Drugs Used for Symptoms Associated with Transverse Myelitis Norman J. Uretsky
and Cheng-Huan Chang

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.

If you have any other medications that you would like for me to discuss or if you have any specific questions about the drugs you are currently taking, I would be pleased to address these concerns in future TMA newsletters. Please send your questions or issues to Sandy Siegel .

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).

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.