Drugs Used for Symptoms Associated with
Transverse Myelitis
Norman J. Uretsky
and Cheng-Huan Chang
Norman J. Uretsky, Ph.D.
is a Professor of Pharmacology in the College of
Pharmacy at The Ohio State University. Dr.
Uretsky's research interests include
neuropharmacology, neurotransmitter release in
animal behavior and neurological diseases. Cheng-Huan
Chang is a Senior Student at The Ohio State
University College of Pharmacy. He will graduate
with a BS in Pharmacy in the Spring Quarter,
1999.
This article will describe some of the drugs that
are used to treat the symptoms that are
associated with Transverse Myelitis. The drugs
were identified through a process of reviewing
the surveys that have been administered to the
TMA members. This article does not attempt to
discuss all of the medications used by TM
patients, but rather, focuses on the medications
that were most frequently noted on the surveys.
For each of the drugs noted, there is a
discussion of their therapeutic effects and the
pharmacological mechanism for those effects, some
of the more common possible adverse effects and
some of the reactions with other drugs.
When your physician
prescribes you any medications, it is important
that you know any possible side-effects that may
be caused by those medications. If you are not
told the possible side-effects, you should ask
your doctor to identify them for you. Should you
experience any of the side-effects, these should
be reported to your physician. When you are
prescribed any medications, your doctor also
needs to know all other medications that you are
taking and their dosages. It is important that
you share this information with your doctor,
particularly if you are being prescribed
medications by more than one physician. It is
also important that you openly share life-style
information with your physician. For example, no
one should consume alcohol in combination with
any of the central nervous system depressants
that are identified in this article. Since
life-style issues are unique to each individual
and the combinations of medications are quite
diverse among the TM population, it is not
feasible to discuss all of the possible
life-style issues that might impact on taking
medications. It is incumbent on each person to be
sure to communicate the necessary information to
their physician so that informed decisions can be
made about life-style issues and the medications
that you are prescribed.
Finally, it is important
that you know the name of the drug that you are
being prescribed. Pharmacists can make mistakes
and you want to be certain that you are taking
the correct drug. Be sure that you know the name
of the drug, and check it for yourself after your
prescription has been filled.
ANTIDEPRESSANTS:
Classification:
Tricyclic antidepressants
Amitriptyline (Elavil)
Nortriptyline (Pamelor)
Imipramine (Tofranil)
Doxepin (Sinequan)
Desipramine (Norpramin)
Trimipramine (Surmontil)
Protriptyline (Vivactil)
Selective serotonin reuptake
inhibitors
Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox)
Others
Nefazodone (Serzone)
Trazadone (Desyrel)
Venlafaxine (Effexor)
Maprotiline (Ludiomil)
Bupropion (Wellbutrin)
AMITRIPTYLINE (Brand Name: Elavil): We
will consider this drug as representative of the
antidepressant drug
class. It is the prototype drug that is effective
in treating depression and certain kinds of pain.
Therapeutic effects: This
drug is classified as a “tricyclic
antidepressant” because of its chemical structure
(3 rings) and its effectiveness in treating the
symptoms of depression. When used for depression,
this drug is often administered concurrently with
psychotherapy. The mechanism of action of
amitriptyline is unclear. It is known to produce
an increase in the effects of two
neurotransmitters (see
glossary), norepinephrine and serotonin, in
the brain by preventing their inactivation.
However, the enhancement of these
neurotransmitters occurs rapidly, while
antidepression may take several weeks of repeated
drug administration for its development. It,
therefore, has been proposed that the increases
in serotonin and norepinephrine transmission
produced by antidepressants, such as
amitriptyline, lead to subsequent changes in the
chemistry of the nervous system that are
ultimately responsible for the eventual relief of
depression.
Although amitriptyline is
classified as an antidepressant, it produces
other effects that would be useful in patients
with transverse myelitis. Amitriptyline
administered together with an opioid drug, such
as morphine, has been shown to augment the
analgesic (pain relieving) effects of the opioid.
In addition, amitriptyline, as well as other
tricyclic antidepressants and possibly
nontricyclic antidepressants (listed
above), appear to be capable of relieving
certain types of pain when administered in the
absence of opioids, particularly neuropathic
pain. The latter refers to pain derived from
abnormal functioning in neurons that mediate pain
sensation (see
glossary). The mechanism of this
pain-relieving effect of amitriptyline (and other
antidepressants) is not clear. It does not seem
to be related to its antidepressant effects,
since relief of pain occurs at lower doses and
develops more rapidly than antidepressant
effects. Recent studies have indicated that
neurons in the spinal cord that release the
neurotransmitters, serotonin and norepinephrine,
from nerve endings inhibit pain transmission.
Accordingly, amitriptyline, which increases the
effects of norepinephrine and serotonin, would be
expected to inhibit pain transmission, causing a
reduction in the intensity of pain. Recently, a
hypothesis has been proposed that the ability of
tricyclic antidepressants to relieve neuropathic
pain is related to the blockade of a
receptor in the spinal
cord for the neurotransmitter, glutamic acid.
More work will have to be done to corroborate
this hypothesis.
Adverse effects of
amitriptyline: Amitriptyline has many different
actions that produce a variety of adverse
effects. Amitriptyline can produce orthostatic or
postural hypotension, which refers to dizziness
and lightheadedness when the patient moves from a
lying down to a sitting position or from a
sitting to a standing position. This effect
occurs mainly at the beginning of therapy, with
tolerance developing when the drug is taken
chronically. Patients who experience postural
hypotension after taking any drug should move
slowly into an upright position to avoid
dizziness and lightheadedness.
Amitriptyline produces
sedation, which is also most intense during the
initial period of drug therapy because eventually
a partial tolerance develops to this effect.
However, the sedation can interfere with the
performance of daytime activities. If sedation is
significant, it can be minimized during the
daytime by administering the drug before bedtime.
The sedation produced by amitriptyline is
augmented if the drug is taken together with
other drugs that contain sedative action. Such
drugs include many antihistamines, alcohol,
sleeping pills, opioids, etc. The sedative effect
of amitriptyline has been related to its ability
to block receptors for the neurotransmitter,
histamine, in the brain.
Amitriptyline
blocks a certain type of
receptor for the neurotransmitter (see
glossary), acetylcholine, and, consequently,
may interfere with the functioning of this
neurotransmitter on various organs. The
transmitter, acetylcholine, which is normally
released from nerve endings, cannot activate
receptors that are blocked, resulting in
symptoms. Therefore, patients, when taking
amitriptyline (or other tricyclic
antidepressants), may experience such symptoms as
blurred vision, dry mouth, constipation, urinary
hesitancy, and increased heart rate. Patients who
are distressed by these effects should notify
their physician.
Amitriptyline and other
tricyclic antidepressants produce a small
increase in the risk of seizures, and thus, the
drug should be administered cautiously to
patients with seizure disorders.
Amitriptyline use can cause
excessive sweating, which may require the patient
to frequently change clothing. The mechanism of
this effect is unclear. Actually, it would be
expected that the blockade of receptors for the
neurotransmitter, acetylcholine (see above) would
decrease rather that increase sweating.
Amitriptyline may increase
appetite, especially for sweets. Again, the
mechanism for this effect is unclear. One theory
is that the increased appetite is related to the
blockade of receptors for the neurotransmitter,
histamine, in the brain, as drugs that block
histamine receptors in the brain generally
increase appetite.
The most serious adverse
effect of amitriptyline is to impair cardiac
function, leading to abnormal cardiac rhythms.
This adverse effect is uncommon except in
patients who overdose or have a preexisting
cardiac condition. Patients at risk for abnormal
rhythms (arrhythmias) should have an
electrocardiogram taken both before and at
intervals during therapy.
Reactions with other drugs:
Amitriptyline can produce adverse interactions
with several drugs. Amitriptyline augments and
prolongs the effects of epinephrine (adrenaline).
Epinephrine is used to delay the absorption of
local anesthetics, to control superficial
bleeding, to reduce nasal congestion, to elevate
blood pressure, to produce mydriasis during
ophthalmic procedures, to overcome atrial-ventricular
heart block, to dilate bronchioles (asthmatic
patients), and to counteract anaphylactic shock.
However, the administration of epinephrine to a
patient taking amitriptyline can lead to
toxicity.
Amitriptyline blocks certain
receptors for acetylcholine producing adverse
effects (see above).
Administering amitriptyline together with other
drugs that block receptors for acetylcholine
would worsen these adverse effects. Thus,
patients should not take amitriptyline together
with scopolamine (used for motion sickness), most
antihistamines (used for allergies), etc.,
because these drugs also block receptors for
acetylcholine.
Amitriptyline and most other
antidepressants should not be administered
together with monoamine oxidase inhibitors (Drugs
used for the treatment of depression). The
combination can produce a marked rise in blood
pressure, called hypertensive crises. This is an
emergency situation that requires that the blood
pressure be reduced immediately to prevent damage
to blood vessels and the heart.
Amitriptyline is metabolized
by the liver to nortriptyline, an active
metabolite marketed under the name of Pamelor.
Nortriptyline is eventually metabolized to an
inactive product that is excreted. Certain drugs,
such as cimetidine (Tagamet), fluoxetine
(Prozac), haloperidol (Haldol), oral
contraceptives and ethanol, can inhibit the
metabolism of amitriptyline and nortriptyline.
This can lead to an increase in blood level of
these substances, resulting in toxicity.
Overdose: Overdose of
amitriptyline can produce central nervous system
symptoms including agitation, confusion,
hallucinations, and seizures. Amitriptyline in
high doses is toxic to the heart (See above),
producing severe abnormal rhythms of the
ventricles, which can cause lethality.
ANTICONVULSANTS
Drugs in this group: These
drugs are used to treat epilepsy and have been
shown to be effective in certain kinds of
neuropathic pain.
Carbamazepine (Tegretol)
Phenytoin (Dilantin)
Valproic acid (Depakene,
Depakote, Evipal)
Gabapentin (Neurontin)
Clonazepam (Klonopin)
CARBAMAZEPINE (Tegretol):
Therapeutic effects and
mechanism: Carbamazepine is used for both tonic-clonic
seizures (full body seizures) as well as partial
seizures. It produces this effect by inhibiting
the entry of the sodium ions into neurons, and
consequently decreases the ability of neurons to
conduct impulses.
Carbamazepine has been shown
to be effective in controlling the manic phase of
manic-depressive disorder.
Carbamazepine has been found
to be effective in the treatment of neuropathic
pain, particularly the pain of trigeminal
neuralgia. In this condition, there is a sharp,
stabbing pain along the sensory distribution of
the trigeminal nerve (along the face and
forehead). Carbamazepine, which is not an
analgesic, causes pain relief, presumably by
inhibiting conduction of impulses in neurons
mediating pain.
Adverse effects:
Carbamazepine produces drowsiness, dizziness, and
impaired coordination. The latter can be
expressed as double vision or decreased ability
to control the movement of the eyeballs. These
effects are reversible when the dose is lowered.
Carbamazepine in a small percentage of patients
can produce water intoxication, leading to a
variety of behavioral changes. It is recommended
that serum sodium content be periodically
monitored. Carbamazepine can cause more dangerous
effects such as severe rashes, liver damage, and
bone marrow impairment. However, these effects
are uncommon but when they occur, the drug must
be discontinued. Patient should be aware of
certain signs indicating abnormalities in the
blood. A decrease in white blood cell counts,
which protects the body from invading
microorganisms, can lead to infection, sore
throat, and fever. A decrease in red blood cells
can lead to fatigue and weakness. A decrease in
platelets can lead to frequent bruising and the
occurrence of small dark red spots in the skin
and mucous membrane. Because of the possibility
of bone marrow depression, complete blood counts
are determined before and during drug therapy.
Usually serum electrolyte levels and liver
function tests are also performed before and
during therapy.
PHENYTOIN
(Dilantin):
Therapeutic effects and
mechanism: Phenytoin, like carbamazepine, is used
for both tonic-clonic convulsions and partial
seizures. It is thought to act in the same way as
carbamazepine, by blocking the entry of sodium
ions into neurons, thereby inhibiting the ability
of neurons to conduct impulses.
Also like carbamazepine,
phenytoin is used for the relief of neuropathic
pain, particularly trigeminal neuralgia.
Adverse reactions: While
phenytoin is often effective in controlling
seizures and pain from neurons, it is a difficult
drug to take because it produces a large number
of adverse effects when the dose of drug is too
high. Thus high doses may produce such central
nervous system symptoms as impaired muscle
coordination, double vision, slurred speech,
tremors, drowsiness, and fatigue, which can be
reversed by lowering the dose. About 20% of
patients using phenytoin chronically develop
swollen gums, caused by an increase in tissue at
that site. Good dental hygiene is thought to
inhibit but not prevent swollen gums from
occurring. Other side effects include certain
vitamin deficiencies, particularly deficiencies
of folic acid and Vitamin D. These deficiencies
occur because phenytoin interferes with the
metabolism of these vitamins. Phenytoin can have
adverse effects on the skin. It can induce
allergic rashes, aggravate preexisting acne, and
stimulate the growth of coarse hair on the face
and body. Phenytoin also interferes with the
metabolism of many drugs.
As if a large number of
adverse effects do not produce enough problems,
the degree of absorption of phenytoin after oral
administration and the metabolism of phenytoin by
liver enzymes is variable. This leads to marked
variations in the blood levels of this drug and
its therapeutic effectiveness. Therefore,
patients taking this drug are usually told not to
change brands of phenytoin if it is effectively
controlling seizures.
VALPROIC ACID
(Depakene, Depakote, Evipal):
Therapeutic Uses and
Mechanism: This is a broad spectrum antiepileptic
drug that is effective in controlling many
different types of seizures, including absence,
tonic-clonic, myoclonic, and atonic seizures. It
is also used to control the manic phase of
manic-depressive disorder. The drug seems to work
in three different ways. First, it acts like
phenytoin and carbamazepine and inhibits impulse
flow by blocking the entry of sodium into
neurons. Second, it inhibits a specific type of
channel (T-type calcium channels) in the neuronal
membrane for charged calcium ions, thereby
preventing the entry of calcium ions through this
channel into the neuron. Finally, it seems to
enhance the effects of the inhibitory
neurotransmitter, GABA.
Recent studies have shown
that valproic acid can relieve neuropathic pain,
and so while not approved for this indication, it
is used for this condition.
Adverse effects: Valproic
acid is a relatively safe drug. However, it is
irritating to the lining of the gastrointestinal
tract, producing nausea, vomiting, and
indigestion. These symptoms can be controlled by
taking valproic acid with food or using an
enteric coated preparation (divalproex sodium -
Depakote), which releases valproic acid in the
intestine but not the stomach. Valproic acid has
been associated with liver damage during the
initial period of therapy. This effect is very
uncommon but can be very severe. Patients at high
risk for this disorder are children younger than
2 years of age who are taking other antiepileptic
drugs. Patients should be aware of signs of liver
toxicity, which consist of loss of appetite,
nausea, abdominal pain, and jaundice. Patients
who develop these symptoms while taking valproic
acid should notify their physician. Liver damage
leads to an increase in enzymes normally found in
liver cells in the blood. Therefore, liver
function tests are usually performed before and
during treatment. Other adverse effects produced
by valproic acid are lethargy, tremor, weight
gain, skin rash, and sometimes a loss of hair.
Valproic acid can decrease platelet count, which
can cause bleeding. It, therefore, should not be
taken with aspirin, ibuprofen (Nuprin, Advil,
Motrin), or naproxen (Aleve), as these drugs
inhibit platelet aggregation and intensify the
bleeding tendency. Almost all the adverse effects
of valproic acid are reversible.
GABAPENTIN
(Neurontin):
Therapeutic Effects and
Mechanism: Gabapentin is classified as an
anticonvulsant that
is useful in treating a variety of different
types of seizures. It is approved by the Food and
Drug Administration for use as an adjunct to
other drugs for the control of partial seizures
(seizures that begin at a focal brain site,
usually the cerebral cortex, and exhibit limited
spread to other brain sites). As one would expect
from the name Gabapentin, the drug is a chemical
analog of the inhibitory neurotransmitter, GABA (see
glossary). However, the drug does not seem to
interact with receptors for GABA, and the
mechanism of action of gabapentin is unclear.
Perhaps it stimulates the release of GABA from
nerve endings, increasing free GABA. The free
GABA could then activate GABA receptors that
would inhibit nerve impulses.
Although gabapentin is not
approved for the treatment of neuropathic pain,
it has been shown to be effective in the
treatment of this condition. The mechanism of
this effect is unclear.
Major adverse reactions:
sleepiness, dizziness, impaired coordination.
CLONAZEPAM
(Klonopin):
Therapeutic Uses and
Mechanism: This drug is a benzodiazepine
derivative. Therefore, it is in the same chemical
family as Librium, Valium, Ativan, and Xanax,
drugs that are often prescribed for anxiety. It
is considered one of the most potent
benzodiazepines and has a long duration of
action. It is used to treat certain types of
seizures. Recently, it has been used to treat
neuropathic pain. The mechanism of action of
clonazepam in producing this effect is unclear at
the present time.
BENZODIAZEPINES:
Definition: The term,
benzodiazepine, refers to the chemical structure
of a variety of drugs that can relieve anxiety,
inhibit convulsions, produce muscle relaxation,
and promote sleep. Generally, the reduction in
anxiety is produced by lower doses of drug, and
the promotion of sleep occurs at higher doses.
Below is a list of the drugs in this class.
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Chlorazepate (Tranxene)
Diazepam (Valium)
Estazolam (ProSom)
Flurazepam (Dalmane)
Halazepam (Paxipam)
Lorazepam (Ativan)
Midazolam (Versed)
Oxazepam (Serax)
Prazepam (Centrax)
Quazepam (Doral)
Temazepam (Restoril)
Triazolam (Halcion)
The drug, zolpidem, marketed
as Ambien, is used to promote sleep. It is not in
the above list because it is chemically not a
benzodiazepine. In fact, zolpidem is marketed as
a nonbenzodiazepine sleeping pill. However, it
acts biologically on one type of receptor for
benzodiazepines to promote sleep. In contrast to
other benzodiazepines, it has little antianxiety,
anticonvulsant, or muscle relaxant effects.
Therapeutic Effects and
Mechanism: As indicated above, the
benzodiazepines can relieve anxiety and at higher
doses promote sleep and induce muscle relaxation.
The use of certain benzodiazepines to relieve
anxiety and other benzodiazepines to promote
sleep is basically a marketing decision by drug
companies. Benzodiazepines are also used to treat
seizure disorders and panic disorder. They are
used to help physically dependent patients
withdraw from alcohol because they are cross
dependent with alcohol and, therefore, will
inhibit the symptoms of alcohol withdrawal.
Benzodiazepines produce their effects by acting
in the central nervous system at many different
sites to enhance the effect of the inhibitory
neurotransmitter, GABA. Thus, benzodiazepines
will inhibit neuronal activity.
Adverse effects: These drugs
are safe when administered orally because they
have relatively weak effects on the
cardiovascular and respiratory systems. However,
certain adverse effects are associated with
benzodiazepine use which can be dangerous. Thus,
these drugs can produce drowsiness, dizziness and
impaired coordination, which many interfere with
the performance of daytime activities. In
addition, benzodiazepines can temporarily impair
the ability of patients to learn new information
(anterograde amnesia). Elderly patients are more
sensitive to the sedative effect of
benzodiazepine and may have relatively poor liver
function, resulting in a decreased rate of
metabolism of these drugs. Therefore, elderly
patients who complain of memory impairment should
be evaluated for the possibility that this
impairment is caused by the use of
benzodiazepines. Even though
physical
dependence frequently develops after chronic
use, the abuse potential of benzodiazepines is
considered to be low. The usual withdrawal
symptoms are anxiety, restlessness, insomnia, and
tremors. It should be noted that severe
withdrawal symptoms could be avoided by
discontinuing the drug slowly and gradually, over
a period of several weeks. Under these
circumstances, withdrawal discomfort is minimal
and may not be detectable.
ANTIARRHYTHMIC DRUGS:
Therapeutic Effects and
Mechanism: This class of drugs is used to treat
abnormal rhythms of the heart. These drugs are
thought to act by inhibiting the entry of charged
metal ions into cardiac cells. Recently, some of
the drugs in this class have been found effective
in treating neuropathic pain. This has been shown
for lidocaine (xylocaine), mexiletine (Mexitil),
and flecainide (Tambocor). While lidocaine must
be administered by injection, the other two drugs
can be given orally.
BACLOFEN (LIORESAL):
Therapeutic Effects and
Mechanism: Baclofen acts within the spinal cord
and the brain to inhibit neuronal activity.
Consequently, baclofen can inhibit hyperactive
reflexes responsible for abnormal and excessive
muscle tone. This effect of baclofen is due to
its ability to bind to and activate a specific
receptor for amino-butyric acid (GABA), called
the GABA-B receptor. GABA is an amino acid and is
the primary inhibitory neurotransmitter in the
central nervous system (see
glossary). A deficiency of this inhibitory
transmitter at synapses in the central nervous
system can produce seizures, impaired
coordination, and spasticity. Baclofen by
activating receptors for GABA in the spinal cord
and brain can counteract these neurological
effects by producing muscle relaxation at a dose
that produces minimal sedation.
Baclofen is used to relieve
spasticity, which is characterized by hyperactive
spinal cord reflexes in response to changes in
position or movement. Spasticity is produced in a
variety of conditions in which there is CNS
injury, such as multiple sclerosis, spinal cord
injury, stroke, and cerebral palsy.
Recent studies indicate that
baclofen can be used to treat neuropathic pain,
presumably by inhibiting pain transmission
through the activation of GABA receptors.
Adverse effects: The most
common adverse effects occur in the central
nervous system, consisting of drowsiness,
dizziness, muscle weakness and fatigue. These
effects are most intense when the drug is first
administered but then gradually subsides as
tolerance develops. These effects can be reduced
by starting treatment with a low dose of the drug
and then gradually increasing the dose (e.g.,
after a 7 day interval). However, these adverse
effects will be enhanced if the drug is taken
together with alcohol or other drugs with CNS
depressant activity (such as opioid analgesics,
benzodiazepines, tricyclic antidepressants,
antihistamines). After baclofen has been
chronically administered, it should be
discontinued slowly, since abrupt withdrawal
after prolonged use can cause anxiety,
hallucinations, seizures, and rebound spasticity.
Symptoms of overdose include
vomiting, coma, seizures, and respiratory
depression. There is no antidote and treatment is
supportive.
DANTROLENE (DANTRIUM):
Therapeutic Effects and
Mechanism: Dantrolene is also used to relieve
spasticity. Drugs used for spasticity include
diazepam (Valium), baclofen (Lioresal) and
dantrolene (Dantrium). While diazepam and
baclofen act at sites within the central nervous
system, dantrolene acts directly in skeletal
muscle. This drug inhibits the release of calcium
ions from storage sites for calcium (called the
sarcoplasmic reticulum). Since it is the release
of calcium ion from these storage sites that
trigger muscle contraction, dantrolene will
inhibit muscle contractions and muscle spasms.
Adverse effects: Probably
the main adverse effect of dantrolene is an
extension of its therapeutic actions. By
preventing the release of calcium ion from muscle
stores, dantrolene inhibits muscle contraction.
However, too much inhibition of calcium release
can lead to muscle weakness and impaired rather
than improved function. This weakness produced by
dantrolene is an important reason why the drug is
not used as frequently as other drugs (baclofen
and diazepam) for spasticity. Dantrolene can also
cause injury to the liver.
Therefore, tests of liver function should be
performed before and during therapy. Other
adverse effects include diarrhea, loss of
appetite, nausea, and rash. It can also cause
drowsiness and, therefore, patients should not
use CNS depressants, e.g., alcohol, when taking
dantrolene.
OXYBUTYNIN (DITROPAN):
Therapeutic Use and
Mechanism: This drug is used as a urinary
antispasmodic. That is, it is used to treat
urinary urgency, frequency, and incontinence.
This drug has two actions important in producing
these effects. First, it causes a direct
relaxation of smooth muscles of the bladder. It
also blocks receptors for the neurotransmitter,
acetylcholine, which is released from nerve
endings supplying the bladder and activates
receptors on smooth muscles of the bladder
causing contraction. By blocking the receptors
for acetylcholine and directly relaxing bladder
smooth muscle, oxybutynin prevents the bladder
smooth muscle from contracting, increases bladder
capacity, reduces spontaneous contractions of the
bladder, and decreases urgency and frequency. If
oxybutynin does not reverse urinary incontinence,
other anticholinergic drugs, such as
propantheline or dicylomine, are usually tried.
Adverse effects: Many of the
adverse effects of Oxybutynin are related to its
ability to block receptors for the
neurotransmitter, acetylcholine, at sites in the
body other than the bladder. Thus, by blocking
these receptors in the eye, the gastrointestinal
tract, the salivary glands, the sweat glands, and
the heart, it can cause blurred vision and light
sensitivity, constipation, dryness of the mouth,
decreased sweating, and increased heart rate,
respectively.
CLONIDINE (CATAPRES):
Therapeutic Effects and
Mechanism: Clonidine hydrochloride is classified
as a centrally acting antihypertensive agent
which is an agonist and
activates alpha-2 adrenergic receptors. The
activation of these receptors in the
cardiovascular regulatory centers in the brain
and spinal cord produces a decrease in
sympathetic tone, resulting in a decrease in
blood pressure and heart rate. Clonidine is not
usually recommended for first-line therapy for
hypertension because there are severe symptoms
(increased blood pressure, heart rate, tremor
agitation, etc.) when the drug is abruptly
discontinued. These effects can be avoided if the
drug is withdrawn gradually.
Clonidine has been used for
the treatment of neuropathic pain. There are
alpha-2 adrenergic receptors located in the
dorsal horn of the spinal cord that regulate pain
transmission. Activation of alpha-2-receptors
have been shown to inhibit pain transmission at
this site, thereby causing neuropathic pain
relief.
Adverse effects: Clonidine
can produce a variety of unpleasant effects, such
as constipation, dry mouth, dry eyes, skin
problems, and sexual difficulties. Patients who
experience constipation can control it by
increasing the amount of high fiber intake and
drinking plenty of water. Dry mouth can be
relieved by sucking sugar-free candies. Dry eyes
can be relieved by using artificial tear eye
drops. Clonidine can also produce allergic
reactions on the skin, and increased sensitivity
to the sun light. Using sun screen can prevent
skin damage. Sexual difficulties include
difficulty achieving orgasm, decreased physical
sensation and delayed ejaculation. It is
important to remember not to stop clonidine
therapy abruptly, since abrupt withdrawal from
clonidine may cause severe symptoms that can be
life-threatening.
Reactions With Other Drugs:
The use of tricyclic
depressants (e.g., amitriptyline)
concurrently with clonidine can decrease the
effect of clonidine. Clonidine can enhance the
CNS-depressant effects of barbiturates, alcohol,
or other sedatives.
PROCHLORPERAZINE (COMPAZINE):
Therapeutic Effects and
Mechanism: This is a drug used to relieve nausea
and vomiting. It produces this effect by
inhibiting a site in the brain called the
chemoreceptor trigger zone. When the
chemoreceptor trigger zone is activated, it
stimulates the vomiting center, causing nausea
and vomiting. The chemoreceptor trigger zone
contains receptors for the neurotransmitter,
dopamine. Blockade of these receptors by
prochlorperazine inhibits the activity of the
chemoreceptor trigger zone, leading to a decrease
in nausea and vomiting.
Adverse effects:
Prochlorperazine use is associated with
drowsiness, dizziness, blurred vision, allergic
skin rash, and hypotension. Prochlorperazine can
induce seizures in patients at risk for seizures.
The drug rarely produces serious side effects,
such as jaundice, leukopenia, and agranulocytosis
(see glossary).
GLOSSARY:
Agonist:
A drug that binds to a receptor and activates it,
thereby producing a response.
Agranulocytosis:
This is a disorder in which there is a decrease
in the number of white blood cells (neutrophils,
eosinophils, and basophils) in the circulation.
This is caused by damage to the bone marrow.
Since these cells are an important part of the
body's defense against infection by
microorganisms, a decrease in these cells
increases the vulnerability to infection.
Patients with agranulocytosis may develop fever,
sore throat, ulcerations and skin lesions. It is
treated with antibiotics.
Anticonvulsant:
Drugs that block or prevent the involuntary
muscle contractions associated with epilepsy.
These drugs are thought to produce their effect
in one of three ways: inhibition of sodium ion
entry into the neuron, inhibition of calcium ion
entry into the neuron, or enhancement of the
effect of the neurotransmitter, GABA. Some
anticonvulsant drugs are used to treat
psychiatric disorders and neuropathic pain.
Antidepressant:
A drug that is used to treat depression but does
not produce stimulant effects. It takes about
two-four weeks for these drugs to be effective.
Many of these drugs are also used to treat
neuropathic pain, but their mechanism of action
is unclear. Recent studies suggest that their
ability to inhibit neuropathic pain may be due to
the blockade of specific receptors on neurons of
the spinal cord for the neurotransmitter,
glutamic acid. This compound is thought to be
important in pain transmission.
Benzodiazepine:
A class of chemically related drugs that have CNS
depressant activity. These drugs can produce a
spectrum of effects, including an antianxiety,
sedative-hypnotic (sleeping pill), and muscle
relaxant effects. These effects are due to an
action of these drugs in different areas of the
brain. Example of these drugs would be lorazepam
(Ativan), diazepam (Valium) and chlordiazepoxide
(Librium).
GABA:
This is the main inhibitory neurotransmitter in
the brain. GABA is released from specific neuron
in the brain and spinal cord into a synaptic
cleft and activates specific receptors on another
neuron, producing an inhibition of conduction.
Thus, the message is one of inhibition. Some
anticonvulsants are believed to exert their
effect through enhancing GABA neurotransmission.
There are different kinds of GABA receptors.
Baclofen (Lioresal) is believed to produce its
effects in the nervous system by directly
activating one kind of receptor for the
neurotransmitter, GABA.
Liver injury:
Some drugs may impair liver function. This effect
is usually reversible when the drug is
discontinued. Symptoms of impairment in liver
function include loss of appetite, nausea,
abdominal pain, and jaundice. The latter refers
to the occurrence of a yellow color in the skin
or in the whites of the eyes. It is due to the
deposition of the compound, bilirubin, a
breakdown product of hemoglobin, which is
normally metabolized by the liver but which can
accumulate in the blood and tissues when the
liver is not functioning normally. Individuals
experiencing these symptoms should notify their
physicians immediately.
Neuropathic pain:
This refers to pain caused by a dysfunction in
neurons of the central or peripheral nervous
systems. This is a condition in which an
abnormality in the neuron causes the conduction
of pain nerve impulses.
Neurotransmitter:
Neurons communicate through chemical messengers
that are released from one neuron, cross a space
(the synaptic cleft) and activate receptors on
another neuron. The neurotransmitter can be
removed from the synaptic cleft by a process,
which transports the neurotransmitter back into
the neuron that released it. This process,
therefore, will remove the neurotransmitter from
the synaptic cleft, thereby terminating its
action. This means the neurotransmitter can no
longer gain access to the receptor. Typical
neurotransmitters are serotonin, norepinephrine,
GABA, and acetylcholine. Many antidepressants
(e.g., amitriptyline) inhibit the process which
transports serotonin and/or norepinephrine back
into the neuron from which they were released,
thereby increasing the levels of these
neurotransmitters in the synaptic cleft. This
results in a greater activation of the next
neuron. Such an action is associated with
antidepression and possibly relief of neuropathic
pain.
Physical dependence:
A condition in which the discontinuation of a
drug that has been taken chronically produces
withdrawal symptoms. The withdrawal symptoms can
be inhibited or reversed by the administration of
the drug or other drugs with a similar mechanism
of action as the original drug. A condition in
which one drug will inhibit the symptoms of
withdrawal from another drug is called cross
dependence.
Receptor: A
molecule located on cells to which a
neurotransmitter or drug binds to produce its
characteristic effect.
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