the bloodstream. In this case, it is considered that intravascular administration (e.g. IV)
does not involve absorption, and there is no loss of drug. So, which route is the fastest route of
absorption? intravascular administration? No, remember that there is no absorption involved in
intravascular administration. That is inhalation, and not as mistakenly considered the intravenous
administration.
Absorption involves several phases. First, the drug needs to be introduced via some route of
administration (oral, topical-dermal, etc.) and in a specific dosage form such as a tablet, capsule,
solution and so on.
Firstly, let’s talk about the effect of dosage form on absorption. For example, for solid dosage
forms, absorption first requires dissolution of the tablet or capsule, thus liberating the drug. The
extent of dissolution and liberating will be involved in absorption including bioavailability.
Secondly, let’s talk about the effect of different route of administration on absorption.
Let’s look ar a clinical sketch
A man with angina has not understood instruction on the use of glyceryl trinitrate tablets. He
swallows them instead of putting them under his tongue. There is no therapeutic benefit.
You may ask swallowing glyceryl trinitrate tablets and putting them under his tongue, what is
the distinction between them?
This involves a phenomena: first-pass metabolism, or also known as first-pass effect, first-pass
elimination. If swallowed, this drug is subject to extensive first-pass metabolism.
First-pass metabolism refers to metabolism of a drug during its passage from the site of
absorption into the systemic circulation..
For example, a drug, when swallowed, will be absorbed first from the stomach and intestine,
and then be carried through the portal vein into the liver before the drug enters the systemic
circulation. Metabolism takes place in two areas: the stomach and intestine, where initial
metabolism through digestion may occur, and the liver, where metabolism and biliary excretion
may occur. The liver metabolizes many drugs, sometimes to such an extent that only a small
amount of active drug emerges from the liver to the rest of the circulatory system. This first pass
through the liver thus greatly reduces the bioavailability of the drug.
All drugs must enter through the liver before entering through the circulation system, and so
most of the time first-pass metabolism occurs in the liver. The liver is usually assumed to be the
major site of first-pass metabolism after a drug administered orally. But the intestine can also
serve as a site for first-pass metabolism, and there are other potential sites: the gastrointestinal
tract, blood, vascular endothelium, lungs, and the arm from which venous samples are taken.
So, in a word, first-pass elimination takes place when a drug is metabolised between its site of
administration and the circulation system. (metabolism of a drug before it reaches systemic
circulation)
What should we do for those drugs with high susceptible to first pass metabolism?
More commonly, when a pharmaceutical company has a drug highly susceptible to first pass
metabolism, they will often try to find other means of administering the drug which can bypass the
digestive system and the liver altogether. Most of these processes involve trying to send the drug
directly into the blood stream. By doing this, the drug avoids liver metabolism and arrives in the
blood stream directly. One example is sublingual administration. Sublingual, meaning "under
the tongue" in Latin, is where a drug is taken in the mouth but not swallow. Instead, it is placed
under the tongue where it is absorbed by the thin tissues covering the many blood vessels under
the tongue and sent into the blood stream. Inhalants are another common form of pharmaceutical
administration that bypasses first pass metabolism.
So, you can see: different routes of administration have different routes of absorption, and then
have different effects on a drug’s bioavailability. Therefore, we will talk about the advantages and
disadvantages of the different routes of administration.
Oral (Enteral) versus Parenteral Administration
Oral ingestion is the most common method of drug administration. I think, maybe, most of us or
all of us have taken medicine orally. It also is the safest, most convenient, and most economical.
Disadvantages to the oral route include limited absorption of some drugs because of first pass
metabolism, as we have discussed before, and emesis as a result of irritation to the GI mucosa. In
addition, when in emergency or when a patient is unconscious, uncooperative, or unable to retain
anything given by mouth，in such a case, oral administration is not appropriate. In such a case,
parenteral therapy may be a necessity. The injection of drugs has its advantages: it is more rapid,
predictable and more accurately. However, the injection of drugs has its disadvantages: Asepsis
must be maintained, and this is of particular concern when drugs are given in intravenous; pain
may accompany the injection; and it is sometimes difficult for patients to perform the injections
themselves if self-medication is necessary.
Oral Ingestion
Since most drug absorption from the GI tract occurs by passive diffusion, absorption is favored
when the drug is in the nonionized and more lipophilic form. Therefore, based on the pH-partition
concept, we would predict that drugs that are weak acids would be better absorbed from the
stomach, as we have discussed before. However, actually, no matter acid or basis drug, both of
them are better absorbed from the intestine. There are many factors involved in oral ingestion
beside pH: such as surface area for absorption, blood flow to the site of absorption(for example, in
severe hypotension, blood flow to muscle may be low and intramuscular drugs may be absorbed
slowly), the physical state of the drug (solution, suspension, or solid dosage form), its water
solubility, and the drug’s concentration at the site of absorption. For example, the surface area
influences the degree of absorption. The greater the surface area, the more absorption takes place.
Therefore, the surface area of the stomach is small and its epithelium is lined with a thick mucous
layer; by contrast, absorption surface area is much larger in the small intestine due to the
villi(approximately 200m2, but the absorption surface area in the stomach is 1 m2 ). The small
intestine has the largest surface area for drug absorption in the GI tract, and its membranes are
more permeable than those in the stomach.For these reasons, most drugs are absorbed primarily in
the small intestine, and acids, despite they is predominantly ionized in the intestine and largely
nonionized in the stomach, are absorbed faster in the intestine than in the stomach.
Because most absorption occurs in the small intestine, gastric emptying is often the rate-limiting
step. Food, especially fatty food, slows gastric emptying (and rate of drug absorption), explaining
why taking some drugs on an empty stomach speeds absorption. Drugs that affect gastric
emptying (eg, parasympatholytic drugs) affect the absorption rate of other drugs.
To maximize adherence, clinicians should prescribe oral suspensions and chewable tablets for
children < 8 yr. In adolescents and adults, most drugs are given orally as tablets or capsules
primarily for convenience, economy, stability, and patient acceptance.
Drugs that are destroyed by gastric secretions or that cause gastric irritation sometimes are
administered in dosage forms with enteric coating that prevents dissolution in the acidic gastric
contents.
Because solid drug forms must dissolve before absorption can occur, dissolution rate determines
availability of the drug for absorption. Dissolution, if slower than absorption, becomes the
rate-limiting step. Manipulating the formulation (ie, the drug's form as salt, crystal, or hydrate) can
change the dissolution rate and thus control overall absorption. This is the basis for
controlled-release ， extended-release, sustained-release, and prolonged-action pharmaceutical
preparations. And now, we will talk about Controlled-Release Preparations.
Controlled-Release Preparations
Controlled-release forms are designed to reduce dosing frequency for drugs with a short
elimination half-life and duration of effect. Potential advantages of such preparations are reduction
in the frequency of administration of the drug as compared with conventional dosage forms, which
possibly improves the patient’s acceptance. These forms offer maintenance of a therapeutic effect
overnight, also limit fluctuation in plasma drug concentration, providing a more uniform
therapeutic effect while minimizing adverse effects.
However, such products have some drawbacks: interpatient variability, trough drug
concentrations and so-called “dose dumping” if dosage form fails. Because the total dose of
controlled-release preparations at one time may be several times than the amount contained in the
conventional preparation. So, if dosage form fails and a lot of drugs were released, toxicity can
occur. Therefore, when you prescribe a controlled-release preparations drug for a patient, you
should notice him that he can not break the drug, the drug should be swallowed as a whole, not
broken into pieces. Absorption rate in Controlled-Release Preparations is slowed by coating drug
particles with wax or other water-insoluble material, by embedding the drug in a matrix that
releases it slowly during transit through the GI tract, or by complexing the drug with ion-exchange
resins. Crushing or otherwise disturbing a controlled-release tablet or capsule can often be
dangerous.
As we have discussed before, one of the disadvantages of oral ingestion is first pass metabolism.
Sometimes, a drug’s first pass metabolism is so severe that a drug almost can not be absorbed.
Let’s look at a clinical sketch.
A man with angina has not understood instruction on the use of glyceryl trinitrate tablets. He
swallows them instead of putting them under his tongue. There is no therapeutic benefit. Comment:
this drug is subject to extensive first-pass metabolism.
In this case, what should we do? For the drug that is susceptible to first pass metabolism in the
mouth, it can be given in a different fashion, for example, Sublingual Administration.
Sublingual Administration
Sublingual, meaning "under the tongue" in Latin, is where a drug is taken in the mouth but not
swallow. Instead, it is placed under the tongue where it is absorbed by the thin tissues covering the
many blood vessels under the tongue and sent into the blood stream. Venous drainage from the
mouth is to the superior vena cava, which protects the drug from rapid hepatic first-pass
metabolism. Just like nitroglycerin in that clinical sketch. If tablet of nitroglycerin were swallowed,
over 90% of them will be eliminated by first-pass metabolism. But if nitroglycerin were put under
the tongue, 80% of them will be absorbed and it will be effective for angina.
Another route of administration that can bypass first pass metabolism to some extent is Rectal
Administration.
Rectal Administration
The rectal route of administration (ROA) is a way of administering drugs into the rectum to be
absorbed by the rectum's blood vessels and into the body's circulatory system.
Approximately 50% of the drug that is absorbed from the rectum will bypass the first-pass
metabolism. This means the drug will reach the circulatory system with significantly less
alteration and in greater concentrations than in oral ingestion. The rectal administration often is
useful when oral ingestion is precluded because the patient is unconscious or uncooperative
particularly relevant to young children.
Another advantage of administering a drug rectally is that it tends to produce less nausea
compared to the oral route and also prevents any amount of the drug from being lost due to emesis
(vomiting, "throwing up", or "puking") since the drug is in the rectum, not the stomach, and the
contents of the rectum are not lost when there is emesis.
However, rectal absorption often is irregular and incomplete, and many drugs can cause
irritation of the rectal mucosa.
Enteral routes are generally the most convenient for the patient, as no punctures or sterile
procedures are necessary. Enteral medications are therefore often preferred in the treatment of
chronic disease. However, some drugs can not be used enterally because their absorption in the
digestive tract is low or unpredictable. when a pharmaceutical company has a drug highly
susceptible to first pass metabolism, they will often try to send the drug directly into the blood
stream. That is Parenteral Injection.
Parenteral Injection.
The major routes of parenteral administration are intravenous, subcutaneous, and intramuscular.
Intravenous
The word intravenous simply means "within a vein". Intravenous injection sends the medication
directly to the blood stream through the veins, which will carry it to the heart and allow it to be
pumped then throughout the body.
There are both advantages and disadvantages to the use of this route of administration.
Advantages of intravenous include: bioavailability of this method is complete and rapid (100%
bioavailability). Also, drug delivery is controlled and achieved with an accuracy and immediacy,
and this is not possible by any other procedure. In acute situations, in emergency medicine and
intensive care medicine, drugs are most often given intravenously. This is the most reliable route.
IV can deliver continuous medication, e.g., morphine for patients in continuous pain, or saline drip
for people needing fluids.
However, it is the most dangerous route of administration because it bypasses most of the
body's natural defenses, and any break in the skin carries a risk of infection, although IV insertion
is an aseptic procedure. If needles are shared, there is risk of HIV and other infectious diseases.
Need for strict asepsis. Another disadvantage is that unfavorable reactions can occur because high
concentrations of drug may be attained rapidly in both plasma and tissues. Therefore, slower
administration of drug is advisable and Intravenous administration of drugs warrants close
monitoring of the patient’s response.
. Furthermore, once the drug is injected, there is often no retreat. If not done properly,
potentially fatal air boluses (bubbles) can occur.
Intramuscular and Subcutaneous
Drugs given IV enter the systemic circulation directly. However, drugs injected IM or sc must
cross one or more biologic membranes to reach the systemic circulation. Absorption from
subcutaneous and intramuscular sites occurs by simple diffusion along the gradient from drug
depot to plasma. Lipid soluble drugs pass readily across the whole surface of the capillary.
Capillaries having large paracellular spaces do not obstruct absorption of even large lipid insoluble
molecules or ions. Very large molecules, such as proteins, movement across capillary membranes
is so slow that most absorption occurs via the lymphatic system.
Intramuscular
Intramuscular (or IM) injection is the injection of a substance directly into a muscle. It is used
for particular forms of medication that are administered in small amounts. Depending on the
chemical properties of the drug, the medication may either be absorbed fairly quickly or more
gradually. Absorption after IM or sc injection may be delayed or erratic for salts of poorly soluble
bases and acids
Let’s look at a clinical sketch, so that you can understand other factors involved in
intramuscular absorption.
A patient with extensive burns is given intramuscular opiate for the pain. His blood pressure is
very low. Adequate pain relief is not achieved for over half an hour.
Comment: in severe hypotension, blood flow to muscle may be low and intramuscular drugs
may be absorbed so slowly that the concentration of opiate is too low to effective.
The rate in Intramuscular is limited by blood flow to the site of absorption and by the
solubility of the substance in the interstitial fluid. Application of heat and muscular exercise
accelerate drug absorption by increasing blood flow, while vasoconstrictors, for example,
adrenaline injected with the drug (local anaesthetic) retard absorption.
Subcutaneous
Injection into the subcutaneous tissue is a route of administration used for drugs such as insulin.
Subcutaneous injection is believed to be the most effective manner to administer some drugs, such
as human growth hormones. Just as the subcutaneous tissue can store fat, it can also provide good
storage space for drugs that need to be released gradually because there is limited blood flow.
Absorption from s.c. site is slower than that from i.m. site, but both generally faster and more
consistent/predictable than oral absorption.
Topical Application.
The word topical is derived from the Ancient Greek topos (plural: topoi), meaning "place" or
"location". A topical effect, in the pharmacodynamic sense, may refer to a local, rather than
systemic, target for a medication. Topical medications may also be inhalational, such as asthma
medications, or applied to the surface of tissues other than the skin, such as eye drops applied to
the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of a tooth. As
a route of administration, topical medications are contrasted with enteral (in the digestive tract)
and parenteral administration (injected into the circulatory system). Topical effect, in the
pharmacodynamic sense, may refer to a local medication. However, many topically administered
drugs have systemic effects, such as skin, eye.
Skin(Transdermal absorption)
Although the skin is a large and logical target for drug delivery, not all drugs readily penetrate
the intact skin. Drugs for transdermal delivery must have suitable skin penetration characteristics
and high potency because the penetration rate and area of application are limited. There are only a
few drug preparations that are suitable for transdermal administration.
Absorption of those that do is dependent on the surface area over which they are applied and
their lipid solubility because the epidermis behaves as a lipid barrier.
Some hydrophobic chemicals, such as steroid hormones, can be absorbed into the body after
being applied to the skin in the form of a cream, gel or lotion. Transdermal patches have become a
popular means of administering some drugs for birth control, hormone replacement therapy, and
prevention of motion sickness. Sometimes, transdermal controlled-release forms are designed to
release the drug for extended periods, sometimes for several days.
Eye
Eye drops often mean a local medication. However, because drug is absorbed via nasolacrimal
canal, undesirable systemic absorption occurs. For example, when β adrenergic receptor
antagonists are administered for glaucoma, it may cause low blood pressure, reduced pulse rate,
fatigue, shortness of breath.
Such risk can be minimized by occluding the lacrimal punctum, (i.e. pressing on the inner
corner of the eye) for a short while after instilling drops.
Distribution of drugs
What’s distribution? Do you remember its definition? Distribution is defined as the reversible
transfer of a drug between one compartment to another. (from one location to another within the
body.)
Once a drug enters into systemic circulation by absorption or direct administration, it must be
distributed into interstitial and intracellular fluids. The drug is easily distributed in highly perfused
organs such as the liver, heart and kidney. It is distributed in small quantities through less perfused
tissues like muscle, fat and peripheral organs. The drug can be moved from the plasma to the
tissue until the equilibrium is established (for unbound drug present in plasma).
The lipid solubility, pH of compartment, extent of binding with plasma protein and tissue
proteins, cardiac output, regional blood flow and capillary permeability are factors in the
distribution of the drug through tissues. The more important determinant of blood- tissue
partitioning is the relative binding of drug to plasma proteins and tissue macromolecules.
Plasma Proteins.
A drug in blood exists in two forms: bound and unbound.
The proteins commonly involved in binding with drugs are albumin, lipoproteins, and
a1-acid-glycoprotein (AGP). Acidic and neutral compounds will tend to bond with albumin, which
is basic, while basic substances will primarily bind to the acidic AGP molecule. Acidic molecules
may also bond with lipoproteins if the albumin is saturated.
As the protein binding is usually reversible, then a chemical equilibrium will exist between the
bound and unbound states, such that:
Protein + drug ⇌ Protein-drug complex
If the concentration of the unbound drug is reduced (being metabolized and/or excreted from
the body), some of the protein-drug complex may split to release more of the compound in order
to maintain equilibrium. The bound portion may act as a reservoir or depot from which the drug is
slowly released as the unbound form.
The bound drug can not cross membrane, and be kept in the blood stream while the unbound
component may be metabolized or excreted, making it the active part. So, if a drug is 95% bound
to a binding protein and 5% is free, that means that 5% is active in the system and causing
pharmacological effects. It is also the fraction that may be metabolized and/or excreted.
The fraction unbound can be altered by a number of variables, such as the concentration of drug
in the body, the amount and quality of plasma protein, and other drugs that bind to plasma proteins.
Higher drug concentrations would lead to a higher fraction unbound, because the plasma protein
would be saturated with drug and any excess drug would be unbound. If the amount of plasma
protein is decreased (such as in catabolism, malnutrition, liver disease, renal disease), there would
also be a higher fraction unbound. Additionally, the quality of the plasma protein may affect how
many drug-binding sites there are on the protein.
Because binding of drugs to plasma proteins such as albumin is nonselective, and more than one
drug can bind to the same site, many drugs with similar physicochemical characteristics can
compete with each other and with endogenous substances for these binding sites, this can result in
noticeable displacement of one drug by another.
For example, assume that Drug A and Drug B are both protein-bound drugs. If Drug A is given,
it will bind to the plasma proteins in the blood. If Drug B is also given, it can displace Drug A
from the protein, thereby increasing Drug A's fraction unbound. This may increase the effects of
Drug A, since only the unbound fraction may exhibit activity.
Before Displacement
After Displacement
% increase in unbound fraction
Drug A
% bound
95
90
% unbound
5
10
+100
Drug B
% bound
50
45
% unbound
50
55
+10
Note that for Drug A, the % increase in unbound fraction is 100% – hence, Drug A's
pharmacologic effect has doubled. This change in pharmacologic effect could have adverse
consequences. This is not strictly true. Drug toxicities based on competition between drugs for
binding sites is not of clinical concern for most therapeutic agents, because the displaced drug will
diffuse into the tissue as well as get metabolized or excreted; the higher of the free drug
concentration is minimal, unless there is concurrent inhibition of metabolism and/or excretion.
This displacement effect of protein binding is most significant with drugs that are highly
protein-bound (>95%) and have a low therapeutic index, such as warfarin. A low therapeutic index
indicates that there is a high risk of toxicity when using the drug. Since warfarin is an
anticoagulant with a low therapeutic index, warfarin may cause bleeding if the correct degree of
pharmacologic effect is not maintained. If a patient on warfarin takes another drug that displaces
warfarin from plasma protein, such as indomethacin, it could result in an increased risk of
bleeding.
Tissue Binding.
Once absorbed, most drugs do not spread evenly throughout the body. Drugs that dissolve in
water (water-soluble drugs), such as the antihypertensive drug atenolol, tend to stay within the
blood and the fluid that surrounds cells (interstitial space). Drugs that dissolve in fat (fat-soluble
drugs), such as the antianxiety drug clorazepate, tend to concentrate in fatty tissues. Other drugs
concentrate mainly in only one small part of the body (for example, iodine concentrates mainly in
the thyroid gland), because the tissues there have a special attraction for (affinity) and ability to
retain the drug.
Some drugs accumulate in certain tissues (for example, digoxin accumulates in heart and
skeletal muscles), which can also act as reservoirs of extra drug. These tissues slowly release the
drug into the bloodstream, keeping blood levels of the drug from decreasing rapidly and thereby
prolonging the effect of the drug. Some drugs, such as those that accumulate in fatty tissues, leave
the tissues so slowly that they circulate in the bloodstream for days after a person has stopped
taking the drug.
Fat As a reservoir
Distribution of a drug may also vary from person to person. For instance, obese people may
store large amounts of fat-soluble drugs, whereas very thin people may store relatively little. Older
people, even when thin, may store large amounts of fat-soluble drugs because the proportion of
body fat increases with age.
Bone
Accumulation of some drugs in certain tissues can act as reservoirs of extra drug, however,
sometimes, this accumulation will harm to the reservoirs. For example, the tetracycline antibiotics
(and other divalent metal-ion chelating agents) and heavy metals may accumulate in bone and
tooth, and cause permanent staining of teeth and weak bones in the baby.
Redistribution.
Highly lipid soluble drugs given by intravenous or inhalation routes are initially distributed to
organs with high blood flow. Later, less vascular but more bulky tissues (such as muscle and fat)
take up the drug—plasma concentration falls and the drug is withdrawn from these sites. If the site
of action of the drug was in one of the highly perfused organs, redistribution results in termination
of the drug action. The greater the lipid solubility of the drug, the faster its redistribution.
A good example of this is the use of the intravenous anesthetic thiopental, a highly lipid-soluble
drug. Because blood flow to the brain is so high, the drug reaches its maximal concentration in
brain within a minute of its intravenous injection. After injection is concluded, the plasma
concentration falls as thiopental diffuses into other tissues, such as muscle. Thus, in this example,
the onset of anesthesia is rapid, but so is its termination.
Central Nervous System and Cerebrospinal Fluid.
The distribution of drugs into the CNS from the blood is unique.
More than 100 years ago it was discovered that if blue dye was injected into the bloodstream of
an animal, that tissues of the whole body EXCEPT the brain and spinal cord would turn blue. To
explain this, scientists thought that a "Blood-Brain-Barrier" (BBB) which prevents materials from
the blood from entering the brain existed. More recently, scientists have discovered much more
about the structure and function of the BBB.
In most parts of the body, the smallest blood vessels, called capillaries, are lined with
endothelial cells. Endothelial tissue has small spaces between each individual cell so substances
can move readily between the inside and the outside of the vessel. However, in the brain, the
endothelial cells fit tightly together (continuous tight junctions) and therefore, drug penetration
into the brain depends on transcellular rather than paracellular transport. (Some molecules, such as
glucose, are transported out of the blood by specific uptake transporters.) Glial cells (astrocytes)
form a layer around brain blood vessels and may be important in the development of the BBB.
General Properties of the BBB include: Large molecules do not pass through the BBB easily,
while allowing the diffusion of small hydrophobic molecules (O2, CO2); low lipid soluble
molecules do not penetrate into the brain. However, lipid soluble molecules, such as barbituate
drugs, rapidly cross through into the brain.
The blood-brain barrier (BBB) is a protective barrier which is designed to keep the environment
in the brain as stable as possible. The BBB has several important functions: Protects the brain
from "foreign substances" in the blood that may injure the brain; Protects the brain from hormones
and neurotransmitters in the rest of the body; Maintains a constant environment for the brain.
Of course, the blood-brain barrier also hinders some helpful things, making the administration
of some medications to treat brain and central nervous conditions rather challenging.
Let’s look at a clinical sketch:
A patient with meningitis is treated with gentamicin. The organism is very sensitive to the
antibiotic in vitro, but the patient shows no improvement.
Comments：This would be very unacceptable clinical practice and the patient may well die.
Gentamicin does not readily cross the blood-brain barrier.
The blood–brain barrier acts very effectively to protect the brain from many common bacterial
infections. Thus, infections of the brain are very rare. Infections of the brain that do occur are
often very serious and difficult to treat. Antibodies are too large to cross the blood–brain
barrier(such as Gentamicin here), and only certain antibiotics are able to pass. The blood–brain
barrier becomes more permeable during inflammation. Meningitis is an inflammation of the
membranes that surround the brain and spinal cord. When the meninges are inflamed, the
blood–brain barrier may be disrupted. This allows some antibiotics move across the BBB.
Depending on the causative pathogen, treatment with third-generation or fourth-generation
cephalosporin is usually prescribed.
Placental Transfer of Drugs.
Drugs administered to mothers have the potential to cross the placenta and reach the fetus.
So, the view that the placenta is an absolute barrier to drugs is, however, completely inaccurate.
The fetus is to some extent exposed to all drugs taken by the mother and drugs may cause
anomalies in the developing fetus.
METABOLISM OF DRUGS
Metabolism is an integral part of drug elimination. Metabolism is the enzymatic conversion of
one chemical compound into another.
When a polar (or ionized) water-soluble drug is absorbed in the body, it is largely excreted
unchanged by the kidneys. However, the majority of drugs are lipid-soluble to some extent.It is
easy for lipid-soluble drugs to pass through membranes and reach their target site, however, it is
difficult for them to be excreted in urine by the kidneys due to the fact that most lipid-soluble
drugs filtered through the glomerulus are largely reabsorbed into the systemic circulation during
passage though the renal tubules.
Such compounds must undergo extensive metabolism. Drug metabolism is often needed to
convert lipid-soluble chemical compounds into lipid-insoluble so that they are not reabsorbed in
the renal tubules and are excreted.
Overall, metabolic processes will convert the drug into a more water-soluble compound by
increasing its polarity. This is an essential step before the drug can be excreted in the body fluids
such as urine or bile. Only a few drugs can be excreted without being metabolized.
Biotransformation of drugs may lead to the following:
(1)
inactivation: most drugs and their metabolites are rendered inactive or less active, e.g.
lidocaine, propranolol and its active metabolite 4-hydroxypropranolol.
(2)
Active metabolite from an active drug: many drugs have been found to be partially
converted to one or more active metabolites, e.g. Codeine and its active metabolite
Morphine.
(3)
Activation of inactive drug: few drugs are inactive and need conversion in the body to
one or more active metabolites. Such a drug is called a prodrug. Such is the case with a
number of angiotensin-converting enzyme (ACE) inhibitors employed in the
management of high blood pressure. Enalapril, for instance, is relatively inactive until
converted by esterase activity to the diacid enalaprilat.
Most drugs are treated by the body like foreign substances, also known as xenobiotics. Drug
metabolism also known as xenobiotic metabolism (from the Greek xenos "stranger" and biotic
"related to living beings"), is the set of metabolic pathways that modify the chemical structure of
xenobiotics, such as drugs and poisons. Although metabolism is generally considered to be a
detoxification process, some of the metabolic products may also have pharmacological activity
and may be toxic.This can happen with some of the compounds in cigarette smoke.
Phase I and Phase II Metabolism
Metabolism is often divided into two phases of biochemical reaction: phase I functionalization
reactions or phase II biosynthetic (conjugation) reactions. Some drugs may undergo just phase I or
just phase II metabolism, but more often, the drug will undergo phase I and then phase II
sequentially.
Phase I Metabolism
Phase I reactions involve formation of a new or modified functional group or exposure a
functional group on the parent compound. Phase I reactions (also termed nonsynthetic reactions)
include oxidation, reduction, hydrolysis, cyclization, decyclization, and addition of oxygen or
removal of hydrogen. This reaction sometimes converts a pharmacologically inactive compound
(a prodrug) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic
molecule into a poisonous one (toxification).(e.g. paracetamol )
If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this
point. However, many phase I products are not eliminated rapidly and undergo a subsequent
reaction in which an endogenous substrate combines with the newly incorporated functional group
to form a highly polar conjugate.
Phase II Metabolism
Phase II metabolism involves conjugation - that is, the attachment of a large charged group to
the drug. The attachment of a charged group makes the metabolite more water soluble and thus
more easily excreted by the kidney. Phase II reactions involve conjugation with an endogenous
substance, such as glucuronic acid, sulfuric acid, acetic acid, an amino acid or glutathione. The
conjugating enzyme exist in many isoforms and show relative substrate and metabolite specificity.
These highly polar conjugates generally are inactive. An important exception is morphine,
which is converted to morphine-6-glucuronide, which has an analgesic effect lasting longer than
that of its parent molecule.
Paracetamol poisoning
Some drug metabolites can be toxic such as those produced from paracetamol. These are are
detoxified by phase II conjugation joining with glutathione. However, in an overdose situation
(2-3 times the maximum therapeutic dose) where the dose of paracetamol is high, there is not
enough glutathione to detoxify the metabolites. They accumulate causing toxicity and can result in
hepatitis. As a solution, compounds (N-Acetylcysteine or methionine) are administration to boost
the levels of glutathione so that phase 2 metabolism can take place, thus detoxifying the
paracetamol metabolites fully and reducing the risk of liver injury.
Site of Biotransformation
The liver is major site of drug metabolism although most tissues are able to metabolize specific
drugs. Other sites of metabolism include the kidney, the lung, and the gastrointestinal tract.
Following oral administration of a drug, a significant portion of the dose may be metabolically
inactivated in either the intestinal epithelium or the liver before the drug reaches the systemic
circulation. This so-called first-pass metabolism significantly limits the oral availability of highly
metabolized drugs. Within a given cell, most drug-metabolizing activity is found in the smooth
endoplasmic reticulum and the cytosol, although drug biotransformations also can occur in the
mitochondria, nuclear envelope, and plasma membrane.
The main enzymes involved in metabolism belong to the cytochrome P450 group. These are a
large family of related enzymes housed in the smooth endoplasmic reticulum of the cell.
Cytochrome P450 Monooxygenase System
Cytochromes P450 enzymes constitute a large superfamily of heme-thiolate proteins and they
are involved in the metabolism of a wide variety of both exogenous and endogenous compounds.
They were first discovered in 1955 in rat liver microsomes and they are characterized by an
intense absorption band at 450 nm in the presence of carbon monoxide. The letter in P450
represents the word pigment as these enzymes are red because of their heme group. The number
450 reflects wavelength of the absorption maximum of the enzyme when it is in the reduced state
and complexed with CO.
The cytochrome P450 (CYP) mixed function monooxygenases are located on the smooth
endoplasmic reticulum of cells throughout the body, but the highest concentrations are found in
the liver (hepatocytes) and small intestine. These enzymes are responsible for the oxidative (Phase
I) metabolism of a wide number of compounds, including many medications.
CYP enzymes have been identified in all domains of life. At least 17 cytochrome P-450 gene
families have been identified in humans, although 3 families are involved in the majority of the
drug biotransformations; these are the cytochrome P-450 1,2 and 3 (CYP1, CYP2 and CYP3). The
enzymes are divided into families based on amino acid sequence similarities, and each family can
be further separated into subfamilies, which are designated by capital letters following the family
designation (e.g., CYP3A). Individual enzymes are subsequently indicated by arabic numerals
(e.g., CYP3A4). An enzyme belongs to a family when the amino acid sequence possesses more
then 40% homology, enzymes with more than 55% homology form a subfamily and individual
enzymes can have to 97% homology between the sequences. Genes encoding CYP enzymes, and
the enzymes themselves, are designated with the abbreviation CYP, followed by a number
indicating the gene family, a capital letter indicating the subfamily, and another numeral for the
individual gene. The convention is to italicise the name when referring to the gene. For example,
CYP2E1 is the gene that encodes the enzyme CYP2E1 – one of the enzymes involved in
paracetamol (acetaminophen) metabolism. A single hepatocyte can contain a variety of
cytochrome P-450 enzymes. An individual enzyme of cytochrome P-450 may be able of
metabolizing many different drugs, but a given drug may be primarily metabolized by a single
enzyme.
Members of the CYP3A subfamily are the most abundant cytochrome enzymes in humans,
accounting for 30% of the cytochrome enzymes in the liver and 70% of those in the gut. CYP3A4
is the major form of cytochrome P-450 in the adult liver and metabolizes the greatest proportions
of drugs. This enzyme and CYP3A3, which are 97% identical and cannot be distinguished from
each other based on the substrates that they metabolize, are the major enzymes expressed in the
small intestine, while CYP3A5 is the major enzyme expressed in the stomach. CYP3A5 is present
in only 20%-30% of Caucasians, but being deficient in CYP3A5 poses no problem because the
CYP3A4 enzyme is available to assume its functions.
The metabolic rate can vary significantly from person to person, and drug dosages that work
quickly and effectively in one individual may not work well for another. Many factors can affect
liver metabolism. Factors such as genetics, environment, nutrition, and age also influence drug
metabolism.
Factors Affecting Drug Metabolism
Factors involved in drug biotransformation:
Genetic Variation (Genetic polymorphism)
Clinical Sketch
The risk of drug toxicity from isoniazid (used for tuberculosis) is higher in Egyptian than in
Eskimo (Inuit) populstions.
Comment: there is a genetic polymorphism in the metabolism of isoniazid: Egyptian are likely
to metabolism it slowly, while Eskimo usually metabolise it rapidly.
Genetic differences have profound effect on the levels of certain drugs in the body, as we see
from the clinical sketch. Genetic variation (polymorphism) accounts for some of the variability in
the effect of drugs. With N-acetyltransferases (involved in Phase II reactions), individual variation
creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly,
split roughly 50:50 in the population of Canada. This variation may have dramatic consequences,
as the slow acetylators are more prone to dose-dependent toxicity.
Cytochrome P450 monooxygenase system enzymes can also vary across individuals, with
deficiencies occurring in 1 - 30% of people, depending on their ethnic background.
For instance, there are poor metabolizers of codeine, and people who metabolize it very quickly.
This can affect the dosage of the drug. People who metabolize it poorly may be prone to overdose
even when taking a low dose, while extensive metabolizers may need a higher dosage.
Environmental Determinants
CYPs are the major enzymes involved in drug metabolism, accounting for about 75% of the
total metabolism.
Drug interaction
Many drugs may increase or decrease the activity of various CYP isozymes either by inducing
the biosynthesis of an isozyme (enzyme induction) or by directly inhibiting the activity of the CYP
(enzyme inhibition). This is a major source of adverse drug interactions, since changes in CYP
enzyme activity may affect the metabolism and clearance of various drugs.
Induction
Clinical sketch
A young woman on the contraceptive pills is found to have tuberculosis. She is started on
treatment and suffers contraceptive failure soon after.
Comments： it would be unacceptable practice to fail to warn the woman that rifampicin (which
induces the liver drug-metabolising enzyme CYP450) is very likely to cause failure of
contraception.
Some drugs can increase the rate of synthesis of cytochrome P450 enzymes and this enzyme
induction can enhance the clearance of other drugs. This leads to lowered concentrations of the
other drugs. Examples of inducing agents are: rifampicin, carbamazepine, Phenobarbital and
phenytoin. Sometimes a drug can induce its own biotransformation, as well as that of other agents,
such as Phenobarbital. Effects of induction can be seen within the first two days of therapy, but it
usually takes more than a week for new enzymes to be synthesized and the maximal effect to
occur.
Inhibition
Other drugs can inhibit cytochrome P450 enzymes (usually by competing for the enzyme’s
active site). Examples of enzyme-inhibiting agents are: cimetidine, erythromycin, ciprofloxacin
and isoniazid. Unlike induction, this is usually seen rapidly after drug exposure (within a couple of
days).
If one drug inhibits the CYP-mediated metabolism of another drug, the second drug may
accumulate within the body to toxic levels. Such drug interactions are especially important to take
into account when using drugs of vital importance to the patient, drugs with important side-effects
and drugs with small therapeutic windows. Hence, these drug interactions may necessitate dosage
adjustments or choosing drugs that do not interact with the CYP system.
Natural compounds may also have such effects. A classic example is grapefruit, which contains
a compound that inhibits the metabolism of many drugs. Many people who take prescription drugs,
especially statins, avoid consuming grapefruit or its juice for this reason. Naturally occurring
compounds may also induce or inhibit CYP activity. Because of this risk, avoiding grapefruit juice
and fresh grapefruits entirely while on drugs is usually advised.
In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a
pharmacologically active metabolite will decrease the duration and intensity of the drug action.
The opposite is also true (e.g., enzyme inhibition). However, in cases where an enzyme is
responsible for metabolizing a pro-drug into a drug, enzyme induction can speed up this
conversion and increase drug levels, potentially causing toxicity.
Various physiological and pathological factors can also affect drug metabolism. Physiological
factors that can influence drug metabolism include age, individual variation (e.g.,
pharmacogenetics), enterohepatic circulation, nutrition, intestinal flora, or sex differences.
Pathological factors can also influence drug metabolism, including liver, kidney, or heart
diseases.
Disease Factors
Diseases can affect all of the processes by which a drug is absorbed, distributed and eliminated
from the body.
Diseases that affect the liver and/or kidneys probably have the greatest effect on drug
concentrations, having a direct effect on metabolism and excretion. If liver function is impaired as
a result of disease or chronic drug use, blood levels will be greatly increased.
Clinical sketch
A man with moderately severe alcoholic liver disease needs flecainide for a cardiac arrhythmia.
The clinical team consults Appendix of the BNF(British National Formulary) and is advised to
give reduced doses.
Comments： flecainide accumulates in patients with chronic liver disease
Impaired liver functions can lead to decreased drug biotransformation. Disease states that can
impair liver function include hepatitis, alcoholic liver disease, biliary cirrhosis and
hepatocarcinoma. Infection can also alter drug biotransformation. There have been reports of
impaired drug elimination during viral infections such as influenza, rhino virus, adenovirus,
herpes simplex virus and infectious mononucleosis.
Age
Infants do not develop a mature enzyme system until more than 2 weeks after birth, therefore,
they have difficulty metabolizing many drugs. Age Young children generally have a lower
metabolic capacity compared with that of subjects between these extremes of age. The enhanced
sensitivity of the very young to drugs can be accounted for by the fact that the microsomal
enzymes, which are responsible for metabolism (particularly conjugation), are not fully active
until several months after birth. Older children (5 years) metabolize drugs at a similar rate to
adults. The dose must be lower, however, to take account of the smaller volume.
With aging, the liver's capacity for metabolism through the CYP450 enzyme system is reduced
by ≥ 30% because hepatic volume and blood flow are decreased. In elderly patients (over 60
years) there is a decreasing capacity for drug metabolism. In addition, the amount of
protein-binding may decrease and renal excretion may be reduced. Thus, drugs that are
metabolized in elderly patients reach higher levels and have prolonged half-lives in the elderly.
In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and
animals than in adults. Therefore, drugs used in infants and elderly generally may require
adjustments in dosage, which require moderate reduction in drug dose.
EXCRETION OF DRUGS
All drugs are eventually eliminated from the body. They may be eliminated after being
chemically altered (metabolized), or they may be eliminated intact. There are three main sites
where drug excretion occurs. The kidney is the most important site and it is where water-soluble
drugs and their metabolites, are excreted through urine. Biliary excretion or fecal excretion is the
process that initiates in the liver and passes through to the gut until the products are finally
excreted along with waste products or feces. The last main method of excretion is through the
lungs e.g. anesthetic gases.
Renal Excretion
Kidneys
Kidneys are not fully developed in newborns. They mature in the first few weeks and attain
normalcy. As people age, kidney function slowly declines(1% decline per year). For example, the
kidneys of an 85-year-old person excrete drugs only about half as efficiently as those of a
35-year-old person. Therefore, in almost all the elderly, some renal impairment has occurred.
Kidney function also can be impaired by many disorders (especially high blood pressure,
diabetes, and recurring kidney infections). In people whose kidney function has declined, the
“normal” dosage of a drug may be too much and may cause side effects.
Let’s look at a clinical sketch.
A patient is given digoxin for atrial fibrillation. He has impaired renal function. No
measurements of digoxin concentration are made, and the patient develops complete heart block.
Comment：digoxin is eliminated unchanged, and accumulates in renal impairment. Therapeutic
drug monitoring is mandatory, and this case illustrates a very low standard of clinical practice.
Therefore, health care practitioners sometimes must adjust the drug dosage based on the amount
of decline in the person's kidney function. People with impaired kidney function require lower
drug doses than those with normal kidney function.
Health care practitioners have several ways to estimate the decline in kidney function.
Sometimes they base an estimate solely on the person's age. However, they can get a more
accurate estimate of kidney function by using the results of tests that measure the level of
creatinine (a waste product) in the blood and sometimes also the urine. They use these results to
calculate how effectively creatinine is removed from the body (called creatinine clearance), which
reflects how well the kidneys are functioning.
There are three important processes involved in kidney excretion; filtration, tubular secretion
and tubular reabsorption. If a disease process occurs resulting in renal impairment, all these three
processes are affected.
1. Glomerular Filtration
The basement membrane and capillaries in glomerulus have a special structure: glomerular
capillaries have pores larger than usual to make the filtration rather easy. In the glomerular all
molecules of low molecular weight are filtered out of the blood. Most drugs are readily filtered
from the blood unless they are tightly bound to large molecules such as plasma protein or have
been incorporated into red blood cells. Thus, drugs bound to plasma proteins remain in the
circulation; only unbound drug is contained in the glomerular filtrate. Thus, glomerular filtration
of a drug depends on its plasma protein binding and renal blood flow.
2. Tubular Reabsorption
In the distal tubule there is passive excretion and re-absorption of lipid soluble drugs. Tubular
reabsorption is quantitatively much more important than tubular secretion. It is mainly a passive
process in which simple diffusion takes place. Simple diffusion is dependent on concentration
gradient. This gradient is created by the salt and water being reabsorbed continuously in the distal
tubule. This leads to an increase in concentration of drugs present in the lumen of renal tubules.
Therefore the concentration gradient is now in the direction of re-absorption, where is from renal
tubules to blood.
Tubular reabsorption is mainly a passive process in which simple diffusion takes place.
Therefore, it depends on lipid solubility and ionization of drugs at the existing urinary pH.
Lipid-soluble drugs filtered at the glomerulus back diffuse in the tubules because 99% of
glomerular filtrate is reabsorbed, but nonlipid-soluble and highly ionized drugs are unable to do so.
Ionized drugs will not diffuse passively. Ionized drugs are surrounded by water molecules, which
increase their size, impeding their passage through the semi-permeable membrane. In contrast,
nonionized drugs will diffuse passively and be reabsorbed in the distal tubule. Urine pH, which
varies from 4.5 to 8.0, may markedly affect drug reabsorption and excretion because urine pH
determines the ionization state of a weak acid or base (see Pharmacokinetics: Passive diffusion).
When urine is acidic weak acid drugs tend to be reabsorbed and decrease excretion. Alternatively
when urine is more alkaline, weak bases are more extensively reabsorbed and decrease
excretion.( Acidification of urine increases reabsorption and decreases excretion of weak acids,
and, in contrast, decreases reabsorption of weak bases. Alkalinization of urine has the opposite
effect.)
The acidity of urine, which is affected by diet, drugs, and kidney disorders, can affect the rate at
which the kidneys excrete some drugs. This fact is made use of in cases of poisoning. In the case
of a drug overdose it is possible to increase the excretion of some drugs by suitable adjustment of
urine pH. For example, in cases of aspirin poisoning, which is an acidic drug, only available
option is to make the urine alkaline (by bicarbonates injection). Thus aspirin is ionized and not
absorbed and increase its excretion. For basic drugs, ammonium chloride and ascorbic acid may
be given for making the medium more acidic to speed up the excretion of the basic drug.
. Giving these compounds only once will not change the pH indefinitely. Instead, they are given
repeatedly as long as the required time.
3. Secretion
Secretion occurs mostly in the proximal tubules. This is an active process. This is why some
drugs can be actively secreted because of tubular secretion. Group of antibiotics called penicillin
and cephalosporins are secreted by tubular secretion.
Several transporters are involved in the process of secretion, such as P-glycoprotein (P-gp) and
the multi-drug-resistance-associated protein type 2 (MRP2).
As secretion is an active process, it has certain attributes: Processes are saturable because
transporters are limited and ultimately all binding sites are occupied. Many drugs may be
competing, may be competitive inhibition of the secretion of one compound by another, which is
the basis of drug interaction.
For example, some diuretics are actively secreted by tubular secretion. Uric acid, an inherent
substance, is also secreted by this. Due to this, competition occurs and secretion of uric acid is
impaired. Individuals predisposed to gout may develop the disease because of hyperuricemia. This
is why serum uric acid levels are checked and proper history is taken for gout.
Another example is of penicillin 90% of which uses tubular secretion. Probenecid was used in
combination with penicillin, at the time in history when penicillin was rare and expensive. This
drug helped to reduce the excretion of the penicillin and thereby prolong penicillin plasma
concentrations (PDR). Now as penicillin is widely available, this drug is not used as this any
more.
Biliary and Fecal Excretion.
Biliary excretion
Some drugs pass through the liver unchanged and are excreted in the bile. Other drugs are
converted to metabolites in the liver before they are excreted in the bile. In both scenarios, the bile
then enters the digestive tract. From there, drugs are either eliminated in feces or reabsorbed into
the bloodstream and thus recycled.
Drugs with a molecular weight of > 300 g/mol and with both polar and lipophilic groups are
more likely to be excreted in bile; smaller molecules are generally excreted only in negligible
amounts. Conjugation, particularly with glucuronic acid, facilitates biliary excretion.
Enterohepatic Cycle
Drugs may be excreted into the bile either in a native form or after metabolism into more polar
conjugates. The bile is released in the gut lumen, from which the native drug can be reabsorbed. In
the small intestine, the enzymes of the intestinal flora may hydrolyze the conjugated metabolites
and free the active drug, which may in turn also be reabsorbed. After penetrating the intestinal
mucosa, the active drug enters the portal vein, which carries it back to the liver. This cycle is
called the enterohepatic cycle and may be repeated several times, significantly prolonging the
body exposure to the drug. Thus, enterohepatic circulation delays elimination of drugs, drugs
undergoing enterohepatic cycling have a prolonged half-life and the dosing interval should thus be
prolonged accordingly.
Let’s look at a clinical sketch:
A young woman on a low-dose combined oral contraceptive pill went on holiday to St
Petersburg with her boyfriend. She had read that many people catch gastroenteritis in this
destination and sought advice from her doctor. He prescribed doxycyline and advised her to take
this throughout her 3-weeks stay. Upon her return, she became concerned that she may be
pregnant and did a pregnancy test: it was positive.
Oral contraceptive steroids are given in very low dose to avoid adverse effect. Reliance is
placed on enterohepatic circulation. In certain situations, lower portion of gut bacteria produce
glucuronidases, which split conjugated drugs and are reabsorbed. This prolongs the duration of
action of drugs unusually. When drugs are being taken along with antibiotics like tetracyclines or
ampicillin, the antibiotics destroy these gut bacteria. Drugs like oral contraceptives have shortened
duration of action. Therapeutic failure might result.
Excretion by Other Routes.
Other Forms of Elimination: Some drugs are excreted in saliva, sweat, breast milk, and even
exhaled air. Most are excreted in small amounts.
Breast milk is important because many drugs are excreted in it. Some effects of the drugs may
be transferred to the baby, which may prove harmful. It is important to know which drugs are not
to be used during breast feeding. Milk being slightly acidic than plasma, weak bases get ionized
and have equal or higher concentration in milk than in plasma. For example, morphine, which is a
basic drug, have higher concentration in milk, which may cause baby respiratory inhibition.
If the mother is taking drugs, she should lactate the baby a few hours after taking drugs or most
preferably half an hour before intake.
Gases and volatile liquids (general anaesthetics, alcohol) are eliminated by lungs, irrespective of
their lipid solubility. Lungs constitute the most different route of drug elimination. This is the only
route by which lipophilic drugs are excreted because they are absorbed through the alveolar
membrane. Examples include general anesthetics, which are gases pumped through the
endotracheal tubes and diffuse across the alveolar membrane. When stop their administration, pure
oxygen is supplied. The body acts as a reservoir and transport occurs in reverse. Thus lipophilic
compounds are lost through the lungs. Alcohol breadth is another example which can be tested by
alcohol breath test, by which alcohol in the excreted air is measured.
INTRODUCTION
Pharmacokinetics provides a mathematical basis to assess the time course of drugs and their
effects in the body. It enables the following processes to be quantified:
Absorption
Distribution
Metabolism
Excretion
These pharmacokinetic processes, often referred to as ADME, determine the drug concentration
in the body when medicines are prescribed. A fundamental understanding of these parameters is
required to design an appropriate drug regimen for a patient. The effectiveness of a dosage
regimen is determined by the concentration of the drug in the body.
DRUG CONCENTRATION IN BLOOD
Ideally, the concentration of drug should be measured at the site of action of the drug; that is, at
the receptor. However, owing to inaccessibility, drug concentrations are normally measured in
whole blood from which serum or plasma is generated. Other body fluids such as saliva, urine and
cerebrospinal fluid (CSF) are sometimes used. It is assumed that drug concentrations in these
fluids are in equilibrium with the drug concentration at the receptor. It is important to note that this
does not imply that the drug concentration in plasma (Cp) is equal to the drug concentration in the
tissues. However, changes in the plasma concentration quantitatively reflect changes in the tissues.
It should be noted that the measured drug concentrations in plasma or serum are often referred
to as drug levels, which is the term that will be used throughout the text. It refers to total drug
concentration, i.e. a combination of bound and free drug that are in equilibrium with each other.
In routine clinical practice, serum drug level monitoring and optimization of a dosage regimen
require the application of clinical pharmacokinetics. A number of drugs show a narrow therapeutic
range and for these drugs therapeutic drug level monitoring is required.
Drug Plasma Concentration Curves
Drug concentrations in the blood can be determined and graphed against time.
Figure 2 – 8A shows a standardized drug plasma concentration curve over time after oral
administration of a typical drug. The Y-axis is a linear scale of drug plasma concentration, often in
μ g/mL or mg/L, and the X-axis is a time scale, usually in hours.
Single-dose Concentration Curves After Intravascular Administration
When a drug is administered by rapid IV injection, the maximum concentration in the blood is
reached almost at once and immediately begins to fall. The profile of this decline can be
determined by monitoring blood levels at periodic intervals and then plotting these concentrations
against time.
Single-dose Concentration Curves After Extravascular Administration
When a drug is administered by an extravascular route, it usually appears in the plasma within a
short time, and its concentration rises steadily until it peaks. Once absorbed into the circulation, it
is subjected simultaneously to distribution, biotransformation, and excretion. During the initial
period, the rate of absorption and distribution exceeds the rate of elimination. The peak plasma
concentration is reached when absorption and elimination rates are equal. Thereafter, the
elimination rate exceeds the rate of absorption because less drug remains available at the site of
administration, and plasma drug levels begin to fall.
Parameters of the plasma drug concentration curve are the maximum concentration ( C max ) ,
the time needed to reach the maximum ( T max ) , the minimum effective concentration ( MEC) ,
and the duration of action . A measure of the total amount of drug during the time course is given
by the area under the curve (AUC).
Area under the Curve
The area under the curve (AUC) refers to the area under a concentration versus time curve for a
drug and is used in the calculation of most other parameters. In Figure 11, which represents data
obtained after an oral dose, AUC can be calculated from the time of dosing to the last data point
by summation of the trapezoids. Extrapolation of the elimination phase allows calculation of the
AUC to infinity; the unit of measurements is of the form grams per litre per hour (g/l per h).
These measures are useful for comparing the bioavailability of different pharmaceutical
formulations or of drugs given by different routes of administration.
Bioavailability (F)
Bioavailability is defined as the fraction (F) of the administered dose of a drug that reaches the
systemic circulation in the active form (unchanged form) following administration by any route.
Extent of Absorption
Bioavailability is the amount of drug that is absorbed after administration by route X compared
with the amount of drug that is absorbed after intravenous (IV) administration. X is any route of
drug administration other than IV.
By definition, when a medication is administered intravenously, its bioavailability is 100%.
However, when a medication is administered via other routes (such as orally), its bioavailability
generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from
patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as
bioavailability must be considered when calculating dosages for non-intravenous routes of
administration.
As shown in Figure 2 – 8B , the oral bioavailability of a particular drug is determined by
dividing the AUC of an orally administered dose of the drug (AUC oral ) by the AUC of an
intravenously administered dose of the same drug (AUC IV ). By definition, an intravenously
administered drug has 100% bioavailability. The bioavailability of drugs administered
intramuscularly or via other routes can be determined in the same manner as the bioavailability of
drugs administered orally. The bioavailability of orally administered drugs is of particular concern
because it can be reduced by many pharmaceutical and biologic factors.
Pharmaceutical factors include the rate and extent of tablet disintegration and drug dissolution.
Biologic factors include the effects of food, which can sequester or inactivate a drug; the effects
of gastric acid, which can inactivate a drug; and the effects of gut and liver enzymes, which can
metabolize a drug during its absorption and first pass through the liver.
Example: Suppose you are testing a compound in clinical trials. You have tentatively named this
compound Newdrug. Newdrug is administered orally and plasma levels determine that only 75%
of the oral dose reaches the circulation. Compared with IV administration where 100% of the dose
reaches the circulation, the bioavailability of Newdrug is 0.75 or 75%. In the case of hypothetical
Newdrug, you discover that some of the drug is inactivated by the acid in the stomach. You
redesign the pill with a coating that is stable in acid but dissolves in the more basic pH of the small
intestine. The bioavailability of the drug increases to 95%. Newdrug becomes a best-selling
product.
Pharmacology also distinguishes between absolute bioavailability and relative bioavailability.
Absolute bioavailability compares the bioavailability of the active drug in systemic circulation
following non-intravenous administration (i.e., after oral, rectal, transdermal, subcutaneous, or
sublingual administration), with the bioavailability of the same drug following intravenous
administration. It is the fraction of the drug absorbed through non-intravenous administration
compared with the corresponding intravenous administration of the same drug. The absolute
bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC
intravenous. Therefore, a drug given by the intravenous route will have an absolute bioavailability
of 100% (f=1), whereas drugs given by other routes usually have an absolute bioavailability of
less than one.
Relative bioavailability is a term used to compare different formulations of the same medication,
for example brand name versus generic. In pharmacology, relative bioavailability measures the
bioavailability (estimated as the AUC) of a formulation (A) of a certain drug when compared with
another formulation (B) of the same drug, usually an established standard, or through
administration via a different route.
Oral formulations of a drug from different manufactures or different batches from the same
manufacture may have the same amount of the drug (chemically equivalent) but may not yield the
same blood levels-biologically inequivalent. Before a drug administered orally in solid dosage
form can be absorbed, it must break into individual particles of the active drug (disintegration).
Tablets and capsules contain a number of other material-diluents, stabilizing agents, binders,
lubricants, etc. The nature of these as well as details of the manufacture process, e.g. force used in
compressing the tablet, may affect disintegration. The released drug must then dissolve in the
aqueous gastrointestinal content. The rate of dissolution is governed by the inherent solubility,
particle size, crystal form and other physical properties of the drug. Differences in bioavailability
may arise due to variations in disintegration and dissolution rates. For example, reduction in
particle size increases the rate of absorption. Two preparations of a drug are considered
bioequivalent only when the rate and extent of bioavailability of the drug from them is not
significantly different under suitable test conditions.
Relative bioavailability is one of the measures used to assess bioequivalence (BE) between two
drug products. For FDA approval, a generic manufacturer must demonstrate that the 90%
confidence interval for the ratio of the mean responses (usually of AUC and the maximum
concentration, Cmax) of its product to that of the "Brand Name drug" is within the limits of 80%
to 125%. While AUC refers to the extent of bioavailability, Cmax refers to the rate of
bioavailability. When Tmax is given, it refers to the time it takes for a drug to reach Cmax.
Rate of Absorption
In addition to the definition given above, bioavailability is sometimes used to indicate both the
extent and the rate at which an administered dose reaches the general circulation. Both the rate of
absorption and the extent of input can influence the clinical effectiveness of a drug. For the three
different dosage forms depicted in Figure2.6, there would be significant differences in the clinical
effect. The three drugs contain the same amount. Note that formulation B is more slowly absorbed
than A, and though ultimately both are absorbed to the same extent (area under the curve same), B
may not produce therapeutic effect; C is absorbed to a lesser extent – lower bioavailability.
A variety of techniques is available for representing the pharmacokinetics of a drug. The most
usual is to view the body as consisting of compartments between which drug moves and from
which elimination occurs. The transfer of drug between these compartments is represented by rate
constants, which are considered below.
QUANTITATIVE
PHARMACOKINETICS
Pharmacokinetic models
To derive and use expressions for pharmacokinetic parameters, the first step is to establish a
mathematical model that accurately relates the plasma drug concentration to the rates of drug
absorption, distribution, and elimination. Pharmacokinetic models are hypothetical structures that
are used to describe the fate of a drug in a biological system following its administration.
One-compartment model
Following drug administration, the body is depicted as a kinetically homogeneous unit (see
Figure 1.1). This assumes that the drug achieves instantaneous distribution throughout the body
and that the drug equilibrates instantaneously between tissues. Thus the drug concentration–time
profile shows a monophasic response (i.e. it is monoexponential; Figure 1.2a). This represents a
one-compartment model.
Two-compartment model
The two-compartment model resolves the body into a central compartment and a peripheral
compartment (see Figure 1.3). Although these compartments have no physiological or anatomical
meaning, it is assumed that the central compartment comprises tissues that are highly perfused
such as heart, lungs, kidneys, liver and brain. The peripheral compartment comprises less
well-perfused tissues such as muscle, fat and skin.
A two-compartment model assumes that, following drug administration into the central
compartment, the drug distributes between that compartment and the peripheral compartment.
However, the drug does not achieve instantaneous distribution, i.e. equilibration, between the two
compartments.
The drug concentration–time profile shows a curve (Figure 1.4a), but the log drug
concentration–time plot shows a biphasic response (Figure 1.4b) and can be used to distinguish
whether a drug shows a one- or two-compartment model.
Figure 1.4b shows a profile in which initially there is a rapid decline in the drug concentration
owing to elimination from the central compartment and distribution to the peripheral compartment.
Hence during this rapid initial phase the drug concentration will decline rapidly from the central
compartment.
After a time interval (t), a distribution equilibrium is achieved between the central and
peripheral compartments, and elimination of the drug is assumed to occur from the central
compartment. As with the one compartment model, all the rate processes are described by
first-order reactions.
The one-compartment model is the simplest model of drug disposition, but the
two-compartment model provides a more accurate representation of the pharmacokinetic behavior
of many drugs ( Fig. 2 – 7 ). With the one-compartment model, drug undergoes absorption into the
blood according to the rate constant, k a , and elimination from the blood with a rate constant, k e .
In the two-compartment model, drugs are absorbed into the central compartment (blood),
distributed from the central compartment to the peripheral compartment (the tissues), and
eliminated from the central compartment. Regardless of the model used, rate constants can be
determined for each process and used to derive expressions for other pharmacokinetic parameters,
such as the elimination half-life (t 1/2 ) of a drug. In this section, the most important parameters of
pharmacokinetics are explained in greater detail.
Multicompartment model
In this model the drug distributes into more than one compartment and the concentration–time
profile shows more than one exponential (Figure 1.5a). Each exponential on the
concentration–time profile describes a compartment. For example, gentamicin can be described by
a three-compartment model following a single IV dose (see Figure 1.5b).
Apparent Volume of Distribution
The apparent volume of distribution is the theoretical volume of fluid into which the total drug
administered would have to be diluted to produce the concentration in plasma. It is usually
reported as liters per kilogram (L/kg). For example, if 1000 mg of a drug is given and the
subsequent plasma concentration is 10 mg/L, that 1000 mg seems to be distributed in 100 L
(dose/volume = concentration; 1000 mg/x L = 10 mg/L; therefore, x = 1000 mg/10 mg/L = 100 L).
The volume of distribution (Vd) has no direct physiological meaning; it is not a ‘real’ volume
and is usually referred to as the apparent volume of distribution. It is defined as that volume of
plasma in which the total amount of drug in the body would be required to be dissolved in order to
reflect the drug concentration attained in plasma. The apparent Vd for a drug is determined by its
degree of water or lipid solubility, the extent of plasma- and tissue-protein binding, and the
perfusion of tissues.
Interpretation of V d
Although the V d does not correspond to an actual body fluid compartment, it does provide a
measure of the extent of distribution of a drug.
A low V d that approximates plasma volume or extracellular fluid volume usually indicates that
the drug’s distribution is restricted to a particular compartment (the plasma or extracellular fluid).
The anticoagulant warfarin has a V d of about 8 L, which reflects a high degree of plasma protein
binding. Drugs that remain in the circulation tend to have a low volume of distribution. When the
V d of a drug is equivalent to total body water (about 40 L, as occurs with ethanol), this usually
indicates that the drug has reached the intracellular fluid as well.
Try another one. Suppose 500 mg of Newdrug is administered to a medical student. The plasma
concentration is 0.01 mg/mL. What is the volume of distribution?*
The volume of distribution is rather large. Your selected medical student is not, however, a huge
water balloon. The only explanation is that the new drug that is highly tissue-bound, very little
drug remains in the circulation; thus, plasma concentration is low and volume of distribution is
high. The drug could be lipid soluble and stored in fat or it could be bound to plasma proteins. As
this example shows, the volume of distribution a hypothetical volume and not a real volume.
The volume of distribution gives a rough accounting of where a drug goes in the body,
especially if you have a feel for the various body fluid compartments and their sizes (Figure 4-1).
Some drugs have volume of distribution values greater than 10,000 L! This means that most of the
drug is in the tissue, and very little is in the plasma circulating. The larger the volume of
distribution, the more likely that the drug is found in the tissues of the body. The smaller the
volume of distribution, the more likely that the drug is confined to the circulatory system.
In addition，it can be used to calculate the dose of a drug needed to achieve a desired plasma
concentration.
For example, we have measured the concentration of a drug in the plasma, and it is 8 μg/mL:
Concentration = 8 μg/mL = 0.008 mg/mL = 8 mg/L
Now, let’s ask a simple question: how much drug is in the body? We know what the
concentration of drug is in the plasma, but we cannot convert that to a total amount without
knowing the volume of the human container. If we know the volume of distribution of the drug is
about 51 L. Now, you can multiply the concentration times the volume of distribution to arrive at
the amount of drug in the body:
Amount = 8 mg/L * 51 L = 408 mg
Drug Clearance
Clearance ( Cl ) is the most fundamental expression of drug elimination. It is defined as the
volume of body fluid (blood) from which a drug is removed per unit of time. Thus, the units for
clearance are given in volume per unit time. Clearance is a descriptive term used to evaluate
efficiency of drug removal from the body. Clearance is not an indicator of how much drug is being
removed; it only represents the theoretical volume of blood which is totally cleared of drug per
unit time.
Clearance is an odd term. Try the following exercise as a way to remember the units.
Suppose we have a 10-liter aquarium that contains 10,000 mg of drug. The concentration is 1
mg/mL. Clearance is 1 L/h. In other words, the aquarium filter and pump clear 1 liter of water in
an hour. At the end of the first hour, 1000 mg of drug has been removed from the aquarium (1000
mL of 1 mg/mL). The aquarium thus has 9000 mg of drug remaining, for a concentration of 0.9
mg/mL. At the end of the second hour, 900 mg of crud has been removed (1000 mL of 0.9
mg/mL). The aquarium now has 8100 mg of crud remaining, for a concentration of 0.81 mg/mL.
This process continues forever. Notice that the time to clear this particular aquarium is not 10
hours. It would take 10 hours (10 liters at 1 L/h) if the clean water was pumped into another
container. In the case of clearance in the aquarium, however, the water is returned to the tank and
dilutes the remaining crud (Figure 3-4). The same principle holds true for clearance of a drug from
the human body.
Whereas the clearance of a particular drug is constant in first order kinetics, it is important to
note that the amount of drug contained in the clearance volume will vary with the plasma drug
concentration. (Elimination rate=CL* Plasma concentration)
Drug can be cleared by renal excretion or by metabolism or both. With respect to the kidney and
liver, etc., total body clearance is the sum of the clearances from the various organs involved in
drug metabolism and elimination, and clearances are additive, that is:
RENAL CLEARANCE.
Renal clearance is defined as the volume of plasma that is totally cleared of a drug in 1 min
during passage through the kidneys. Renal clearance can be calculated as the renal excretion rate
divided by the plasma drug concentration (see Box 2-2 ). The renal clearance of drugs depends on
urine pH, extent of plasma-protein binding, and renal plasma flow.
Drugs that are eliminated primarily by glomerular filtration, with little tubular secretion or
reabsorption, will have a renal clearance that is approximately equal to the creatinine clearance,
which is normally about 100 mL/min in an adult. A renal drug clearance that is higher than the
creatinine clearance indicates that the drug is a substance that undergoes tubular secretion. A renal
drug clearance that is lower than the creatinine clearance suggests that the drug is highly bound to
plasma proteins or that it undergoes passive reabsorption from the renal tubules.
HEPATIC CLEARANCE. Hepatic clearance is defined as the volume of plasma that is totally
cleared of drug in 1 min during passage through the liver. Most drugs, except highly hydrophilic
compounds, are cleared from the plasma mainly by biotransformation in the liver, although biliary
excretion can also contribute to the hepatic clearance of a drug. The main factors that determine
hepatic clearance include hepatic blood flow (delivery of drug to the liver), uptake of the unbound
drug by the hepatocytes from the blood, metabolic transformation of the drug by microsomal or
other enzyme systems, and rate of biliary secretion.
Hepatic clearance is more difficult to determine than renal clearance. This is because hepatic
drug elimination includes the biotransformation and biliary excretion of parent compounds. For
this reason, hepatic clearance is usually determined by multiplying hepatic blood flow by the
arteriovenous drug concentration difference.
FIRST-ORDER KINETICS
The order of a reaction refers to the way in which the concentration of drug or reactant
influences the rate of a chemical reaction. For most drugs, we need only consider first-order and
zero-order.
Definition First order elimination kinetics : "Elimination of a constant fraction per time unit of
the drug quantity present in the organism. The elimination is proportional to the drug
concentration."
Definition Zero-order elimination kinetics : "Elimination of a constant quantity per time unit of
the drug quantity present in the organism.
First order elimination kinetics
Most drugs exhibit first-order kinetics, in which the rate of drug elimination (amount of drug
eliminated per unit time) is proportional to the plasma drug concentration.
Here is an example of a first order process:
Time Amount remaining Amount
Fraction
(hrs)
in body
eliminated eliminated
0
1000
-
-
1
850
150
0.15
2
723
127
0.15
3
614
109
0.15
4
522
92
0.15
5
444
78
0.15
The serum level curve observed from a drug eliminated by a first order process:
Note that the rate of drug elimination is not the same as the elimination rate constant, ke
(fraction of drug eliminated per unit time). Clearance of a drug is different from the elimination
rate.
Remember clearance? As explained above，it’s the volume of fluid cleared of a drug per unit
time. In contrast, the elimination rate is the rate of removal of drug in weight per unit time. For
drugs with first-order kinetics, clearance and elimination rate are related, as shown in the
following equation:
CL=Rate of removal of drug (mg/min)/ Plasma concentration of drug (mg/ml)
CL=Elimination rate/ Plasma concentration
Elimination rate=CL* Plasma concentration
A drug’s rate of elimination is equal to the plasma drug concentration multiplied by the drug
clearance; the elimination rate declines as the plasma concentration declines (see Fig. 2 – 10A ).
Most drugs used in clinical practice at therapeutic dosages will show first-order rate processes;
that is, the rate of elimination of most drugs will be first-order. However, there are notable
exceptions, for example phenytoin and high-dose salicylates. In essence, for drugs that show a
first-order elimination process one can show that, as the amount of drug administered increases,
the body is able to eliminate the drug accordingly and accumulation will not occur. If you double
the dose you will double the plasma concentration. However, if you continue to increase the
amount of drug administered then all drugs will change from showing a first-order process to a
zero-order process, for example in an overdose situation.
Zero-Order Kinetics
A few drugs (e.g., ethanol) exhibit zero-order kinetics, in which the rate of drug elimination is
constant and independent of plasma drug concentration (see Fig. 2 – 10B ).
The clearance in zero-order kinetics is inversely proportional to the drug concentration(Whereas
the clearance of a particular drug is constant in first order kinetics); and a small increase in dosage
can produce a disproportionate increase in the plasma drug concentration.
In many cases, the reason that the rate of drug elimination is constant is that the elimination
process becomes saturated. This occurs, for example, at most plasma concentrations of ethanol . In
some cases, drugs exhibit zero-order elimination when high doses are administered, which occurs,
for example, with aspirin and the anticonvulsant phenytoin ( DILANTIN ) or when a hepatic or
renal disease has impaired the drug elimination processes.
Elimination Half-Life (t 1/2 )
Elimination half-life (t 1/2 ) is the time required to reduce the plasma drug concentration by
50%. It can be calculated from the elimination rate constant, but it is usually determined from the
plasma drug concentration curve ( Fig. 2 – 11 ). The half-life can also be expressed in terms of the
drug’s clearance and volume of distribution, indicating that the drug’s half-life will change when
either of these factors is altered. The formula for relating half-life to clearance and volume of
distribution is given in the legend of Figure 2 – 11. Disease, age, and other physiologic variables
can alter drug clearance or volume of distribution and thereby change the elimination half-life.
This parameter is very useful for estimating how long it will take for levels to be reduced by
half the original concentration. It can be used to estimate for how long a drug should be stopped if
a patient has toxic drug levels, assuming the drug shows linear one-compartment
pharmacokinetics. The longer the half life, the longer it will take the drug to be purged from the
body.
Rate: For almost all drugs, the metabolism rate in any given pathway has an upper limit
(capacity limitation). However, at therapeutic concentrations of most drugs, usually only a small
fraction of the metabolizing enzyme's sites are occupied, and the metabolism rate increases with
drug concentration. In such cases, called first-order elimination (or kinetics), the metabolism rate
of the drug is a constant fraction of the drug remaining in the body (ie, the drug has a specific
half-life). For example, if 500 mg is present in the body at time zero, after metabolism, 250 mg
may be present at 1 h and 125 mg at 2 h (illustrating a half-life of 1 h). However, when most of the
enzyme sites are occupied, metabolism occurs at its maximal rate and does not change in
proportion to drug concentration; instead, a fixed amount of drug is metabolized per unit time
(zero-order kinetics). In this case, if 500 mg is present in the body at time zero, after metabolism,
450 mg may be present at 1 h and 400 mg at 2 h (illustrating a maximal clearance of 50 mg/h and
no specific half-life). As drug concentration increases, metabolism shifts from first-order to
zero-order kinetics.
Half-life can be used to determine the appropriate dosage interval to achieve a target
concentration–time profile. A dosing interval of about a half-life is appropriate for drugs with
half-lives of approximately 8-24 hours allowing dosing once, twice or three times daily. It is
usually not practicable to administer drugs with shorter half-lives more frequently. If such a drug
has a large therapeutic index, so that a large degree of fluctuation over the dosing interval does not
result in toxicity due to high peak concentrations (e.g. many antibiotics and beta-blocking drugs),
it can be given at intervals longer than the half-life.
CONTINUOUS DOSE AND MULTIPLE DOSE KINETICS
Multiple doses
In some cases, the desired therapeutic effect of a drug is produced with a single dose. However,
to achieve a satisfactory response, it is frequently necessary to maintain drug concentrations in the
therapeutic range for a longer time. Rather than administering large doses, which could be
potentially toxic, repeated safe doses at regular intervals or continuous IV delivery are generally
necessary.
Steady state
When a drug that exhibits first-order pharmacokinetics is administered to a patient continuously
or intermittently, the drug will accumulate until it reaches a plateau or steady state plasma drug
concentration.
The basis for this accumulation to a steady state is shown in Figure 2 – 12 . When the drug is
first administered, the rate of administration is much greater than the rate of elimination, because
the plasma concentration is so low. As the drug continues to be administered, the rate of drug
elimination gradually increases, whereas the rate of administration remains constant. Eventually,
as the plasma concentration rises sufficiently, the rate of drug elimination equals the rate of drug
administration. At this point, the steady-state equilibrium is achieved.
Effect of dose on the Steady-State
The higher the dose, the higher the steady-state levels, but the time to achieve steady-state
levels is independent of dose (see Figure 1.8). Note that the fluctuations in Cp max and Cp min are
greatest with higher doses.
Effect of dosing interval on the Steady-State
Consider a drug having a half-life of 3 h. When the dosing interval, is less than the half-life,
t1/2, greater accumulation occurs, i.e. higher steady-state levels are higher and there is less
fluctuation in Cp max and Cp min (see Figure 1.9, curve A). When the dosing interval, is greater
than the half-life t1/2, then a lower accumulation occurs with greater fluctuation in Cp max and
Cp min (see Figure 1.9, curve C).
If the dosing interval is much greater than the half-life of the drug, then Cp min approaches zero.
Under these conditions no accumulation will occur and the plasma concentration–time profile will
be the result of administration of a series of single doses.
Time to reach steady state
For a drug with one-compartment characteristics, the time to reach steady state is independent
of the dose, the number of doses administered, and the dosing interval, but it is directly
proportional to the half-life.
The time required for a drug concentration to reach steady state is determined by the drug's
half-life. It takes one half-life to reach 50%, 2 half-lives to reach 75%(150/2), 3 half-lives to reach
87.5%(175/2), 3.3 half-lives to reach 90%, and 4 half-lives to reach 93.75% of steady state....In
most clinical situations, the attainment of steady state can be assumed after 4-5 half-lives."
If we take Klonopin's longest half-life number, which is 50 hours, that would be 50hours x 5 =
250 hours = 10.42 days. So it takes around 10 days for Klonopin to build to full strength is the
blood stream and likewise it takes about that time for the drug to be eliminated.
The same numbers 4-5 half-lives are used to calculate the elimination of the drug.
The time required for a drug to be eliminated is determined by the drug's half-life. It takes one
half-life to reach 50%, 2 half-lives to reach 25%(50/2), 3 half-lives to reach 12.5%(25/2), 3.3
half-lives to reach 10%, and 4 half-lives to reach 6.25% of steady state....In most clinical
situations, the time for the drug to be eliminated can be assumed after 4-5 half-lives."
Note that build up and elimination of all drugs can be calculated in the same way.
A drug administered intermittently will accumulate to a steady state at the same rate as a drug
given by continuous infusion, but the plasma drug concentration will fluctuate as each dose is
absorbed and eliminated. The average steadystate plasma drug concentration with intermittent
intravenous administration will be the same as if the equivalent dose were administered by
continuous infusion ( Fig. 2 – 13C ).
Therapeutic Drug Monitoring
Drug Half-Life, Steady State, and Recommended Sample Collection Time
Therapeutic drug monitoring (TDM) is commonly used to help maintain drug levels within the
therapeutic window, the concentration range in which a drug exerts its clinical effect with minimal
adverse effects for most patients. TDM is particularly useful for monitoring drugs that are used
long-term and have a narrow therapeutic range.
Blood samples are usually collected at steady state to obtain clinically useful serum drug
concentrations.1 When a fixed dose is administered at regular intervals, a drug will accumulate in
the body during the absorption phase until it reaches steady state, during which the rate of drug
intake equals the rate of drug elimination.1 The time required to reach steady state depends on the
elimination half-life of the drug. Under conditions of first-order kinetics in a one-compartment
distribution model (drug is rapidly and evenly distributed throughout the body) and in the absence
of a loading dose, at least 5 half-lives are required to achieve a steady state.1,3
Except in medical emergencies, the monitored drug should be allowed to reach a new steady
state following a dosage change and the addition or discontinuation of a co-administered drug.
Similarly, the same amount of time needs to elapse to almost completely eliminate a discontinued
drug that had reached steady state.
Once steady state has been reached, peak and/or trough serum samples may be collected after
the next scheduled dose. For peak samples, that would typically be 2 to 3 hours after an oral dose,
30 to 60 minutes after an intravenous dose, 2 to 4 hours after an intramuscular dose,2 or 1 to 1.5
hours after an intranasal dose. Trough samples are drawn just before administration of the next
scheduled dose.
Maintenance Dose
A maintenance dose is given to establish or maintain the desired steady-state plasma drug
concentration. For drugs given intermittently, the maintenance dose is one of a series of doses
administered at regular intervals. The maintenance dose is calculated as the rate of drug
elimination multiplied by the dosage intervals. If the drug is administered orally, its bioavailability
must also be included in the equation.
Loading Dose
A loading dose, or priming dose, is given to rapidly establish a therapeutic plasma drug
concentration.
A loading dose is an initial higher dose of a drug that may be given at the beginning of a course
of treatment before dropping down to a lower maintenance dose.
A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e.
have a long systemic half-life. If the drug has a very long half-life (e.g. phenobarbitone with a
half-life of 4 days), and we have considered a dosing interval equal to the half -life of the drug, it
means that it will still take 3-5 half-lives (12-20 days in this example) to reach steady state.
For a drug such as this, a doctor might prescribe a loading dose of one gram to be taken on the
first day. That immediately gets the drug's concentration in the body up to the
therapeutically-useful level.
A loading dose could be used, but may not be feasible. The use of a loading dose may
sometimes cause problems if adverse effects occur because of the initial high plasma drug
concentrations before redistribution occurs. The loading dose, which is larger than the
maintenance dose, is generally administered as a single dose, but it can be divided into fractions
that are given over several hours. A divided loading dose is sometimes used for drugs that are
more toxic, for example, digitalis glycosides used to treat congestive heart failure. Another
example is digoxin, where it is common for the loading dose to be divided into 3 parts given at
8-hourly intervals.