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OVERVIEW
Pharmacology is the rational discussion or study of drugs and their interactions with the
body. Classically there are two major divisions of pharmacology: pharmacodynamics and
pharmacokinetics. Pharmacodynamics is the study of actions of drugs on the body—what
effects a drug has on the patient, including mechanisms of action, beneficial and adverse
effects of the drug, and the drug’s clinical applications.
Pharmacodynamics describes the processes through which a drug brings about its effect in
the body. To begin to comprehend this, we must start by breaking down the interaction to a
molecular level and create models to further our understanding. The fundamental principle
behind a drug’s action is that to cause effect, it must interact with its target.
Drug Targets
Drugs alter the activity or prevent the activation of a target molecule in some way.
Although the term drug receptor is used generally to indicate the initial site of drug action,
these molecular targets are composed of the following broad types.
Receptors
In the strictest pharmacologic sense, receptors are molecular entities that evolved
specifically to bind certain substances, with the purpose of cellular communication (e.g.,
cardiac β-adrenergic receptors). The concept of the receptor was introduced at the end of the
nineteenth century (Langley, 1878) and beginning of the twentieth century (Ehrlich, 1909).
This in turn spurred considerable and ongoing research into the nature of the interaction
between drugs and receptors.
General Sites
General sites may not have specifically evolved as communication mechanisms and thus
may or may not adhere to all pharmacodynamic principles discussed earlier (e.g., intrinsic
activity). Nevertheless, in a general sense these can act as receptors for drug action. Examples
of general sites mediating drug action include the following:
■ Components in key signaling or metabolic pathways
■ Ion channels or transporters found in the cell membrane
■ Intracellular or extracellular enzymes
■ Structural components
Unidentified Targets
Finally, the molecular targets for some drugs have not been completely elucidated yet. An
example would be the target for inhaled general anesthetics.
SITES OF DRUG ACTION
Although some notable exceptions exist, a fundamental principle of pharmacology is that
drugs must interact with a molecular target to exert an effect. The targets may be membrane
or cytosolic receptors, ion channels, transporters, signal transduction kinases, enzymes, or
specific sequences of RNA or DNA, but the pharmacodynamic principles that govern these
interactions remain the same. Drugs bind to specific targets, activating (stimulating) or
inactivating (blocking) their functions and altering their biological responses. Drug
interaction with molecular targets is the initiating event in a multistep process that ultimately
alters tissue function.
For most drugs, the site of action is a specific macromolecule, generally termed a receptor
or a drug target.
Receptors (i.e., drug targets) fall into many classes, but two types predominate:
1.Molecules, such as enzymes and deoxyribonucleic acid (DNA), which are essential to a
cell’s normal biological function or replication, and Biological molecules that have evolved
specifically for intercellular communication.
The former molecules could be considered generalized and the latter specialized receptors.
Generalized receptors can include biological molecules with any function, including enzymes,
lipids, or nucleic acids.
Specialized receptors include molecules like ion channels and proteins in the plasma
membrane, designed to detect chemical signals and initiate a cellular response via activation
of signal transduction pathways.
The biological function of these molecules is to respond to neurotransmitters, hormones,
cytokines, and autocoids and convey information to the cell, resulting in an altered cellular
response. These types of receptors are the primary targets of most drugs in clinical use.
Confusion can arise at this point over the interchangeable use of the term ‘receptor’. The
word receptor has been used as a general term for the molecular site of action of any drug
(described here as a target) or more specifically as a cell membrane associated structure
involved in the transduction of an endogenous signalling process; the latter use is applied
here.
For the purposes of current discussion, the target will be referred to as a specialized
receptors.
The concept of receptors was first proposed more than a century ago by the German
chemist Paul Ehrlich, who was trying to develop specific drugs to treat parasitic infections.
He proposed the idea of specific ‘‘side chains’’ on cells that would interact with a drug, based
on mutually complementary structures. Each cell would have particular characteristics to
recognize particular molecules. He proposed that a drug binds to a receptor much like a key
fits into a lock. This lock and key hypothesis is still relevant to how we understand receptors
today. It emphasizes the idea that the drug and receptor must be structurally complementary
to recognize each other and initiate an effect.
Receptors are a primary focus for investigating the mechanisms by which drugs act. With
the sequencing of the human genome, the structures and varieties of most receptors have now
been identified. This advance has revealed many new receptors that could be potential drug
targets for further pharmaceutical development. The major features of receptors are listed in
Box 1-1.
An in-depth discussion of molecular targets and a description of these processes will be
presented later in this chapter (see the discussion of molecular mechanisms of drug action).
Let us first consider the relationship between drug binding to its target receptors and the
ultimate response of the tissue.
DRUG-RECEPTOR INTERACTIONS
Most drugs exert their effects, both beneficial and harmful, by interacting with
receptors—that is, specialized target macromolecules—present on the cell surface or
intracellularly. Receptors bind drugs and mediate their pharmacologic actions.
In each case, the formation of the drug-receptor complex leads to a biologic response, and
the magnitude of the response is proportional to the number of drug-receptor complexes:
Drug + Receptor
Drug-receptor complex — Biologic effect
Unoccupied receptor does not influence intracellular processes.
Occupied receptor changes physical/chemical properties, which leads to interaction with
cellular molecules to cause a biologic response.
At its most fundamental level, the interaction of drug and receptor follows the law of mass
action. The law of mass action dictates that:
▲ The combination of drug (also called ligand) and receptor depends on the concentrations
of each
▲ The amount of drug-receptor complex formed determines the magnitude of the response
▲ A minimum number of drug receptor complexes must be formed for a response to be
initiated (threshold)
▲ As drug concentration increases, the number of drug-receptor complexes increases and
drug effect increases
▲ A point will be reached at which all receptors are bound to drug, and therefore no further
drug-receptor complexes can be formed and the response does not increase any further
(saturation)
Factors Affecting Drug-Target Interactions
Two basic properties of the drug-receptor interaction contribute importantly to drug
responses: the ability of the drug to bind to its receptor, and the ability of the drug to alter the
activity of its receptor.
[D]+[R] ↔ [DR] → Effect
Often, the lock-and-key concept is useful to understand the way drugs work. In this analogy,
the target is the lock and the drug is the key. If the key fits the lock and is able to open it (i.e.,
activate it), the drug is called an agonist. If the key fits the lock but can’t get the lock to open
(i.e., just blocks the lock), the drug is called an antagonist.
Receptor Binding and Affinity
To initiate a cellular response，a drug must first bind to a receptor. In most cases, drugs
bind to their receptor by forming hydrogen, ionic, or hydrophobic (Van der Waals) bonds
with a receptor site. These weak bonds are reversible and enable the drug to dissociate from
the receptor as the tissue concentration of the drug declines. In a few cases, drugs form
relatively permanent covalent bonds with a specific receptor (Covalent bonds = strong bonds
and long-lasting or irreversible effects, Covalent bonds require considerable energy to break
and are classified as irreversible when formed in drug-receptor complexes.). This occurs, for
example, with antineoplastic drugs that bind to DNA and with drugs that irreversibly inhibit
the enzyme cholinesterase.
The tendency of a drug to combine with its receptor is called affinity, which is a measure
of the strength of the drug-receptor complex. The affinity constant (also known as the
association constant , KA) of a drug indicates how readily it will bind to its target, which is
the ratio of the associated form to the dissociated forms
KA = [DR]
[D] x [R]
However, Affinity can be widely defined in terms of the KD (the dissociation constant of
the drug for the target, which is the ratio of the dissociated forms to the associated form:
[D]+[R] ↔ [DR]
KD = [D] x [R]
[DR]
In this instance, affinity is the inverse of the KD (1/KD).The smaller the KD, the greater
affinity a drug has for its receptor (KA=1/KD). Low KD means there is high affinity because
the drug “likes” to be bound to a receptor, does not want to leave the receptor, therefore, the
low dissociation.
DR/RT=D/(D+KD) 1-2
where RT represents the total number of receptors
From Equation 1-2, it is clear that when half of the receptors are occupied, KD equals [D];
thus KD is the concentration of drug when half of the receptor population is occupied. This
means that drugs with a high KD (low affinity) will require a high concentration for
occupancy, whereas drugs with a low KD (high affinity) require lower concentrations.
Every drug/receptor combination will have a characteristic KD. For example, glutamate has
approximately millimolar affinity for its receptors, whereas some β-adrenergic antagonists
have nanomolar affinities for their receptors.
Most drugs have a KD in the micromolar to nanomolar (10-6 to 10-9 M) range of drug
concentrations. As discussed below, receptor affinity is the primary determinant of drug
potency.
The formation of the drug- receptor complex leads to a biological response. The magnitude
of the response is proportional to the number of drug-receptor complexes.
Intrinsic activity (Efficacy)
Activation of the Molecular Target
However, practitioners found two drugs that have equal affinities (binding) for a specific
target but have different efficacies (degree of response) , why?
This observation suggests that other factors, in addition to affinity and receptor
occupancy, determine the strength of response. Accordingly, an additional modifier termed
intrinsic activity was proposed. This use of the word "efficacy" was introduced by
Stephenson (1956) to describe the way in which agonists vary in the response they produce,
even when they occupy the same number of receptors.
Intrinsic activity (Efficacy) indicates the ability of drug-receptor complex to activate the
receptor and initiate downstream events, leading to an effect. Efficacy is not directly related
to receptor affinity and differs among various drugs.
Drugs are categorized based on their intrinsic activity at a given receptor:
Drugs that have both receptor affinity and efficacy are called agonists, whereas drugs that
have receptor affinity but lack efficacy are called antagonists.
Often, the lock-and-key concept is useful to understand the way drugs work. In this
analogy, the target is the lock and the drug is the key. If the key fits the lock and is able to
open it (i.e., activate it), the drug is called an agonist. If the key fits the lock but can’t get the
lock to open (i.e., just blocks the lock), the drug is called an antagonist.
Both agonists and antagonists have common components sufficient for receptor affinity,
but only agonists have the structure required for efficacy.
■ An agonist is a compound that binds to the receptor and produces the biological response,
like a key will fit into a lock and turn it.
■ An agonist can be a drug or the endogenous ligand for the receptor. Activation of the
receptor by agonist binding initiates a conformational change in the receptor and
activation of one or more downstream signaling pathways. An example of the action of an
agonist is provided by the effect of acetylcholine on the nicotinic cholinergic receptor at
the neuromuscular junction. When acetylcholine binds to its binding sites on the external
surface of this receptor, the channel opens and allows Na+ to flow down its
electrochemical gradient and depolarize the muscle cell.
■ Increasing concentrations of the agonist will increase the biological response until there
are no more receptors for the agonist to bind or a maximal response has been reached.
■ Full agonists (sometimes called agonists) produce maximum activation of the receptor
and elicit a maximum response from the tissue. They are assigned an intrinsic activity of
1.
Antagonists are drugs that bind to the receptor but do not have the unique structural
features necessary to activate it (they are assigned an intrinsic activity of 0). In the lock and
key analogy, antagonists can fit in the lock but cannot open it.
Like agonists, antagonists fit into a specific binding site within the receptor but lack the
proper structural features to initiate a conformational change leading to receptor activation.
They have no effect of their own. However, because they occupy the binding site of the
receptor, antagonists inhibit activation by agonists. The antagonists can block the effect of an
agonist or they can reverse the effect of an agonist.
An example of an antagonist is naloxone, an opioid antagonist. Naloxone has no effect of
its own but will completely reverse the effects of any opioid agonist that has been
administered. Sometimes the antagonist reverses or blocks the effect of endogenously
produced compounds, such as epinephrine or norepinephrine. This is the mechanism of action
of β-blockers.
Binding of an antagonist to a receptor does not produce a biological effect.
Partial agonists exhibit intrinsic activity between 0 and 1. A partial agonist produces the
biological response but cannot produce 100% of the biological response even at very high
doses. In other words, despite occupying all of the receptors, the biological response for
partial agonists is lower than that of full agonists.
Partial agonists have a dual activity, that is, they act partially as agonists and partially as
antagonists.
When used alone, a partial agonist will act like a weak agonist because partial agonists
produce weaker activation of the receptor than full agonists or the endogenous ligand. Partial
agonists produce only partial activation of the receptor and its downstream signaling events.
In the presence of a full agonist, a partial agonist will act like an antagonist because the
partial agonist will compete for receptors and bind to a certain proportion of receptors
previously bound by full agonist. Because the partial agonist produces weaker activation of
the receptor than full agonist, the net effect will be less cumulative receptor activation.
Therefore, the partial agonist will prevent the full agonist from binding the receptor and
exerting a maximal response. The key point is that partial agonists are often used clinically to
competitively inhibit the responses of full agonists.
The clinical effect of a partial agonist will depend on its intrinsic activity and the
concentration of the endogenous ligand. If concentrations of the endogenous ligand are really
low, then a partial agonist will increase receptor activation, functioning as a weak agonist. In
contrast, if concentrations of endogenous ligand are high, the partial agonist will compete for
receptors and bind to a certain proportion of receptors previously bound by endogenous
ligand. Because the partial agonist produces weaker activation of the receptor than
endogenous ligand, the net effect will be less cumulative receptor activation. This will
produce inhibition of the response mediated by the endogenous ligand, and the partial agonist
will act as a weak antagonist.
Inverse agonists, which are also called negative antagonists, are involved in a special type
of drug-receptor interaction. Inverse agonists inhibit rather than activate the receptor.
The term inverse agonist has been around for a number of years. Originally, it was used to
describe the action of some drugs in the benzodiazepine class. Currently the term is also used
in connection with G protein-coupled receptors. Current theory states that G protein-coupled
receptors are in an equilibrium between an active and inactive state. Inverse agonists bind to
the receptor and tip the equilibrium toward the inactive state, while agonists bind the receptor
and tip the equilibrium toward the active state.
The effect of inverse agonists is based on the finding, in some cases, that receptors exhibit
baseline (ongoing or constitutive) activity in the absence of agonist binding. An agonist
increases the activity above its basal level while an inverse agonist decreases the activity
below the basal level. Antagonists are different. Antagonists also bind to the receptor，but
they have no effect on the basal state.
Inverse agonists and antagonists will elicit similar effects because both types of drugs will
reverse the effects of endogenous ligands. Antagonists have no activity in the absence of
agonists or inverse agonists, they do, however, block the effects of both the agonists and
inverse agonists, for e.g. flumazenil opposes the action of both BZD and beta carboline..
Only a few inverse agonists are identified. An example of a receptor that possesses basal
activity is the GABAA receptor located in the central nervous system. Agonists for the
GABAA receptor (such as the benzodiazepines alprazolam and diazepam) elicit a sedative
effect while inverse agonists have anxiogenic (for example, Ro15-4513) or even convulsive
effects (certain beta-carbolines),for e.g. beta carboline produces effects opposite to the BZDs
on BZD receptor.
The efficacy of a full agonist is by definition 100%, an antagonist has 0%, while an inverse
agonist has < 0% (i.e., negative) efficacy.
Thus, the ultimate action of a drug will depend on both its affinity and its intrinsic activity.
It is important to remember that affinity and intrinsic activity are distinct properties.
Usually receptors will be in equilibrium between active and inactive state and when
agonist binds the receptor and brings conformational changes and pushed towards active side
and intrinsic activity( efficacy) is present and is positive eg morphine binds to opiod receptor
increases its action
Antagonist binds to receptor where.....affinity is present but efficacy is absent (most cases
are competative inhibition) ie... efficacy is zero eg naloxone binds to opiod receptor
competively inhibits morphine binding but efficacy is zero
Inverse agonist binds to receptors where it binds and efficacy is pushed towards negative
side eg:beta carbolines binds to bzd receptors downs its efficacy below zero.
Quantifying Drug-Target Interactions:
DOSE-RESPONSE RELATIONSHIPS_
Ultimately, to make informed clinical decisions, it is necessary to understand the
relationship between the amount of drug given and the anticipated effect in the patient. This
relationship is described quantitatively by the dose-response relationship.
The dose-response relationship is a mathematic relationship between the dose of a drug
and the body's reaction to it. The relationship of dose to response can be illustrated as a graph
called a dose-response curve. The dose is represented on the x-axis. The response is
represented on the y-axis. The measured dose (usually in milligrams, micrograms, or grams
per kilogram of body-weight for oral exposures or milligrams per cubic meter of ambient air
for inhalation exposures) is generally plotted on the X axis.
There are two basic types of dose-response curves—graded and quantal—and each
provides useful information for therapeutic decisions.
Graded Dose-Response Curves
■Describes the graded responses of an individual to varying doses of the chemical
■ Measure an effect that is continuous such that, in theory, any value is possible in a given
range (0% through 100%). That is, they vary from minimum to maximum response.
■ Plotting the magnitude of the response against increasing doses of a drug produces a
graph that has the general shape depicted in Figure 2.6A. The dose-response relationship for
most drugs is exponential, often assuming the shape of a rectangular hyperbola.
■To make analysis of this curve easier (make it easier to compare drug potencies), we do a
mathematical trick of making the x scale a logarithmic scale. By doing this, the curve is
converted to a sigmoid curve (S-shaped curve). Advantages of this curve:
· It is linear over 20-80% of the occupancy range
· It is more easier to quantitative values looking off the curve
· It can show a much larger range of concentrations. At low concentrations, we are able to
see the rapid changes that occur, while at the higher concentrations, where things are much
more boring, we don’t see much.
■ By plotting response vs log dose, we can transform a graded dose-response curve into
more linear (sigmoidal) relationships. This facilitates comparison of the dose response curves
for drugs that work by similar mechanisms of action. Without knowing anything about the
mechanisms of opioids or aspirin, a glance at Figure 2-1C tells you that hydromorphone,
morphine, and codeine work by the same mechanism, but aspirin works by a different
mechanism. Often, the slope of the curves and the maximal effects are identical for drugs that
work via the same mechanism. These curves also tell you that of the three opioids,
hydromorphone is the most potent. Potency is a comparative term that is used to compare two
or more drugs that have different affinities for binding to the same
target.
A standard dose-response curve is defined by four parameters: the baseline response
(Bottom), the maximum response (Top), the slope, and the drug concentration that provokes a
response halfway between baseline and maximum (EC50).
■ The first point along the graph where a response above zero is reached is usually referred
to as a threshold-dose (MEC). This is an important concept of dose-response relationships.
Below the threshold dose, there is no measurable response. For most beneficial or
recreational drugs, the desired effects are found at doses slightly greater than the threshold
dose.
With an increasing dose of drug, there is an increase in the response, until we get to a point
at which no further response is achieved. This is the maximal effect (Emax) of a drug.
■Emax is a measure of maximal response or efficacy of the drug, not a dose or concentration.
Once the maximal response is achieved, increasing the concentration/dose of the drug will
not produce a further therapeutic effect but can lead to toxic effects.
■Slope: Knowledge of the slope (change in response per unit dose) is important in
comparing the toxicity of various drugs (see Figure 8). For some drugs a small increase in
dose causes a large increase in response (toxicant A, steep slope). For other drugs a much
larger increase in dose is required to cause the same increase in response (toxicant B, shallow
slope).
The drug concentration that provokes a response halfway between baseline and maximum
(EC50)
EC50 (half maximal effective concentration) is the concentration that produces 50% of the
Emax.
■ It is easy to misunderstand the definition of EC50. It is defined quite simply as the
concentration of drug that provokes a response half way between the baseline (Bottom) and
maximum response (Top). It is impossible to define the EC50 until you first define the
baseline and maximum response.
■ EC50 is an index of the potency of the drug.
Potency is a measure of the amount of drug necessary to produce an effect of a given
magnitude. For a number of reasons, the concentration producing an effect that is fifty
percent of the maximum is used to determine potency; it commonly designated as the EC 50. It
is measured simply as the inverse of the EC50 for that drug.
The lower the EC50, the less the concentration of a drug is required to produce 50% of
maximum effect and the higher the potency. A highly potent drug (e.g., morphine, alprazolam,
chlorpromazine) evokes a larger response at low concentrations, while a drug of lower
potency (ibuprofen, acetylsalicylic acid) evokes a small response at low concentrations.
The EC50 and Emax are useful parameters to assess drugs. In Figure 1-2, A, Drug A is
more potent than Drug B or Drug C, whereas Drugs B and C have equal potency.
In Figure 1-2, A, Drug B has the greatest efficacy, followed by Drug C, whereas Drug A,
despite being the most potent, has the least efficacy. Drug C is equipotent with Drug B but
has less efficacy.
Thus, potency and efficacy can vary independently. It is important not to confuse the two
concepts.
Potency is often expressed as the dose of a drug required to achieve 50% of the desired
therapeutic effect. This is the ED50 (effective dose).
Efficacy is the maximal response a drug can produce. Potency is a measure of the dose
that is required to produce a response.
For example, one drug (drug A) produces complete eradication of premature ventricular
contractions (PVCs) at a dose of 10 mg. A second drug (drug B) produces complete
eradication of PVCs at a dose of 20 mg. Therefore, both drugs have the same efficacy
(complete eradication of PVCs), but drug A is more potent than drug B. It takes less of drug A
to produce the same effect. A third drug (drug C) can reduce the PVCs by only 60%, and it
takes a dose of 50 mg to achieve that effect. Therefore, drug C has less efficacy and less
potency in the reduction of PVCs compared with both drug A and drug B.
Efficacy and potency are terms that students sometimes confuse. These terms are used for
comparisons between drugs. Thus, potency and efficacy can vary independently.
A potent drug is not always the most efficacious. In contrast, many drugs with high
efficacy have a low potency. It is commonly thought that more potent drugs are more
effective. Because it takes less of a drug to achieve an effect does not mean that the drug is
more effective. For example, both 500 mg of acetaminophen and 200 mg of ibuprofen resolve
a headache. Although ibuprofen is more potent because it requires a lower amount of drug,
both drugs eliminate the headache. They are equally effective.
In fact, in most cases the maximal response (Emax) or efficacy is more important than
drug potency in drug selection. (In fact, in most cases potency is secondary to Emax in drug
selection) Drugs with higher Emax values have higher pharmacologic efficacy. For example,
the diuretic furosemide eliminates much more salt and water through urine than does the
diuretic chlorothiazide. Thus, furosemide has greater efficacy than chlorothiazide. However,
in situations in which the absorption of drug is very poor, such that only small quantities of
the drug reach the target, potency can be a critical consideration.
However, greater potency or efficacy does not necessarily mean that one drug is
preferable to another. When judging the relative merits of drugs for a patient, doctors
consider many factors, such as side effects, potential toxicity, duration of effect (which
determines the number of doses needed each day), and cost.
Because of interindividual variability, each patient may respond in ways that differ from
the average. The second type of dose-response curves, quantal dose-response curves, provide
an estimate of this variability.
Quantal Dose-Response Curves
■describes the distribution of responses to different doses in a population of individuals
Quantal responses are all-or-none responses to a drug. The effects in quantal (“all-or-none”
(yes-or-no response)) dose-response are not continuous. For example, after the administration
of a hypnotic drug, a patient is either asleep or not. There is no in-between.
Quantal dose-response curves do the following:
Quantal dose-response curves describe the relationship between drug dosage and the
frequency with which a biologic effect occurs. For example, in individuals administered an
sleep aids medication, Y-axis is the percentage of individuals experiencing sleep at any given
dose. These curves often take the shape of a normal frequency distribution (i.e., bell shape).
This tells us the dosage that induced sleep may vary among various people. Most folks will
fall asleep with a medium-range dose, but there will be outliers—some will be very sensitive
to the drug at low doses, whereas others will be relatively resistant to hypnotic effects until
higher drug levels are achieved.
■Even graded responses can be considered to be quantal if a predetermined level of the
graded response is designated as the point at which a response occurs or not. For example, a
quantal dose-response relationship can be determined in a population for the antihypertensive
drug atenolol. A positive response is defined as at least a 5 mm Hg fall in diastolic blood
pressure.
Quantal dose-response curves are useful for determining doses to which most of the
population responds. This type of information can be useful in determining a starting dosage
to achieve a given level of effect.
■ Quantal dose-response curves are often plotted in a cumulative manner, comparing the
dose of drug on the x-axis with the cumulative percentage of subjects responding to that
dose on the y-axis.
▲Slope (variation in magnitude of response among test subjects in the same population
given the same dose of drug): Provide an estimate of the variability in response of the patient
population to the drug. A steep slope indicates that all the patients respond in a narrow range
of doses, whereas a shallow slope indicates considerable variability in the ability of the drug
to elicit a response in the patient population.
▲By plotting in a cumulative manner, we can transform a bell shape curve into sigmoidal
curve. This type of sigmoidal curve yields useful safety information when the all-or-nothing
responses are defined as therapeutic maximal responses, toxic responses, or lethal responses..
▲ Provide an ED50 value that reflects the dose of drug that produces a effective
response in 50% of the population (also called the median effective dose).
• TD50 (median toxic dose), is the dose that produces toxic effects in 50% of the patient
population.
• LD50 (median lethal dose), the dose at which 50% of patients die
• Comparison of these parameters can provide an estimate of the relative safety of
treatment.
The therapeutic index is defined as the TD50 (the dose that results in toxicity in 50% of the
population) divided by the ED50 (the dose at which 50% of the patients meet the predefined
criteria (also called the median effective dose)).
Therapeutic index (TI) or therapeutic ratio is the ratio of the LD50 and ED50. The TI is a
statement of relative safety of a drug. Large values of TI are desirable because they indicate
that the doses that produce death are much greater than those that produce a therapeutic effect.
For example, if the LD50 is 200 mg and the ED50 is 20 mg, the TI would be 10 (200/20). A
clinician would consider a drug safer if it had a TI of 10 than if it had a TI of 3.
As a rule of thumb, when a drug’s therapeutic index is less than 10 (meaning that less than
a tenfold increase in the therapeutic dose will lead to 50% toxicity), then the drug is defined
as having a narrow therapeutic window.
For example, Figure 2.11 shows the responses to warfarin, an oral anticoagulant with a
narrow therapeutic index, and penicillin, an antimicrobial drug with a large therapeutic index.
1. Warfarin (example of a drug with a small therapeutic index): As the dose of warfarin is
increased, a greater fraction of the patients respond (for this drug, the desired response is a
two-fold increase in prothrombin time) until eventually all patients respond (see Figure 2.11
A). However, at higher doses of warfarin，a toxic response occurs, namely a high degree of
anticoagulation that results in hemorrhage. Note that when the therapeutic index is low, it is
possible to have a range of concentrations where the effective and toxic responses overlap.
That is, some patients hemorrhage, whereas others achieve the desired two-fold prolongation
of prothrombin time. Variation in patient response is therefore most likely to occur with a
drug showing a narro.
2.
Penicillin (example of a drug with a large therapeutic index): For drugs with a large
therapeutic index, such as penicillin (see Figure 2.11B), it is safe and common to give
doses in excess (often about ten-fold excess) of that which is minimally required to
achieve a desired response. In this case, bioavailability does not critically alter the
therapeutic effects.
Ehrlich introduced the concept of therapeutic index in the beginning of last century. Since
then the implications have undergone radical change because of the development of clinical
pharmacology and scientific analysis of clinical data. Earlier, therapeutic index (TI) was
derived from animal experiments, and was defined as the ratio of LD50 (or TD50) to ED50
for some therapcutically relevant effect.
The use of the ED50 and LD50 doses to derive the TI may be misleading as to safety,
depending on the slope of the dose-response curves for therapeutic and lethal effects. To
overcome this deficiency, toxicologists often use another term to denote the safety of a drug –
the Margin of Safety (MOS).
The MOS is usually calculated as the ratio of the dose that is just within the lethal range
(LD1) to the dose that is 99% effective (ED99). The MOS = LD01/ED99. A physician must
use caution in prescribing a drug in which the MOS is less than 1. • Certain safety factor:
The certain safety factor is the dose of drug that produces a lethal effect in 1% of the
population (LD1) divided by the dose that produces a therapeutic effect in 99% of the
population (ED99) (LD1/ED99).
• Therapeutic window is a loosely defined term that generally refers to the range of doses
that produce therapeutic effects with minimal toxic effects. It can be viewed as the lack of
overlap between the quantal dose-response curves for therapeutic and toxic or lethal effects.
There are several indices of the degree of this overlap.
• Protective index: The protective index is calculated as the dose for an undesirable
effect in 50% of patients (TD50) divided by the ED50 for the desired effect (TD50/ED50).
• For both the certain safety factor and the protective index, large values signify that
there is little overlap between the therapeutic and toxic or lethal effects of the drug, and thus
there is a relatively large margin of safety for its use.
Antagonism as a Mechanism of Drug Action
By definition, antagonists can bind their receptors, they, however, have no intrinsic
activity and, therefore, produce no effect by themselves. Nevertheless, an antagonist may be
very clinically “efficacious” or beneficial because it blocks activation of the receptor by
endogenous agonist.
Antagonists, such as β-adrenergic receptor antagonists, (“β-blockers”) have affinity, but no
efficacy, for β-adrenergic receptors. These drugs compete for and block endogenous
norepinephrine or epinephrine from stimulating adrenergic receptors.
Pharmacologic Antagonists
The majority of antagonists used as drug therapy are pharmacologic antagonists. The
antagonist prevents agonist binding the receptor and inhibits the biologic effects generated by
the agonist. The interaction between antagonist and agonist can take several forms, including
competitive reversible, competitive irreversible, and noncompetitive antagonism.
■ Competitive reversible antagonism (also called competitive surmountable antagonism)
▲ The antagonist competes directly for the target receptor with the agonist molecule.
Because the antagonists theoretically have no effect of their own, we need to consider their
effect on the agonist. In the graph in Figure 2-5，we determined the biological effect produced
by a series of concentrations of agonist. We then repeat the same experiment in the presence
of a fixed concentration of an antagonist. This shifts the curve to the right, making the agonist
look less potent.
This is easy to remember and understand. These antagonists are competitive; that is，they
compete for the same site on-the receptor that the agonist wants. If the agonist wins, a
response is produced. If the antagonist wins，no response is produced. In order to activate the
receptor the agonist must bind as normal, but now it faces competition from the antagonist.
As we increase the concentration of agonist, we increase the odds that an agonist molecule
will win the receptor spot and produce an effect. At a high enough agonist concentration, the
poor antagonist doesn’t have a chance at the receptor; it is simply outnumbered.
Therefore a competitive antagonist reduces the response to the agonist. However, if the
concentration of the agonist is increased, it can overcome the receptor blockade caused by the
competitive antagonist.
In other words, blockade by competitive antagonists is surmountable by increasing the
concentration of agonist. With two drugs competing for the same binding site, the drug with
the higher concentration will dominate. Ultimately, an agonist concentration will be reached,
at which all of the receptors needed to elicit a maximal response are occupied by agonist and
a maximal effect will be elicited, but Emax is not affected.
Figure 1 showed:
▲ Increasing the concentration of antagonist produces a greater rightward displacement of
the agonist dose-response curve, and the ED50 value for the agonist increases progressively.
However, a maximal effect can always be reached by increasing the dose of agonist. The
rightward parallel shift of the agonist dose-response curves but with preserved Emax is
characteristic of competitive reversible antagonism (see Figure 1-3).
▲ The magnitude of the rightward shift of the agonist dose-response curve with
increasing antagonist doses is an index of the affinity of the antagonist for the receptor and
can be quantified by calculating a dose ratio, calculated as the ED50 in the presence of
antagonist divided by the ED50 in the absence of antagonist. The dose ratio is used to
calculate a pA2 value, an index of the affinity of the antagonist.
▲The pA2 value indicates the concentration of antagonist when double the agonist is
required to have the same effect on the receptor as when no antagonist is present. The pA2 is
the negative logarithm of the dose of antagonist that necessitates a doubling of agonist dose—
in other words, a dose ratio of 2.
▲ The pA2 scale is an index of antagonist affinity for the receptor. A lower pA2 signifies
greater antagonist affinity with greater effects at lower doses.
■ Competitive irreversible antagonism (also called competitive insurmountable
antagonism) (in older literature these are also labeled as noncompetitive antagonists)
Up to now we have been talking about reversible drug-receptor interactions, but what
happens when an antagonist binds a receptor and won’t let go? This occurs if covalent bonds
form, which are very strong and are not easily broken.
▲ The antagonist competes directly with the agonist for receptor binding as described
previously. As the concentration of antagonist rises, more receptors become blocked
irreversibly. However, the binding forces between the antagonist and receptor are so strong
that the antagonist-receptor complex is virtually irreversible. This leaves fewer receptors for
the agonist to work with, so its maximal effect is reduced permanently, as no amount of
agonist can undo the antagonist-receptor bond. This is shown in Figure 8; there is a
downward shift representing a reduced effect, but KD remains the same.
▲ An important characteristic of this type of antagonism that distinguishes it from
competitive reversible antagonism is that Emax is reduced and the dose response curve
downward, indicating that the agonist can no longer exert maximal effects at any therapeutic
dose.
Drugs that bind covalently to their molecular targets have the benefit of extended duration
of action. There are a number of different noncompetitive antagonists, but most drugs in this
class are irreversible alkylating agents. An example of this class of drug is
phenoxybenzamine, a drug that acts predominantly on α1 adrenergic receptors and is used to
mitigate the effects of catecholamines secreted by adrenal tumors (see Chapter 11). Drugs of
this class contain highly reactive groups, and when they bind to receptors, they form covalent
bonds, occupying the binding site in an essentially irreversible, nonsurmountable manner.
Because they decrease the number of available receptors, noncompetitive antagonists will
usually decrease the maximum response to an agonist without affecting its EC50
(concentration causing half-maximal effect). An advantage of a noncompetitive antagonist is
its long-lasting effect. Because the drug binds a receptor irreversibly, the drug effect lasts
until new receptors are synthesized.
■ Noncompetitive antagonism (also called allotropic or allosteric antagonism)
Noncompetitive antagonists bind to the receptor at a site different from the agonist.
▲
Noncompetitive antagonists do not directly compete with the agonist for binding at
the same binding site but nevertheless impair the ability of an agonist to bind to or
activate the receptor, and thus they prevent a response.
▲ Noncompetitive antagonism can occur through a number of mechanisms:
• Reduction in affinity of agonist binding site for the agonist
• Blockade of agonist-induced change in receptor
• Blockade of coupling of receptor to coupling or signaling mechanisms
▲
Let’s repeat the earlier experiment. We first determine the biological effect produced by
increasing concentrations of an agonist. We then plot the results as shown in Figure 2-5. We
repeat these measurements in the presence of a fixed concentration of an antagonist. The
antagonist binds to its own site and blocks the effect of the agonist. Increasing concentrations
of the agonist cannot overcome this blockade. Therefore, the maximal biological response
produced by the agonist appears to have decreased because of our addition of the
noncompetitive antagonist. Figure 7 shows that in the presence of a fixed dose of
non-competitive antagonist the slope of the curve is flattened, but its position (KD) remains
the same.
▲ Noncompetitive antagonists will exert functional effects similar to those of competitive
irreversible antagonists in that both types of antagonist will decrease the Emax or efficacy of
the agonist.
▲ Because the agonist and antagonist act at different sites on the molecular target,
increasing concentrations of agonist cannot overcome the inhibitory action of the antagonist.
Thus, the effect of a noncompetitive antagonist will be independent of fluctuations in levels
of the endogenous agonist, much like that of a competitive irreversible antagonist.
MOLECULAR MECHANISMS MEDIATING
DRUG ACTION
Extracellular Transduction Mechanisms
A number of dugs act outside of the cell to affect cellular function. Generally, these types
of drugs act via the following:
■ Extracellular enzymes. Drugs acting via this mechanism alter the activity of
extracellular enzymes involved in the synthesis or degradation of endogenous signaling
molecules. These drugs affect the levels of endogenous compounds that then alter cellular
function by acting on their receptors. Examples of clinical utility for this mechanism include:
▲ Angiotensin-converting enzyme (ACE) inhibitors, which prevent the formation of
angiotensin II and are used in the treatment of hypertension
▲ Inhibition of acetylcholinesterase, which results in increased levels of acetylcholine for
the treatment of:
• Neuromuscular disorders
• Glaucoma
Transmembrane Transduction Mechanisms
To this point we have considered the drug response as being elicited by agonist binding to
and activating a receptor. In fact, there are many intervening steps between drug binding or
receptor activation and the ultimate tissue response. In many cases this is because the drug is
not able to interact directly with the cellular mechanisms eliciting the response.( In many
cases, the drug or endogenous ligand is a hydrophilic substance that cannot easily cross the
plasma membrane of the cell and binds to receptors or other targets embedded in the plasma
membrane.) Instead, the drug must rely on intermediaries to relay (transduce) the drug signal
to the cellular communication (second messenger signaling) and effector systems that
ultimately cause the response. In addition, these transduction and signaling mechanisms are
also integral in integrating convergent inputs to the cell and to modulation of drug responses
by cells.
Receptor Coupling and Transduction Mechanisms
In pharmacology, transduction refers to the conversion of the information contained in the
drug molecule (e.g., size, shape) into a signal that can be recognized and acted on by the cell.
This process of receptor coupling, or transduction, is critically important to generating the
ultimate biologic response. Only minute amounts of drug are generally necessary to initiate or
inhibit a response, because transduction mechanisms greatly amplify the signal generated by
the drug-target complex. Indeed, many currently used drugs do not interact directly with
endogenous substances or their receptors but rather interact with transduction events to cause
their actions.
MAJOR RECEPTOR FAMILIES
Pharmacology defines a receptor as any biologic molecule to which a drug binds and
produces a measurable response. Thus, enzymes and structural proteins can be considered to be
pharmacologic receptors. However, the richest sources of therapeutically exploitable
pharmacologic receptors are proteins that are responsible for transducing extracellular signals
into intracellular responses. These receptors may be divided into four families: 1) ligand-gated
ion channels, 2) G protein-coupled receptors, 3) enzyme-linked receptors, and 4) intracellular
receptors.
A. Ligand-gated ion channels or receptor-operated channels. These ion channels possess a
receptor for an endogenous ligand to which the drug can bind. They are composed of a
multimeric protein complex that constitutes both the receptor and the ion channel.
Ligand-gated Ion Channels (LGICs) are a group of transmembrane ion channels that open
when a signal molecule (ligand) binds to an extracellular receptor region of the channel
protein. This binding changes the structural arrangements of the channel protein, which then
causes the channels to open or close in response to the binding of a chemical messenger such
as a neurotransmitter. This ligand-gated ion channel, a type of ionotropic receptor, allows
specific ions (like Na+, K+, Ca2+, or Cl-) to flow in and out of the membrane.
Examples include the following:
• Cholinergic receptors located in skeletal muscle bind nicotine, resulting in opening of
sodium channels, initiation of an action potential in the muscle, and finally muscle
contraction. Neuromuscular (paralyzing) drugs antagonize this nicotinic receptor, thereby
preventing muscle contraction.
B. G protein-coupled receptors
G protein–coupled receptors (GPCRs). GPCRs, also called seven transmembrane pass
receptors, are a large class of receptors that mediate the majority of endogenous transmitter
and hormone driven responses (Figure 1-5).
▲ G proteins are trimeric macromolecules that consist of α, β, and γ subunits.
▲ Ligand activation of the receptor causes the GPCR to interact with G proteins.
• Gα is activated by binding of guanosine-5’-triphosphate (GTP) and dissociation of the
Gα-GTP complex from the receptor and from its companion βγ subunits.
• Activated Gα-GTP complex then activates downstream effector systems (e.g., adenylate
cyclase) to initiate a cascade of cellular events (e.g., cyclic adenosine monophosphate [cAMP]
production) that lead to activation of the effector system and the biologic response.
• Approximately 30% of all clinically used drugs interact with GPCR.
The second messenger cyclic adenosine monophosphate (cyclic AMP, or cAMP), inositol
triphosphate (IP3), diacylglycerol (DAG), and Ca+2 activate or inhibit unique cellular
enzymes in each target cell. Cyclic AMP activates a number of tissue-specific
cAMP-dependent protein kinases. These kinases phosphorylate other enzymes or proteins
that ultimately affect intracellular processes such as ion channel activity, release of
neurotransmitter, regulation of transcription, and numerous other processes. For example, one
of the best studied kinases, protein kinase A, is activated by the increase of cAMP produced
by epinephrine binding to β2- adrenoceptors in muscle. Protein kinase A phosphorylates the
enzyme glycogen phosphorylase, which then increases the breakdown of glycogen to free
glucose, providing the fiiel needed by the muscles to respond to the event that initiated the
release of epinephrine.
C. Enzyme-linked receptors
Receptor-coupled enzymes bypass the G protein coupling mechanism and link directly to
cellular communication cascades. The receptor is directly coupled in some way to kinase
enzymatic activity within the cell. Ligand binding stimulates the kinase enzymatic activity,
which then initiates and amplifies intracellular signals and feedback responses by changing
the phosphorylation status of cellular proteins.
D. Intracellular receptors
The fourth family of receptors differs considerably from the other three in that the receptor is
entirely intracellular and, therefore, the ligand must diffuse into the cell to interact with the
receptor (Figure 2.4). Lipophilic drugs passively cross the cell membrane and thus do not
require cell membrane receptors. As shown in Figure 1-8, one target for these drugs is an
intracellular receptor that activates transcriptional pathways. In this mechanism, the agonist
receptor complex diffuses to DNA, where it binds to DNA binding elements. Via this
mechanism drugs act directly or through recruitment of coactivators or co-repressors, which
increase or decrease transcription of RNA to ultimately change protein expression. This
process is referred to as ligand gated transcriptional regulation. In many cases these drugs
effect long-term changes by affecting gene transcription. Receptors using this coupling
mechanism include:
■ Sex hormones: estrogen, androgens
■ Glucocorticoids
■ Mineralocorticoids
■ Thyroid or retinoid receptor family
■ Vitamin D receptors
RECEPTOR DESENSITIZATION AND
SUPERSENSITIVITY
The response of any cell to hormones or neurotransmitters is tightly regulated and can vary
depending on other stimuli impinging on the cell. Very often, the number of receptors in the
membrane of a cell or responsiveness of the receptors themselves is regulated.
One hormone can sensitize a cell to the effects of another hormone, and more commonly,
when a cell is continuously exposed to stimulation by a transmitter or hormone, it may
become desensitized. Repeated or continuous administration of an agonist (or an antagonist)
may lead to changes in the responsiveness of the receptor. To prevent potential damage to the
cell (for example, high concentrations of calcium initiating cell death), several mechanisms
have evolved to protect a cell from excessive stimulation. When repeated administration of a
drug results in a diminished effect, the phenomenon is called tachyphylaxis. The receptor
becomes desensitized to the action of the drug (Figure 2.5). Other types of desensitization
occur when receptors are down-regulated. Binding of the agonist results in molecular changes
in the membrane-bound receptors such that the receptor undergoes endocytosis and is
sequestered from further agonist interaction. These receptors may be recycled to the cell
surface, restoring sensitivity, or, alternatively, may be further processed and degraded,
decreasing the total number of receptors available. Some receptors, particularly voltage-gated
channels, require a finite time (rest period) following stimulation before they can be activated
again. During this recovery phase they are said to be “refractory” or “unresponsive.”
An example of this phenomenon is the loss of the ability of inhaled β2 adrenergic
agonists to dilate the bronchi of asthmatic patients after repeated use of the drug (see Chapter
16).
Receptors may also be up regulated, and this phenomenon can result in receptor
supersensitivity. Up regulation can occur after exposure of the receptor to an antagonist, or
inhibition of transmitter synthesis or release. In addition, other hormones can increase
receptor number. For example, excessive production of thyroid hormone can increase the
synthesis of b adrenergic receptors in cardiac tissue, leading to some of the signs and
symptoms of Graves’ disease (see Chapter 42). Thus the number of cell-surface receptors,
and thereby hormone sensitivity, can be continuously regulated. This property of receptor
biology can be exploited therapeutically. For example, during the third trimester of pregnancy,
under the influence of nuclear hormones, the number of b2 adrenergic receptors on uterine
smooth muscle is dramatically increased, allowing the use of selective b2 adrenergic agonists,
like terbutaline, to delay premature labor (see Chapter 11).
Although we classify drugs according to their principal actions, it is clear that no drug
causes only a single, specific effect. It is exceedingly unlikely that any kind of drug molecule
will bind to only a single type of receptor molecule. Even if the chemical structure of a drug
allowed it to bind to only one kind of receptor, the biochemical processes controlled by such
receptors would take place in many cell types and would be coupled to many other
biochemical functions; as a result, the patient and the prescriber would probably perceive
more than one drug effect.
Drug effects may be desired (therapeutic effects) as antihypertesive， antidiabetic,
anticoagulant effect or undesired (adverse effects) which means any effect produced by the
drug other than the therapeutic effect.
Adverse Drug Reactions
No therapy that is effective is free of adverse effects.
Any substance that is capable of producing a therapeutic effect can also produce unwanted
or adverse effects. The risk of such effects ranges from near zero (with, for example, nystatin
and hydroxocobalamin) to high (with, for example, immunosuppressive or antineoplastic
drugs).
Definition
TheWorld Health Organization’s definition of an adverse drug reaction is “a response to a
drug that is noxious and unintended and occurs at doses normally used in man for the
prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.
This definition has been widely used, but has defects. One obvious defect is that adverse
reactions can occur at doses other than those that are used in the way that the definition
describes, for example after a test dose for an adverse reaction. Furthermore, the use of the
word noxious excludes adverse reactions that may be inconvenient but not harmful, such as
bruising after the use of aspirin or cough from the use of an ACE inhibitor, which a patient
may consider important.
An alternative definition, which specifically excludes trivial unwanted reactions (for
example, a slight dryness of the mouth), is “a harmful or significantly unpleasant effect
caused by a drug at doses intended for therapeutic effect (or prophylaxis or diagnosis), which
warrants reduction of dose or withdrawal of the drug and/or foretells hazard from future
administration”. However, these definitions (and others reviewed elsewhere exclude error as
a source of adverse reactions. Moreover, they exclude reactions to test doses and reactions
due to contaminants (for example, in herbal medicines) or supposedly inactive excipients in a
pharmaceutical formulation.
The following definition of an adverse drug reaction, slightly modified from an earlier
version,
avoids these and other problems [58]: “an appreciably harmful or unpleasant reaction,
resulting from an intervention related to the use of a medicinal product, usually predicting
hazard from future administration and warranting prevention, or specific treatment, or
alteration of the dosage regimen, or withdrawal of the product”.
ABCDE SYSTEM (ADVERSE EVENTS OF TYPE A, B, C, D, E)
Adverse drug reaction is a broad term comprising many problems associated with drug use.
It includes side effects, toxicity, drug–drug interactions, drug–physiology interactions,
drug–laboratory test interactions, allergic reactions, and idiosyncratic reactions.
Adverse drug reactions are frequently classified as ‘type A’ and ‘type B’ reactions. An
extended version of this classification system is shown here:
About 80% of all adverse drug reactions are type A and for most prescription this type of
reaction is described in handbooks such as the physician’s desk reference.
Type “B” reactions are not dose dependent and except one reaction type, are not usually
related to the pharmacological reactions of the drug. They are often not discovered until after
the drug has been marketed. Both environmental and genetic factors are then thought to be
important in the development of reactions of this type.
There are many adverse reactions, which cannot be classified because the mechanisms
responsible for them are not known. These reactions are uncommon, unpredictable and not
reproducible in animal models. Unfortunately, accurate calculation of the incidence of
adverse drug reactions is difficult since most of these reactions go unreported.
TYPE A ADVERSE REACTION
Rawlins and Thompson of Newcastle, Great Britain, have classified adverse events into
type A and type B on the basis of the mechanism of action. A type A event is one that is due
to an extension of the active pharmacologic properties of the drug (A indicates augmented).
They are also called predictable or anticipated events. They are generally less severe and
more frequent than type B events. This augmented pharmacologic action may occur at the
targeted receptors or at other nontargeted receptors producing lateral effects, parallel effects,
or side effects.
They are usually detected during the clinical trials done before marketing.
There are two subclasses:
Side effect (Predictable, dose-related)
Any unintended effect (undesired pharmacologic effect) of a pharmaceutical product,
occurring at doses normally used and is related to the pharmacological properties of a drug.
Drugs often produce side effects by the same mechanism that is responsible for their
therapeutic effect on the target organ. For example, atropine may cause dry mouth and
urinary retention by the same mechanism that reduces gastric add secretion in the treatment
of peptic ulcer, namely，by muscarinic receptor antagonism. This type of adverse effect may
be managed by reducing the drug dosage or by substituting a drug that is more selective for
the target organ.
Excessive therapeutic effect (Toxicity/overdose (Predictable, dose-related))
(Pharmacological toxic reaction is an exaggerated normal response to the drug due to drug
overdose, such as hypotension with antihypertensive drugs, hypoglycemia with antidiabetic
drugs. ) This adverse drug reaction is associated with the overdose of the drug and may be an
extension of its therapeutic effect or may be an effect on another system. This results from
the excess stimulation of targeted receptors by the therapeutic agent. For example,
Morphine-induced sedation/respiratory depression; Paracetamol overdose causing liver
toxicity
Only unintentional overdoses are classified as ADRs i.e. due to error The most common
reason for drug overdose is a failure to take into account the size of the patient; overdose
toxicity is more common in children and the frail elderly. The second most common reason
for overdose is failure to adjust dosing to take into account the patient’s inability to
metabolize or eliminate the drug. Therefore, if the doctor is aware of the proper dose and alert
to the patient’s size as well as their liver and kidney function, chances of overdosing are
minimized.
TYPE B ADVERSE REACTION
A type B reaction is one that is not due to an extension of the active pharmacologic
properties of the drug; the B indicates bizarre. They are called pharmacologically unexpected,
unpredictable, or idiosyncratic adverse reactions.
There are two subclasses:
ALLERGY
An allergic reaction is an immune system-mediated response to an allergen. Most drugs are
too small to be antigenic by themselves, so they, acting as a hapten (incomplete antigen),
must combine with an endogenous protein to form an antigen that induces antibody
production. The antigen and antibody subsequently interact with body tissues, and the
resultant cascade of events includes histamine release to produce a wide variety of adverse
effects.
In the Gell and Coombs classification system, allergic reactions are divided into four
general types, each of which can be produced by drugs. Type I reactions are immediate
hypersensitivity reactions that are mediated by immunoglobulin E antibodies. Examples of
these reactions are urticaria (hives), atopic dermatitis, and anaphylactic shock. Type II
reactions are cytolytic reactions that involve immune complement and are mediated by
immunoglobulins G and M. Examples are hemolytic anemia, thrombocytopenia, and
drug-induced lupus erythematosus. Type III reactions are mediated by immune complexes.
The deposition of antigen-antibody complexes in vascular endothelium leads to inflammation,
lymphadenopathy, and fever (serum sickness). An example is the severe skin rash seen in
patients with a life- threatening form of drug-induced immune vasculitis that is known as
Stevens-Johnson syndrome. Type IV reactions are delayed hypersensitivity reactions that are
mediated by sensitized lymphocytes. An example is the ampicillin- induced skin rash that
occurs in patients with viral mononucleosis.
In this condition, the abnormal reaction occurs usually from the second or subsequent
doses. The first dose (antigen) generally stimulates the body to produce some reactive
substance (antibody), which sensitizes the tissues of the body. When a second dose of that
drug is given the reaction {antigen—antibody reaction 1 occurs in the tissue called allergic
reaction. The reactions may be immediate (anaphylactic) or a delayed one (hypersensitivity).
The anaphylactic reactions are—fall of blood pressure, shock, collapse, bronchospasm,
cyanosis and even death. The hypersensitivity reactions are—urticaria, skin rash, asthma,
drug fever, dermatitis, hepatitis, hay fever etc.
Management
Immediate and acute allergic reactions lead to acute anaphylactic shock which is dangerous
for patient and may even be fatal e.g. penicillin, sera, vaccines. Steps which can be taken
include:
History taking of previous allergic reactions
Test dose should be given first
Drugs required to deal with emergency should be kept ready
Sometimes skin rashes or urticaria along with fever and pain in joints and swelling of
lymph nodes may occur after a few days. This is delayed type of allergy called serum
sickness type reaction.
The primary approach to allergic reactions is to avoid them by obtaining a thorough patient
health history with respect to allergic reactions. The doctor should interview the patient about
allergies. When a patient claims to have had an allergic reaction, further questioning is
necessary.
Allergic responses are treated by withdrawal of the drug and possibly antihistamines or
corticosteroids. Depending on the severity of the reaction, as in the case of laryngeal swelling
(anaphylaxis), it may be necessary to give an injection of epinephrine to physiologically
reverse the allergic response.
A pseudoallergy is a bodily reaction with symptoms similar to that of an allergy but it lacks
immunological specificity.
Idiosyncratic
Idiosyncratic reactions are unexpected drug reactions caused by a genetically determined
susceptibility. The term idiosyncratic is often used in a broad sense to designate qualitatively
abnormal adverse reactions that occur in a given individual and whose mechanism is not yet
understood. This reaction occurs usually from the very first dose of the drug. These reactions
are usually quite rare and in some cases may be due to a genetic or acquired enzyme
abnormality with the formation of toxic metabolites. This is also known as primary toxicity.
About half the people in the United States have low activity of N-acetyltransferase, a liver
enzyme that helps metabolize some drugs and many toxins. People with low activity of this
enzyme metabolize many drugs slowly, and these drugs tend to reach higher blood levels and
remain in the body longer than in people with high activity of N-acetyltransferase.
About 1 in 1,500 people have low levels of pseudocholinesterase, a blood enzyme that
inactivates drugs such as succinylcholine, which is given with anesthesia to temporarily relax
muscles. Although this enzyme deficiency isn't common, its consequences are important. If
succinylcholine isn't inactivated, it leads to paralysis of muscles, including those involved in
breathing. This may require prolonged use of a ventilator.
Glucose-6-phosphate dehydrogenase, or G6PD, is an enzyme normally present in red
blood cells that protects these cells from certain toxic chemicals. About 10 percent of black
men and fewer black women have G6PD deficiency. Some drugs (for example, chloroquine,
pamaquine, and primaquine, used to treat malaria, and aspirin, probenecid, and vitamin K)
destroy the red blood cells in people with G6PD deficiency, causing hemolytic anemia.
Types C, D, and E are not mechanisms but characteristics of their manifestations; they are
not referred to frequently in the literature. The letter C refers to continuous, chronic. Type D
refers to delayed in appearance, making them difficult to diagnose. Type E refers to end of
use.
Type C reactions (Continuous reaction or Chronic)
Type C reactions are due to long term use e.g. NSAIDs causing analgesic nephropathy due
to long term usage of drugs and changing doses.
These reactions are associated with long-term drug therapy e.g. Benzodiazepine
dependence and Analgesic nephropathy. They are well known and can be anticipated.
Tend to be both serious and (relatively) common and have profound effect on public health
e.g. NSAIDS induced renal failure, oral contraceptive induced diabetic microangiopathy and
breast tumors.
Type D reactions (Delayed adverse reactions)
Type D refers to a delayed type of reaction (‘D’ for delayed)such as carcinogenic and
teratogenic effects. These reactions are delayed in onset and are very rare since extensive
mutagenicity and carcinogenicity studies are done before drug is licensed.
Teratogenesis is a prenatal toxicity characterized by structural or functional defects in the
developing embryo or fetus. Thalidomide went on the market as a treatment for morning
sickness in more than 40 countries beginning in 1958. It was soon found to have teratogenic
effects—producing severe malformations in infants born of mothers who had taken the drug
during early pregnancy. These included phocomelia (“seal limbs,” in which the long bones in
the arms and legs fail to develop)
Carcinogenesis is the ability of some substances to induce cancer.
Uncommon, usually dose related and occur sometime after drug use e.g. adenocarcinoma
in daughters of women who have taken diethylstilboestrol, bladder cancers following long
term cyclophosphomide, gene toxicity of some drugs, carcinoma of the renal pelvis following
phenacetin etc. Mechanisms:
1. DNA alteration
Griesofulvin (antifungal) & alkylating cytotoxics (cancer), they are anti-mitotic, acting on
spindle formation
2. Immunosuppression
Immunosuppressant increase incidence of cancer e.g. organ transplantation & methotrexate
in rheumatoid arthritis
3. Hormonal
Long term use of estrogen replacement in post menopausal therapy may induce
endometrial cancer
Type E reactions (Ending of drug)
Type E, or ‘end-of-use’ reactions, are associated with the withdrawal of a medicine. Type
E (end of treatment) ADRs occur when drug treatment is terminated suddenly.
–Sudden discontinuation ( abrupt withdrawal) (Withdrawal reactions)
An example is insomnia, anxiety and perceptual disturbances following the withdrawal of
benzodiazepines
Uncommon and related to discontinuation that is too abrupt e.g. Addisonian crisis (adrenal
insufficiency) following steroid withdrawal, opiate withdrawal syndrome, rebound
convulsions on withdrawal of carbamazepine in non-epileptic patients, myocardial infarction
following beta blocker withdrawal.
Type F refers to unexpected failure of therapy (‘F’ for failure).
Common, often dose-related and caused by drug interactions e.g. inadequate dose of oral
contraceptive or concomitant administration with enzyme -inducing drugs
Type F (failure of treatment) ADRs can be particularly informative if thoroughly
investigated. There can be a multitude of reasons for treatment failure and a direct
drug-related cause is unusual.
Reporting
ADR reporting is important when new agents with limited clinical experience enter the
marketplace. Initial reports of adverse reaction have taken up to seven years for trends to
begin to appear in the literature. Thus, efforts in postmarketing surveillance have helped in
the ability to recognize trends earlier.
The need for reporting ADRs should be considered as important as treatment and overall
care of the patient. The Food and Drug Administration (FDA) legally mandates that
pharmaceutical manufacturers report all ADRs. In instances of death, unexpected, or serious
reactions, ADRs must be reported to the FDA within 15 days. In comparison, ADRs reported
by health professional occur on a voluntary basis. The Joint Commission on Accreditation of
Healthcare Organizations (JCAHO) requires hospitals to have written procedures for ADR
reporting, evaluating, and monitoring. In addition, the JCAHO requires institutions to have a
means in which ADRs can be utilized to improve patient care. Typically, the hospital’s
pharmacy and therapeutics (P and T) committee reviews monthly summaries of ADRs. The
reporting of ADRs occurring in other settings is still unclear. This is the case with ambulatory
or community settings. However, the impetus is to devise means in which to capture ADRs in
non-traditional arenas.
FACTORS MODIFYING DRUG ACTION
A therapeutic dose of a drug is the amount required to elicit a desired effect. The dose is
usually expressed as a range. The minimum dose or the lower limit of the dose is essential for
eliciting an intended therapeutic response whereas the maximum dose or the higher limit of
the dose is the amount of the drug substance that can be tolerated by an average individual.
The pharmacist is much concerned with the maximum limit of the doses which, if
exceeded, may cause untoward effects in the patient. The actual dose of a drug is to be
decided by the prescriber depending on patient's age, sex, symptoms, his medication history
and the factors like tolerance, idiosyncrasy, route of administration etc.
The response produced by a therapeutic dose of a given drug can vary among patients, and
this is influenced by biological variations.
•I. Physiological Factors.
•II. Pathological Factors (Diseases).
•III. Genetic Factors.
•IV. Environmental Factors.
•V. Interaction with other drugs.
I. Physiological Factors
•Age
•Sex
•Pregnancy and Lactation
•Body weight
•Food
I. Physiological Factors
1. AGE
In neonates，and especially in premature infants, the capacity to metabolize and excrete
drugs is often greatly reduced because of low levels of drug biotransformation enzymes.
Oxidative reactions and glucuronate conjugation occur at a lower rate in neonates than in
adults, whereas sulfate conjugation is well developed in neonates. Consequently, some drugs
that are metabolized primarily by glucuronate conjugation in adults (drugs such as
acetaminophen) are metabolized chiefly by sulfate conjugation in neonates. Nevertheless, the
overall rate of biotransformation of most drugs is lower in neonates and infants than it is in
adults.
In comparison with children and young adults, elderly adults also tend to have a reduced
capacity to metabolize drugs. Biotransformation via oxidative reactions usually declines more
than biotransformation via drug conjugation. Therefore it may be safer to use drugs that are
conjugated when the choice is available. For example, benzodiazepines that are metabolized
by conjugation, such as lorazepam and temazepam，are believed to be safer for treatment of
the elderly than are benzodiazepines that undergo oxidative biotransformation (e.g.,
diazepam).
Renal function is lower in neonates and elderly adults than it is in young adults, and this
affects the renal excretion of many drugs. For example, the half-lives of aminoglycoside
antibiotics are greatly prolonged in neonates. Glomerular filtration declines 35% between the
ages of 20 and 90 years, with a corresponding reduction in the renal elimination of many
drugs.
A factor in the consideration of a drug to be used and the modifications of drug dosage is
the response of different age groups to the effects of drugs. For instance, children are more
reactive to certain drugs (narcotics). And because of general physical deterioration, the aged
patient responds differently to drugs than the younger individual. So the very young and the
very old tend to have increased sensitivity to drugs，the dosage per kilogram of body weight
should be reduced when most drugs are used in the treatment of these populations.
This will increase the possibility of an overdose, even at normally prescribed levels
because most drugs are developed and tested in young to middle-aged adults. (The adult dose
is for people between 18 and 60 years of age.)Drug dosages for these two groups must be
carefully calculated and treatment starts with very small doses. The British Pharmacopoeia
gives average dose for the adult person between eighteen to sixty years of age. The children
below 18 and persons above 60 should be given a dose below the adult dose to avoid adverse
effect. In general, children require smaller doses than adults. Either Young's formula (based
on age) or Clark's formula (based on weight) can be used for calculating the doses for
children but the formula based on body surface area is more reliable.
2. SEX.
Drug dosage may be subject to modification because of the sex factor. (Women usually,
require a relatively smaller dose than man.) A decreased drug dosage might be necessary for
women in contrast to the larger amount given to men, because of the difference of
susceptibility of men and women to the effects of drugs. Gender based differences in drug
response appear to be related to hormonal fluctuations. Gender differences may also be due to
differences in body composition. Males need higher doses than females owing to the higher
bulky muscles and androgen which is an enzyme inducer.
•Testosterone increases the rate of biotransformation of drugs.
•Decreased metabolism of some drugs in female (Diazepam).
•Females are more susceptible to autonomic drugs ( estrogen inhibits choline estrase).
Women used to be excluded from drug studies. In 1993 the FDA stated that women will
be included in clinical drug trials. Since then many studies have been completed and show
that men and women do show differences in absorption, distribution, metabolism, and
excretion (ADME).
Drugs should he avoided as far as possible during pregnancy and lactation to prevent
harmful effect on the fetus and the baby.
Drugs administered during pregnancy may be harmful to the development of the fetus
because of their teratogenic effects. Drugs may cross the placental barrier.
Agents that are excreted in milk during lactation may be also harmful to the infant.
3. Pregnancy
Drugs taken by a woman during pregnancy or lactation can cause adverse effects in the
fetus or infant.
The risk of drug-induced developmental abnormalities known as teratogenic effects is the
greatest during the period of organogenesis from the 4th to the 10th week of gestation. After
the 10th week, the major risk is to the development of the brain and spinal cord. An estimated
1% to 5% of fetal malformations are attributed to drugs. Although only a few drugs have
been proven to cause teratogenic effects, the safety of many other drugs has not yet been
determined.
The FDA has divided drugs into five categories based on their safety in pregnant women.
Drugs in Categories A and B are relatively safe. Drugs in Category A have been shown in
clinical studies to pose no risk to the fetus, whereas those in Category B may have shown risk
in animal studies but not in human studies. For drugs in Category C, adverse effects on the
fetus have been demonstrated in animals, but there are insufficient data in pregnant women,
so risk to the fetus cannot be ruled out. Drugs in Category D show positive evidence of risk to
the fetus, and drugs in Category X are contraindicated during pregnancy.
Drugs of choice for pregnant women are listed in clinical references and are selected on the
basis of their safety to the fetus as well as their therapeutic efficacy. For example, penicillin，
cephalosporin, and macrolide antibiotics (all Category B drugs) are preferred for treating
many infections in pregnant women, whereas tetracycline antibiotics (Category D) should be
avoided. Acetaminophen (Category B) is usually the analgesic of choice in pregnancy, but
ibuprofen and related drugs are also in Category B and may be used when required. For the
treatment of nausea and vomiting of pregnancy, the combination of pyridoxine (Category A)
in combination with doxylamine (Category B) is the only medication specifically labeled for
this indication by the FDA. Other drugs considered relatively safe for use in pregnancy
include insulin and metformin (GLUCOPHAGE) for treating diabetes mellitus (both
Category B drugs), famotidine (PEPCID) and omeprazole (PRILOSEC) for reducing gastric
acidity (Category B drugs), diphenhydramine (BENADRYL) for treating allergic reactions
(Category B), and tricyclic antidepressants such as desipramine (NORPRAMIN) for treating
mood depression (Category B). Most antiepileptic drugs pose some risk to the fetus, and the
selection of drugs for treating epilepsy in pregnant women requires careful consideration of
the risks and benefits of such medication.
Some drugs can be taken by lactating women without posing a risk to their breast-fed
infants. Other drugs place the infant at risk for toxicity. As a general rule, breast feeding
should be avoided if a drug taken by the mother would cause the infant’s plasma drug
concentration to be greater than 50% of the mother’s plasma concentration. Clinical
references provide guidelines on the use of specific drugs by lactating women.
Weight
Weight is a factor in determining drug dosage for infants, children, or obese patients.
The magnitude of drug response is a function of the concentration of drug attained at the
site of action, and the drug concentration at site of action is based on the ratio between the
amount of drug administered and size of the body.
The usual doses for drugs are mentioned generally for 70 kg adult. The dose calculations
for abnormally thin or obese patients are required to calculate on the basis of body weight.
Dosage adjustments based on weight are generally not made for adults who are slightly
overweight. Usually a person of large stature requires a larger amount of a drug than the
individual of smaller body stature.
Food
Drugs taken by mouth must be absorbed through the lining of the stomach or the small
intestine. The food may affect the rate and the extent of absorption from the GI tract.
Consequently, the presence of food in the digestive tract may reduce absorption of a drug.
(Dairy products contain calcium and may decrease the absorption of tetracycline and
fluorquinolone derivatives by forming a complex (when molecules of different chemicals
bind together-protein binding) Often, many antibiotics should be administered at least 1 hour
before or two hours after each meal to achieve the appropriate levels of absorption.
The action of drugs taken by mouth is greatly modified due to the presence or absence of
food, in the stomach and intestine. The irritant drugs, like iron is better tolerated and absorbed
when given after food. Adrenaline, Insulin, etc. should be given by Injection for they are
destroyed by the digestive enzymes when given by mouth. Magnesium sulphate acts as
purgative when given by mouth but acts as sedative when given by I. V. Sleeping pills acts
better when given at bed time than during day time.
Dietary Supplements
Dietary supplements, including medicinal herbs, are products (besides tobacco) that
contain a vitamin, mineral, herb, or amino acid and that are intended as a supplement to the
normal diet. Supplements are regulated as foods, not as drugs, so they are not tested as
comprehensively. However, they may interact with prescription or over-the-counter drugs.
People who take dietary supplements should tell their doctors and pharmacists, so that
interactions can be avoided.
Alcohol: Although many people do not consider alcohol a nutrient, it affects body
processes and interacts with many drugs. For example, taking alcohol with the antibiotic
metronidazole can cause flushing, headache, palpitations, and nausea and vomiting. Doctors
or pharmacists can answer questions about possible alcohol and drug interactions.
II. Pathological Factors
Pathological conditions of the body also modify the drug action. Diseases cause individual
variation in drug response
Hepatic and renal disease may reduce the capacity of the liver and kidneys to biotransform
and excrete drugs，thereby reducing drug clearance and necessitating a dosage reduction to
avoid toxicity. Heart failure and other conditions that reduce hepatic blood flow may also
reduce drug biotransformation. Oxidative drug metabolism is usually impaired in patients
with hepatic disease, whereas conjugation processes may be little affected.
Guidelines for dosage adjustment in patients with hepatic or renal disease are available and
can be found in clinical references. Dosage adjustments are made by reducing the dose,
increasing the interval between doses, or both. Adjustments for individual patients are usually
based on laboratory measurements of renal or hepatic function and on plasma drug
concentration.
Drug effect can be modified when a pathologic condition is present. For example, a patient
with hyperthyroidism may he highly sensitive to small amounts of a nervous system
stimulant, such as caffeine, or a patient with a cranial injury may be highly sensitive to
morphine, because of its respiratory depressant effect, whereas the hyperthyroid patient can
better tolerate the drug.
III. Genetic Factors
GENETIC POLYMORPHISM
Genetic variation (polymorphism) accounts for some of the variability in the effect of
drugs.
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. Isoniazid may be acetylated either rapidly or slowly according to
genetic difference in the person. In American black and white population 50% are rapid and
50% are slow acetylates and in Latin Americans 35% slow acetylates and hence more toxicity
in them. (Because of their genetic makeup, some people metabolize drugs slowly; a drug may
accumulate in the body and cause toxicity. Other people have a genetic makeup that causes
them to metabolize drugs quickly; a drug may be metabolized so quickly that drug levels in
the blood never become high enough for the drug to be effective.)
Genetic differences influence the dose of a drug and response to drugs among the races and
certain persons in the same population. Genetic differences in the way drugs affect the body
(pharmacodynamics) are much less common than differences in the way the body affects
drugs (pharmacokinetics). The largest contributing factor to variability is metabolism. The
study of genetic differences in the response to drugs is called pharmacogenetics.
( Pharmacogenetics is the study of the relationship between genetic factors and drug
response.) 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.
The P-450 enzyme system is the liver's major mechanism for inactivating drugs. The levels
of P-450 activity determine not only the rate at which drugs become inactivated but also the
point at which the enzyme system becomes overwhelmed. Many factors can alter P-450
activity. Differences in the activity of this enzyme system profoundly influence drug effects.
For example, in people with normal enzyme levels, the effects of the sleep aid flurazepam
last about 18 hours; in people with low enzyme levels, the effects can last more than 3 days.
Sometimes genetic differences affect drug metabolism in other ways. For example, at usual
dose levels, a drug may be metabolized at normal speed; but in some people, if a drug is
given at a high dose or with another drug that uses the same system to metabolize it, the
system may be overwhelmed and the drug may reach toxic levels.
Example:
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.
About half the people in the United States have low activity of N-acetyltransferase, a liver
enzyme that helps metabolize some drugs and many toxins. People with low activity of this
enzyme metabolize many drugs slowly, and these drugs tend to reach higher blood levels and
remain in the body longer than in people with high activity of N-acetyltransferase.
Certain anesthetics cause a very high fever (a condition called malignant hyperthermia) in
about 1 in 20,000 people. Malignant hyperthermia stems from a genetic defect in muscles that
makes them overly sensitive to some anesthetics. Muscles stiffen, the heart races, and blood
pressure falls. Although malignant hyperthermia isn't common, it is life threatening.
To make sure a person gets enough drug for a therapeutic effect with little toxicity, doctors
must individualize therapy: They must select the right drug; consider the age, sex, size, diet,
race, and ethnic origin of the person; and adjust the dose carefully. The presence of disease,
use of other drugs, and limited knowledge about interactions of these factors complicate this
process.
IV. Environmental Factors
Microsomal Enzyme Inducers
–Tobacco Smoke
–Smokers metabolize drugs more rapidly than non smoker.
Chemicals in cigarette smoke can increase the activity of some liver enzymes. This is why
smoking decreases the effectiveness of some analgesics (such as propoxyphene) and some
drugs used for lung problems (such as theophylline).
e.g., Hydrocarbons in tobacco smoke, charcoal broiled meat induce CYP1A
V. Drug interaction
A drug interaction is defined as a change in the pharmacologic effect of a drug that results
when it is given concurrently with another drug or with food. Drug interactions may be
caused by changes in the pharmaceutical，pharmacodynamic, or pharmacokinetic properties
of the affected drug (Table 4-3).
Pharmaceutical Interactions
Pharmaceutical interactions are physicochemical interactions and are caused by a chemical
reaction between drugs before their administration or absorption. Pharmaceutical interactions
occur most frequently when drug solutions are combined before they are given intravenously.
For example, if a penicillin solution and an aminoglycoside solution are mixed, they will
form an insoluble precipitate, because penicillins are negatively charged and aminoglycosides
are positively charged. Many other drugs are incompatible and should not be combined
before they are administered.
Pharmaceutical interactions are too numerous to list in detail, but they can be simply
avoided:
-by using only dextrose or saline for drug infusion;
-by not mixing drugs in the same infusion solution, unless the mixture is known to be safe
(For example potassium chloride with insulin).
Pharmacodynamic interactions
– antagonism
– synergism - 2 drugs act on a target organ by different mechanisms with the effect being
greater
than the sum of the separate effects of the drugs
– additivity - 2 drugs act on the same receptors and the combined effect is the sum of the
2 drugs’ effects, up to a maximum effect
– potentiation - type of synergism in which one drug has no effect but can increase the
effect of the other drug
Pharmacodynamic interactions occur when two drugs have additive，synergistic, or
antagonistic effects on a tissue, organ system, microbe, or tumor cells.
additivity - 2 drugs act on the same receptors and the combined effect is the sum of the 2
drugs’ effects, up to a maximum effect
synergism - 2 drugs act on a target organ by different mechanisms with the effect being
greater
than the sum of the separate effects of the drugs
An additive effect is equal to the sum of the individual drug effects, whereas a synergistic
effect is greater than the sum of the individual drug effects. When two drugs with similar
mechanisms are given together, they typically produce additive effects. This is also referred
to as summation. However, if the effect of two drugs exceeds the sum of their individual
effects, this is referred to as potentiation or synergism. When two drugs with different
mechanisms are given together, they will have the effect being greater than the sum of the
separate effects of the drugs. This is also referred to as synergism (2+2=6). Synergism may
be used clinically as in the case of oral contraceptives given. However, synergism is not
always beneficial as seen in the co-administration of alcohol and antidepressants. Potentiation
requires that the drugs act at different receptors or effector systems. (potentiation - type of
synergism in which one drug has no effect but can increase the effect of the other drug)An
example of potentiation would be the increase in beneficial effects noted in the treatment of
AIDS by combination therapy with AZT (a nucleoside analog that inhibits HIV reverse
transcriptase) and a protease inhibitor (protease activity is important for viral replication), or
the combined effects of norepinephrine and cocaine on arterial blood pressure.
Antagonism occurs when an agonist and antagonist interacts at the receptor. This happens
with beta- agonists such as salbutamol, and beta- blockers (antagonists) such as propranolol.
For example, naloxone reverses the effects of opiates.
Pharmacokinetic Interactions
In pharmacokinetic interactions, a drug alters the absorption, distribution，
biotransformation, or excretion of another drug or drugs.
Altered Drug Absorption
There are several mechanisms by which a drug may affect the absorption and
bioavailability of another drug. One mechanism involves binding to another drug in the gut
and preventing its absorption. For example, cholestyramine, a bile acid sequestrant, binds to
digoxin and prevents its absorption. Another mechanism involves altering gastric or intestinal
motility so as to affect the absorption of another drug. Drugs tend to be absorbed more
rapidly from the intestines than from the stomach. Therefore a drug that slows gastric
emptying, such as atropine，often delays the absorption of another drug. A drug that increases
intestinal motility, such as a laxative, may reduce the time available for the absorption of
another drug, thereby causing its incomplete absorption.
Altered Drug Distribution
Protein-binding displacement
Protein-binding displacement causes an increase in the circulating concentration of
unbound drug. This will cause higher concentrations of the original drug in the plasma and a
possible toxicity reaction. However, this primarily occurs with highly protein bound medical
drugs that have narrow therapeutic margins of safety, such as the anticoagulant warfarin
(protein binding 98%) and phenytoin (protein binding 90%)
Many drugs displace other drugs from plasma proteins and thereby increase the plasma
concentration of the free (unbound) drug, but the magnitude and duration of this effect are
usually small. As the free drug concentration increases, so does the drug’s rate of elimination,
and any change in the drug’s effect on target tissues is usually short-lived. Such interactions
are at worst transient, and if the precipitant drug is introduced slowly they are not clinically
important.
Altered Drug Biotransformation
The most important area of drug–drug interactions is drug metabolism.
Some drugs can alter this enzyme system, causing the inactivation of another drug to
proceed more quickly or more slowly than usual. Some drugs induce the synthesis of these
enzymes, thereby accelerating their own metabolism and the metabolism of other drugs.
Some drugs inhibit these metabolizing enzymes, thereby slowing their own metabolization or
slowing the metabolization of other drugs.
Induction of drug metabolism
Induction of the metabolism of a drug reduces the amount of drug in the body, and
therefore reduces its effects. An important example is unwanted pregnancy when an enzyme
inducing drug such as carbamazepine, phenytoin, or rifampicin is taken along with an oral
contraceptive.
For example, because barbiturates such as phenobarbital increase the liver's enzyme
activity, drugs such as warfarin become less effective when taken during the same period.
Therefore, doctors may need to increase the doses of certain drugs to compensate for this
effect. However, if phenobarbital is later stopped, the levels of other drugs may increase
dramatically, leading to potentially serious side effects.
Enzyme induction is usually maximal after several days of continuing drug administration.
Enzyme induction increases the clearance and reduces the half-life of drugs biotransformed
by the enzyme. When the inducing drug is discontinued, the synthesis of P450 enzymes
gradually returns to the pretreatment level.
Inducers of cytochrome P450 enzymes include barbiturates，carbamazepine，and rifampin,
which bind to regulatory domains of cytochrome P450 (CYP) genes and increase gene
transcription. These agents induce the CYP1A2, CYP2C9, CYP2C19, and CYP3A4 isozymes,
whereas the CYP2D6 and CYP2E1 isozymes are not readily induced by commonly used
drugs. The rate of induction depends on the dose and frequency of administration.
Inhibition of drug metabolism
The antiulcer drug cimetidine and the antibiotics ciprofloxacin and erythromycin are
examples of drugs that may slow liver enzyme activity, prolonging the action of the drug
theophylline. Erythromycin affects the metabolism of the antiallergy drugs terfenadine and
astemizole, leading to a potentially serious buildup of these drugs.
A large number of drugs bind to and inhibit CYP isozymes. CYP3A4 is selectively
inhibited by erythromycin, itraconazole，and doxycycline, whereas other drugs such as
cimetidine，ketoconazole, and fluoxetine inhibit several CYP isozymes. Significant
interactions occur when these drugs reduce the clearance and increase the plasma
concentration of other drugs. For example, itraconazole inhibits the biotransformation of
HMG-CoA reductase inhibitors，such as lovastatin and atorvastatin，by CYP3A4. This
inhibition increases plasma levels severalfold, sometimes leading to severe muscle
inflammation and rhabdomyolysis. Grapefruit juice has been found to contain bioflavonoid
compounds that inhibit CYP3A4 and thereby elevate concentrations of drugs such as
felodipine (PLENDIL) that are metabolized by this enzyme.
Altered Drug Excretion
Drugs can alter the renal or biliary excretion of other drugs by several mechanisms.
A drug may affect the rate at which the kidneys excrete another drug. For example, some
drugs alter the urine's acidity, which in turn affects the excretion of other drugs. In large
doses, vitamin C can do this. A few drugs, such as carbonic anhydrase inhibitors, alter the
renal pH. This in turn can change the ratio of another drug’s ionized form to its nonionized
form and affect its renal excretion.
The enterohepatic cycling of some drugs is dependent on intestinal bacteria that hydrolyze
drug conjugates excreted by the bile and thereby enable the more lipid-soluble parent
compound to be reabsorbed into the circulation. Antibiotics administered concurrently with
these drugs may kill the bacteria and reduce the enterohepatic cycling and plasma drug
concentrations. When antibiotics are taken concurrently with oral contraceptives containing
estrogen, for example, they may reduce the plasma concentration of estrogen and cause
contraceptive failure (Fig. 4-3).
FIGURIT. 4-3 Interaction of antibiotics with estrogens found in oral contraceptives.
Estrogen is conjugated with glucuronate and sulfate in the liver, and the conjugates are
excreted via the bile into the intestines. Intestinal bacteria hydrolyze the conjugates, and
estrogen is reabsorbed into the circulation. The enterohepatic cycling is interrupted if
concurrently administered antibiotics destroy the intestinal bacteria. Contraceptive failure
may result.
Competition for renal tubular secretion reduces drug excretion. For example, probenecid
inhibits the tubular secretion of penicillins, increasing the blood concentration of the
penicillin and prolonging its therapeutic effects; this interaction could be beneficial in
patients with cystic fibrosis, in whom the tubular secretion of beta-lactam antibiotics is
increased, due to increased activity of the tubular organic anion transporter.
Amiodarone, quinidine, and verapamil inhibit the tubular secretion of digoxin by inhibiting
the transport protein P glycoprotein, increasing plasma digoxin concentrations and potentially
causing toxicity.
Thiazide diuretics inhibit the renal tubular secretion of lithium and can cause lithium
toxicity.
Clinical Significance of Drug Interactions
The clinical significance of drug interactions varies widely.
Although combined drug effects are sometimes beneficial, drug interactions are most often
unwanted and harmful. Drug interactions may intensify or diminish a drug's effects or worsen
its side effects. Most drug-drug interactions involve prescription drugs, but some involve
nonprescription (over-the-counter) drugs--most commonly, aspirin, antacids, and
decongestants.
The risk of developing a drug interaction depends on the number of drugs used, the
tendency of particular drugs to interact, and the amount of drug taken. Many drug interactions
are discovered during testing of drugs. Doctors, nurses, and pharmacists can reduce the
incidence of serious problems by keeping informed about potential drug interactions.
Reference books and computer software programs can help. People under the care of several
doctors are at highest risk because each doctor may not know all of the drugs being taken.
The risk of drug interactions can be reduced by using one pharmacy to fill all prescriptions.
In some cases, toxicity is severe and can be prevented only by avoiding the concurrent
administration of drugs. In other cases, toxicity can be avoided by proper dosage adjustment
and other measures (see Table 4-4). For example, when quinidine and digoxin are
administered concurrently, a subnormal dose of digoxin should be used to prevent adverse
effects. Fortunately, many drug interactions are of minor significance, and the interacting
drugs can usually be administered concurrently without affecting their efficacy or the
patient’s safety. Drug interactions are more likely to occur if the affected drug has a low
therapeutic index or is being used to treat a critically ill patient. However, polypharmacy,
which refers to the use of multiple medications by a patient, is linked to many adverse effects
and toxicity caused by drug interactions, especially in the elderly.
To make sure a person gets enough drugs for a therapeutic effect with little toxicity,
doctors must individualize therapy: They must select the right drug; consider the age, sex,
size, diet, race, and ethnic origin of the person; and adjust the dose carefully. The presence of
disease, use of other drugs, and limited knowledge about interactions of these factors
complicate this process.