There are three basic goals in the treatment of multiple sclerosis (MS): Slowing
disability progression, reducing the relapsing rate, and reducing brain lesions.
Any treatment for those suffering from MS, whether symptomatic or etiological,
should be adapted depending on the individual patient's: needs, demands of their
surrounding environment, type and degree of disability, and treatment goals.
Improvement commonly persists for several months beyond the treatment period,
mostly as a result of reconditioning and adaptation and appropriate use of
medical and social support at home. The quality of life for someone with MS is
typically determined by disability and handicap more than by functional deficits
and disease progression.
In 1993, disease-modifying therapies (DMTs) made their first appearance and gave
many hope that a "true" treatment had finally arrived. A lot has changed since
that time and one can just imagine what the future holds for those with MS - the
possibilities yet to come in treatments and a chance that maybe a cure is truly
possible. Up until this time, there were no DMTs and for those with MS and their
futures were taken away by uncontrolled progression of the disease.
This brings us now to the present time where there are currently several types of
immunomodulators available to treat MS. These treatments or drugs basically work
by interfering with or preventing the body from attacking itself: they include
interferon betas (such as Avonex & Betaseron), glatiramer acetate (Copaxone),
natalizumab (Tysabri), and now oral drugs (such as Gilenya & Tecfidera). Each therapy
has its own mechanism of action (MoA) and, as a consequence, each has a different
efficacy and safety profile.
There are 3 very important marks that need to be monitored to see if a treatment
is effective: Magnetic resonance imaging (MRI) activity,
relapses, and disease progression.
If everything looks good after checking on these three things, then a treatment or
medication is probably working and would be considered therapeutically effective.
The future of medications section takes a look at the promise of personalized
medications. These would be those that are specifically made or fine-tuned for
an individual based on their genetic makeup. Most drugs don't work the same from
one person to the next, mainly because every persons genetic makeup is
different. If a drug can be made or modified specifically for each person, then
the trial and error experienced by many could be eliminated.
Also included here are medications for symptom management. These medications
target all of the problems that arise from its wrath. One simple disease can
have an enormous cascading effect on your body.
The final section is regarding progressive multifocal leukoencephalopathy (PML)
and its role in treatment options. With the recent recurrence of PML associated
with treatment by Tysabri, concern and caution is warranted. It's believed by
many that no specific medication causes PML, but it's indicted that it can be
the trigger that activates it.
Due to the amount of clinical trials around the world, it can become easy to
leave out or not mention some of those hopeful drugs. It's also important to
remember that many of the drugs entering clinical trials don't make it out for
whatever reason. It's unfortunate that it can take years from starting trials
and then possibly making it to the market, but it's a necessary evil for our
future and safety.
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It's important to understand how medications work. When a medication is given
orally, injected, or infused, the way that the body handles it can vary
dramatically. Once medications find their way to where they need to work in the
body, it needs to be understood that hundreds of things happen along the way.
One action triggers another, and medicines work to either mask a symptom (like a
stuffy nose) or fix a problem (like a bacterial infection).
Pharmacology is the scientific field that studies how a body reacts to medicines
and how medicines affect the body. Pharmacokinetics then deals with understanding
the entire cycle of a medicine's life inside the body. Knowing more about each of
the four main stages of pharmacokinetics, collectively referred to as ADME, aids
the design of medicines that are more effective and that produce fewer side effects.
The four basic stages of a medicine's life in the body are called ADME:
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Absorption |
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Distribution |
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Metabolism |
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Excretion |
The first stage of ADME is A, for absorption.
Medicines can enter the body in many different ways, and they are absorbed when
they travel from the site of administration into the body's circulation. A few
of the most common ways to administer drugs are oral (swallowing a pill or
liquid), intramuscular (an injection in a muscle), subcutaneous (an injection
just under the skin), intravenous (through a vein), or transdermal (through a
skin patch).
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Drugs enter different layers of skin via intramuscular, subcutaneous, or
transdermal delivery methods.
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A drug faces its biggest hurdles during absorption. Medicines taken by mouth are
shuttled via a special blood vessel leading from the digestive tract to the
liver, where a large amount may be destroyed by metabolic enzymes in the
so-called "first-pass effect." Other routes of drug administration bypass the
liver, entering the bloodstream directly or via the skin or lungs.
Once a drug gets absorbed, the next or second stage of ADME is D, for
distribution. Most often, the bloodstream carries
medicines throughout the body. During this step, side effects can occur when a drug
has an effect in an organ other than the target organ. For a pain reliever, the target
might be a sore muscle in the leg, but irritation of the stomach could be a side
effect. Many factors influence distribution, such as the presence of protein and
fat molecules in the blood that can put drug molecules out of commission by
grabbing onto them.
Drugs destined for the central nervous system (CNS) face an enormous hurdle: a
nearly impenetrable barricade called the blood-brain barrier. This blockade is
built from a tightly woven mesh of capillaries cemented together to protect the
brain from potentially dangerous substances such as poisons or viruses. Yet
pharmacologists have devised various ways to sneak some drugs past this barrier.
After a medicine has been distributed throughout the body and has done its job, the
drug is broken down in this third stage, or metabolized,
the M in ADME. The breaking down of a drug molecule usually involves two steps that
take place mostly in the body's chemical processing plant, the liver. The liver is
a site of continuous and frenzied, yet carefully controlled, activity. Everything that
enters the bloodstream—whether swallowed, injected, inhaled, absorbed through
the skin, or produced by the body itself—is carried to this largest internal
organ. There, substances are chemically pummeled, twisted, cut apart, stuck
together, and transformed.
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A drug's life in the body. Medicines taken by mouth (oral) pass through
the liver before they are absorbed into the bloodstream. Other forms of
drug administration bypass the liver, entering the blood directly.
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The biotransformations that take place in the liver are performed by the body's
busiest proteins, its enzymes. Every one of your cells has a variety of enzymes, drawn
from a repertoire of hundreds of thousands. Each enzyme specializes in a particular job.
Some break molecules apart, while others link small molecules into long chains. With drugs,
the first step is usually to make the substance easier to get rid of in urine.
Many of the products of enzymatic breakdown (metabolites) are less chemically active than
the original molecule. For this reason, scientists refer to the liver as a "detoxifying"
organ. Occasionally, however, drug metabolites can have chemical activities of their own—sometimes
as powerful as those of the original drug. When prescribing certain drugs, doctors must take into
account these added effects. Once liver enzymes are finished working on a medicine, the now-inactive
drug undergoes the fourth and final stage of its time in the body, the E in ADME is the
excretion, as it exits via the urine or feces.
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Interferons are proteins that are part of your natural defenses. They tell your immune system that
germs or cancer cells are in your body and they trigger killer immune cells to fight those invaders.
Interferons got their name because they "interfere" with viruses and keep them from multiplying.
In 1986, the first lab-made interferon was created to treat certain types of cancer. It was one of
the earliest treatments to work with your immune system to fight illness and was later approved as
a treatment for several other conditions, including hepatitis and MS.
Almost every cell in your body makes interferons. There are three main types:
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Interferon-alpha (or interferon-alfa) |
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Interferon-beta |
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Interferon-gamma |
Cells that have been infected with viruses or other germs give off interferon-alpha
and interferon-beta as a warning signal to your immune system. That triggers immune
cells called white blood cells to release interferon-gamma to fight the germs.
Interferons work in a few different ways by:
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Alerting your immune system so it can go after the virus or cancer |
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Help your immune system recognize the virus or cancer |
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Tell immune cells to attack |
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Stop virus and cancer cells from growing and dividing |
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Help healthy cells fight infection |
Interferon-beta is what we will focus on because it treats different types of MS.
It eases inflammation in your brain and spinal cord to prevent nerve damage and
can make it less likely for you to have a flare-up.
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One of the most important principles of pharmacology and research is a concept
called dose-response. Just as the term implies, this notion refers to the
relationship between the amount of a drug and its effect. Researchers use
dose-response data because these mathematical relationships signify that a
medicine is working according to a specific interaction between different
molecules in the body.
Sometimes, it takes years to figure out exactly which molecules are working
together, but when testing a potential medicine, researchers must first show
that three things are true in an experiment. First, if the drug isn't there, you
don't get any effect. Second, adding more of the drug (up to a certain point)
causes an incremental change in effect. Third, taking the drug away (or masking
its action with a molecule that blocks the drug) means there is no effect.
Regardless of how a drug effect occurs, through binding or chemical interaction,
the concentration of the drug at the site of action controls the effect. However,
response to concentration may be complex and is often nonlinear. The relationship
between the drug dose, regardless of route used, and the drug concentration at
the cellular level is even more complex.
Dose-response, which involves the principles of pharmacokinetics and pharmacodynamics,
determines the required dose and frequency as well as the therapeutic index for a
drug in a population. The therapeutic index (ratio of the minimum toxic concentration
to the median effective concentration) helps determine the efficacy and safety of a
drug. Increasing the dose of a drug with a small therapeutic index increases the
probability of toxicity or ineffectiveness of the drug.
Drugs affect only the rate at which existing biologic functions proceed. Drugs don't
change the basic nature of these functions or create new functions. For example,
drugs can speed up or slow down the biochemical reactions that cause muscles to
contract, kidney cells to regulate the volume of water and salts retained or
eliminated by the body, and nerves to transmit messages.
Drugs can't restore structures or functions already damaged beyond repair by the body.
This fundamental limitation of drug action underlies much of the current frustration
in trying to treat degenerative diseases such as MS, heart failure, arthritis, muscular
dystrophy, Parkinson disease, and Alzheimer disease. Nonetheless, some drugs can help
the body repair itself. For example, by stopping an infection, antibiotics can allow
the body to repair damage caused by the infection.
Reversibility
Most interactions between a drug and a receptor or between a drug and an enzyme
are reversible: After a while, the drug disengages, and the receptor or enzyme
resumes normal function. Sometimes an interaction is largely irreversible, and
the drug’s effect persists until the body manufactures more enzyme. For example,
omeprazole, a drug used in the management of gastroesophageal reflux and ulcers,
irreversibly inhibits an enzyme involved in the secretion of stomach acid.
Affinity and Intrinsic Activity
A drug's action is affected by the quantity of drug that reaches the receptor
and the degree of attraction (affinity) between it and its receptor on the cell's
surface. Once bound to their receptor, drugs vary in their ability to produce an
effect (intrinsic activity). A drug's affinity and intrinsic activity are
determined by its chemical structure.
Drugs that activate receptors (agonists) must have both great affinity and
intrinsic activity: They must bind effectively to their receptors, and the drug
bound to its receptor (drug-receptor complex) must be capable of producing an
effect in the targeted area. In contrast, drugs that block receptors (antagonists)
must bind effectively but have little or no intrinsic activity because their
function is to prevent an agonist from interacting with its receptors.
Potency, Efficacy, and Effectiveness
A drug’s effects can be evaluated in terms of potency, efficacy, or effectiveness.
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Potency (strength) - refers to the amount of
drug needed to produce an effect, such as pain relief. For example,
if 5 milligrams (mg) of drug A relieves pain as effectively as 10 mg
of drug B, then drug A is twice as potent as drug B. |
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Efficacy - is a drug's capacity to produce an
effect, such as lowering blood pressure. For example, drug A eliminates
much more salt and water through urine than does drug B. Thus, drug A
has greater efficacy than drug B. |
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Effectiveness - differs from efficacy in that it
takes into account how well a drug works in real-world use. Often, a drug
that is efficacious in clinical trials is not very effective in actual use.
For example, a drug may have high efficacy in lowering blood pressure but
may have low effectiveness because it causes so many side effects that
people take it less often than they should or stop taking it entirely.
Thus, effectiveness tends to be lower than efficacy. |
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Greater potency, efficacy, or effectiveness doesn't necessarily mean that one drug is
preferable to another. When determining the relative merits of drugs for a person, doctors
consider many factors, such as side effects, potential toxicity, duration of effect
(how many needed per day), and cost.
"The right dose differentiates a poison and a remedy." -Paracelsus
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