a drug that helps to reduce the tendency of the brain to have a seizure. Although their primary use is for epilepsy, anticonvulsants are also used to treat psychiatric disorders, pain syndromes, and migraines.
a sensory experience that precedes a neurologic event, such as a migraine or seizure. During an aura, the patient may see, smell, or hear something unusual, or have a strange feeling, such as déjà vu (the feeling that one has been in a new place previously). In the case of seizures, the aura is actually a simple partial seizure.
a neurological event caused by abnormal electrical activity in the brain. Seizures come in many types. Some cause a patient to fall and thrash about on the floor, and others cause a loss of awareness without falling.
a strong, unexpected, often painful muscle contraction.
an involuntary, fast musculoskeletal movement. Tremors can be due to neurological conditions, such as Parkinson’s disease and multiple sclerosis, excessive intake of stimulants, such as caffeine, or may be a harmless genetic condition, such as essential tremor. Tremors may affect the hands, chin, and other parts of the body.
After completing this chapter, you should be able to
Describe how lesions in the brain and peripheral nervous system are related to neurological diseases.
List the causes, symptoms, and expected course of the following illnesses:
Headache—migraine, cluster, and tension.
Describe the psychosocial consequences for patients and families of patients with neurologic disorders.
State the generic and brand names of representative medications used to treat neurologic disorders, along with dosage forms and available doses.
List the mechanism of action, common adverse effects, and special precautions of medications used to treat neurologic disorders.
Neurologic disorders tend to be chronic illnesses, many of which are progressive in the decline of function. They include conditions ranging from those as common as migraine headaches to rare genetic diseases. Some diseases affect memory and reasoning, such as Alzheimer’s disease. Others, such as multiple sclerosis and amyotrophic lateral sclerosis, cause deterioration in the body while the mind is mostly intact. And many, such as epilepsy, are subject to social stigma, due to the sudden and often frightening onset of seizures or the muscle rigidity and hallucinations associated with Parkinson’s disease. Many of these conditions cause stress not only for the patient but also for caregivers and loved ones. Occasionally, medications can cause neurologic deficits.
In the past 30 years, there has been an enormous increase in the availability of medications to treat many of these diseases but none to cure them. Many of the medications in use are prescribed to delay disease progression; others are indicated to help manage the symptoms. People with neurologic diseases may have life spans close to normal but with 20 years or more of progressing disability. Patients and their families need health workers who understand the difficulties posed by their conditions.
What causes neurologic disorders? As the name implies, there are problems within the nervous system—the brain, spinal cord, and peripheral nerves that communicate with every part of the body. When this system is working well, we can multiply, remember old songs, walk a balance beam, hit a target with an arrow, and carry on a normal conversation. Our chewing and swallowing are coordinated so that we don’t choke. Our bowels and bladders do their jobs without stubbornly balking at their tasks. Our fingers can feel hot and cold objects, and we can feel a pebble in our shoe. We can pick up a quarter from the floor without falling over. We readily fall asleep when we are tired at night and wake up rested in the morning. Any of these systems can be thrown off by disease. Sometimes the disease attacks the nerves themselves. Sometimes there is a particular area of the brain that is affected. Often particular neurotransmitters—chemicals that carry messages from one nerve to another—are out of balance.
Many of the medications used to treat neurologic disorders are specific to a certain disease. Others are prescribed for several different conditions. Some medications used to treat epilepsy are also used to treat pain conditions, migraine headaches, and mood disorders. Some medications used to treat depression are also used to treat pain and migraine. There are many overlapping characteristics of neurologic diseases and psychiatric diseases (Chapter 7). Neurologic disorders are more likely to be detected by a physical examination and diagnostic procedures, such as MRI (magnetic resonance imaging) scans and EEGs (electroencephalograms). Psychiatric diseases are more likely to be diagnosed by the patients’ descriptions of their emotions, thoughts, and behavior. There is often overlap—patients with neurologic disorders frequently experience depression, for example.
Headache disorders are one of the most common neurologic conditions we encounter. Many conditions can cause headaches, and we must not treat this condition lightly. In addition, the overuse of over-the-counter (OTC) headache medications can lead to a condition of chronic daily headache, which is difficult to manage. Patients who describe frequent headaches, headaches that accompany certain activities (for example, coughing or sex), or a new headache that is the worst they have ever had, should see a doctor for evaluation. See Medication Table 6-1 for a list of medications commonly prescribed for the treatment of headache. (Medication Tables are located at the end of the chapter.)
R. B. is a 32-year-old woman who goes to her doctor because of a 6-month history of throbbing headaches on the right side of her head. She has been having these headaches once or twice a week. Before the headache starts, she sees beams of light that come together to form a figure that looks like the letter c, which floats around changing position and color. When she has the headaches, she also feels sick to her stomach and cannot stand to be around any light or noise. She has to go into a dark room and sleep. The headache is not relieved by two tablets of either aspirin 325 mg or ibuprofen 200 mg and generally lasts all day unless she is able to lie in a dark room and sleep. The headaches usually interfere with her ability to continue work. R. B. does not know what triggers her headaches but says she gets more headaches the week before her period. She says that both her mother and grandmother had “sick headaches.”
What kind of headache does R. B. most likely have?
For occasional tension headaches, OTC acetaminophen, ibuprofen, or naproxen is usually sufficient. (These medications are covered in detail in other chapters; please consult the index.) The patient can also be questioned about caffeine use. Sudden withdrawal from a daily high intake of caffeine can cause severe headaches, which can be treated by reintroducing a source of caffeine and gradually decreasing the amount ingested over several days.
Migraine headaches are a particularly distressing and incapacitating type of headache that is very common and may even occur in children. Migraines are characterized by throbbing on one side of the head. Patients are sensitive to light, sound, or both. Migraines are also known as “sick headaches” because they are frequently accompanied by nausea. In some patients the headache is preceded by a visual aura. Migraines are often relieved by sleep.
Many migraine sufferers are able to detect headache triggers by charting their headaches on a calendar. They can monitor how often the headaches occur, their intensity, and if a food or beverage appeared to cause the headache. Women often find that their headaches are more likely to occur at a certain time during their menstrual cycle. As with patients with tension headaches, patients with frequent migraine headaches should be encouraged to see a doctor to help better manage the problem. Infrequent migraines often will respond to OTC pain medications and rest, but more frequent migraines are better treated with medicines that prevent or reduce the frequency of the headaches, as well as medications that are used to stop the headache once it has started.
Cluster headaches are less common than migraine but also very debilitating when they occur. Unlike migraines, which are more common in women, cluster headaches are much more likely to occur in men. The headache is a short but intensely painful sensation. Cluster headache sufferers often describe the pain as feeling as if they had a knife stabbing one eyeball. In addition to intense pain on one side of the head, they often have a reddened, teary eye and runny nose. Cluster headache sufferers are not usually sensitive to light or sound. The headache is not relieved by sleep—in fact, the headache sometimes starts while the patient is asleep. Sometimes the patient will pace around or go outside if the weather is cold in an attempt to get some relief. This kind of headache usually only lasts a few minutes, but the patient experiences clusters of these short headaches—several in a day or over a few weeks—and then they will disappear for an extended period.
What medication might R. B.’s doctor prescribe?
Because cluster headaches are very short in duration, oral medications are not useful since they take too long to work. For quick relief, injectable sumatriptan is used. Inhaled oxygen will abort an attack for some people. The strategy is also to prevent the attacks by using medications prophylactically, although not all of the medications used prophylactically for migraines are effective for cluster headaches. Drugs used for cluster headache prophylaxis include verapamil and certain anticonvulsants.
The approach to managing migraine headaches is both to try to prevent them (prophylactic therapy) and to treat the headache when it occurs. Treating the headache at the first sign of onset is usually more effective at getting rid of it than waiting to try to treat a full-blown migraine. Prophylactic medications include several classes of drugs originally intended for other problems (and covered in other chapters of this text). Beta-blockers (eg, metoprolol, propranolol) were originally used to treat high blood pressure. Antidepressants (amitriptyline and venlafaxine) and antiepileptic drugs (valproate and topiramate) can be used to prevent migraines. Usually, drugs used for prevention must be taken by the patient for several weeks to get the best effects. Patients need to be patient and keep a headache diary to monitor benefits. The reduction in headache frequency may take several weeks to occur.
Medications used to stop an attack that has already developed include drugs derived from ergot and the triptan (selective serotonin agonist) class. Both of these classes of drugs act by increasing serotonin activity to constrict blood vessels in the cranium and possibly reduce inflammation that is contributing to the headache.
Ergot-derived drugs include dihydroergotamine, which is available as an injection and as a nasal spray, and ergotamine tablets. Ergot is a fungus that grows on grain. In the Middle Ages, people who consumed this fungus experienced toxic symptoms, such as hallucinations, muscle spasms, and gangrene due to blood vessel constriction. In small doses, drugs derived from ergot cause constriction of blood vessels affected by the migraine reaction. These medications must not be used in women who are pregnant, because they can cause contractions of the uterus, resulting in miscarriage. In addition, they can cause nausea, vomiting, and numbness and tingling in the fingers, toes, and face. They should not be used at the same time or within a day of other ergots or triptans. Patients with heart and blood vessel disease should not use these medications. These medications are only used at the time of the attack and are limited in how often they may be repeated.
The triptan class (selective serotonin agonists) is the most popular drug class used to stop migraine attacks when ibuprofen or other OTC products are not sufficient. There are many drugs in this category: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. They all act in the same way but differ in how quickly they work, how long their effects last, dosage forms, and some drug interactions. Dosage forms in this class include tablets, orally dissolving tablets, and nasal sprays. Sumatriptan is the only drug in this class available for administration by subcutaneous (SUBQ) injection. These drugs are used at the first sign of migraine. Side effects can include dizziness, chest tightness, nausea, numbness, and sweating.1
Lasmiditan (Reyvow) is an oral serotonin receptor agonist that targets a different receptor than the triptans do.2 It is indicated for the treatment of acute migraine. Lasmiditan may cause intense drowsiness, and patients must not drive or operate machinery for several hours after taking this medication.
Because of the risk of serotonin syndrome, serotonin receptor agonists must be used with caution in patients who are taking other medications with activity affecting serotonin, such as selective serotonin reuptake inhibitors (SSRIs) and some antidepressants. Serotonin syndrome can cause abnormal muscle contractions, incoordination, and cardiovascular problems that can be life threatening.
Patients with ischemic heart disease (angina, coronary heart disease, and others) should not use medications from the triptan class.
A newer class of drugs specifically targets the activity of the trigeminal nerve, which has been implicated in migraine pain. Drugs in this class are called calcitonin gene-related peptide (CGRP) antagonists (“blockers”).2 Unlike ergot derivatives and triptans, drugs that target CGRP activity do not directly cause constriction of blood vessels. Some of these agents are monoclonal antibodies—proteins biologically engineered to bind CGRP or its receptors—and are used for migraine prevention. Most of the monoclonal antibody CGRP antagonists—erenumab, fremanezumab, and galcanezumab—are injected subcutaneously monthly. Fremanezumab may also be administered quarterly (every 3 months). Another CGRP blocking monoclonal antibody, eptinezumab, is administered by intravenous infusion every 3 months. Galcanezumab is also approved for the treatment of episodic cluster headaches. All may cause hypersensitivity reactions, usually mild, and injection site reactions. Erenumab may also cause constipation. Three other CGRP receptor antagonists are approved for use in the treatment of migraine. These agents—atogepant, ubrogepant and rimegepant (also called gepants)—differ from the monoclonal antibodies mentioned earlier, and are smaller molecules that block the ability of CGRP to bind to its receptors. The gepants are administered orally.2 Atogepant (Qulipta) is a once-daily oral dose for migraine prevention. Ubrogepant (Ubrelvy) is taken as a single oral dose when a migraine begins; the dose may be repeated two hours later if needed. Rimegepant (Nurtec) is an orally disintegrating tablet usually taken every other day to prevent migraine, but has been used to treat attacks in patients for whom triptans are ineffective or contraindicated.3 The gepants have a low incidence of side effects, but some patients experience nausea and fatigue or drowsiness.
L. D. is a 72-year-old woman with high blood pressure and diabetes. While dining out with her husband, she suddenly became confused and began slurring her words. Her husband also noticed that her face was droopy on the left side. The restaurant manager called the emergency squad. The paramedics examined her and said that she appeared to be having a stroke. They transported L. D. along with her husband to the hospital in their town that has a stroke treatment center. L. D.’s blood pressure was 180/122 mm Hg on arrival, and her glucose level was 153 mg/dL. The CT scan was normal.
Why was it important for L. D. to be rushed to the hospital rather than waiting awhile to see if her symptoms went away?
Stroke is a condition caused by either bleeding or a clot in the brain. A stroke due to bleeding in the brain is called a hemorrhagic stroke. A stroke due to a blood clot, which cuts off the blood supply to a section of the brain, is called a thrombotic stroke. In adults, thrombotic strokes are much more common than hemorrhagic strokes. Both kinds can cause severe debility or death. If a thrombotic stroke is detected early enough, medication may be able to dissolve the clot and resume the blood flow in the brain before permanent damage occurs. It is very important to recognize the symptoms of stroke and get help immediately. Symptoms of a stroke are a sudden severe headache, sudden weakness, or inability to talk or walk. Symptoms are usually on one side of the body. When a stroke is suspected, it is important to call for emergency help to get the patient to a hospital that is equipped to evaluate and treat stroke patients quickly. If the patient meets the qualifications for receiving medication (alteplase, described below) to break up the clot (for a thrombotic stroke that has occurred less than 3 hours ago, in a patient who has not had recent surgery or bleeding problems), the medication can often return the patient to his or her original level of functioning. Risks of stroke include uncontrolled high blood pressure, age, atrial fibrillation (a heart rhythm problem), and diabetes. In addition to treating the stroke, it is also important to treat blood pressure or heart rhythm problems. Patients are also routinely started on antiplatelet or anticoagulant therapy to reduce the risk of another clot forming. Antiplatelet agents used include aspirin, clopidogrel, and dipyridamole. (These agents are discussed in detail in Chapter 16.) The anticoagulant, apixaban, is another option. (See Chapter 26.) In addition, stroke patients are usually started on a statin drug (see Chapter 16), which has been shown to reduce the occurrence of future strokes.
Since there was no sign of bleeding, the physician said that L. D. was having a thrombotic stroke. Which treatment could be prescribed to break up the clot? What did the emergency room team need to know about L. D. first?
Alteplase, also called tPA or tissue plasminogen activator, breaks up the clot (details in Chapter 16) that has caused a thrombotic stroke. Alteplase is administered by intravenous (IV) infusion as soon as the patient has been deemed to qualify for its use. Since alteplase can dissolve any clots in the body, a patient who has had recent surgery or bleeding problems usually cannot take this drug. Also, excessively high blood pressure must be brought to a safer level before alteplase is given.
Parkinson’s disease (PD) is a condition that affects about 1 million people in the United States. This disease is not common in younger patients, but the incidence increases with age. PD is named for an English physician, James Parkinson, who described people he met in the street who had similar characteristics. His description is still considered accurate today. The most common traits associated with PD are bradykinesia (general slowness of movement), muscular rigidity, balance problems, and tremor. The tremor is described as “pill rolling,” meaning the fingers (usually the forefinger and middle finger) rub against the thumb at a specific frequency. This tremor usually appears only on one side of the body in the early stages of the disease. Sometimes it is not present at all, but everyone with PD will have problems with slowness and rigidity.
W. S. is a 62-year-old man who comes to his doctor’s office complaining that he feels achy and tired all the time, and his right hand shakes. He says that he often drops tools or dishes. On examination, W. S. appears in good health, with no previous problems since he broke his arm 2 years ago. His posture is stooped, and he walks with a shuffling gait. Neurological examination shows balance problems and rigidity in his right hand. W. S. also says he has developed constipation even though his diet hasn’t changed, and his wife says he thrashes around in his sleep. W. S. works as a construction foreman and likes to do woodworking in his spare time. He says he is thinking of retiring early because he feels like he is slowing down too much.
What symptoms of PD does W. S. exhibit?
What effects might PD have on W. S.’s activities of daily living?
Patients with PD are at a high risk for falls due to the rigidity and balance problems. Medications that can cause orthostatic hypotension (decreased blood pressure when getting out of bed or up from a chair), including some medications used to treat PD, can greatly increase this risk.
The movement problems due to PD are caused by the loss of dopamine activity in the area of the brain called the substantia nigra. By the time symptoms such as tremor and rigidity are detected, the brain has lost more than 80% of its dopamine activity. Some patients report earlier problems, such as loss of the sense of smell, depression, and rapid eye movement sleep behavior disorder in the years preceding the diagnosis of PD. Movement problems are not the only symptoms of PD. Most patients also have problems with oily skin, constipation, and drooling. Some will develop hallucinations (which can also be caused by PD medications), muscle spasms, and dementia.
In treating PD, the challenge is to give adequate amounts of medication so that the patient is able to move for as long as possible during the day without causing side effects due to those medications, such as hallucinations, dyskinesias (excessive abnormal movements), and dystonic reactions (muscle spasms). As the disease progresses, this balance becomes more difficult. In talking with a patient with PD, you may notice that the patient gives you very little nonverbal expressions of understanding. The face often appears mask-like, and the voice may be low in volume and range of expression. Answers may come slowly. These are also common PD traits and, unfortunately, they contribute to patient isolation. The patient’s handwriting often becomes very small (micrographia); the patient’s posture is usually stooped, and he or she often walks with a slow, shuffling gait. Because PD medications can also cause abnormal movements, the patient may appear to sway or writhe at certain times—usually when the drug is in its peak phase. As the disease progresses, the patient will usually need a cane, walker, or wheelchair.
Patients with PD may have trouble opening child-resistant prescription bottles due to rigidity or tremor. They or their physicians may authorize dispensing in packaging that is easier to open, but they must be reminded to keep their medications out of the reach of children.
Which drugs might W. S. be taking for PD?
Medications used to treat PD are aimed at increasing the dopamine activity in the brain. These medications fall into several categories. (See Medication Table 6-2.) Anticholinergic drugs are sometimes used. The neurotransmitter, acetylcholine, is in a balance with dopamine, as if they were on the opposing seats of a seesaw. When the level of dopamine is low, acetylcholine is overly active. Using an anticholinergic drug returns this balance closer to normal by reducing the activity of acetylcholine. Anticholinergic drugs are mostly used to reduce tremor activity. They can also be useful in reducing drooling. However, because most PD patients are elderly, anticholinergics must be used very cautiously because they can increase the risk of delirium and falls. Anticholinergic drugs used to treat PD include benztropine (Cogentin), biperiden (Akineton), and trihexyphenidyl (Artane).
Monoamine oxidase inhibitors are another class of medications that have the effect of increasing levels (and, thus, activity) of dopamine in the brain by inhibiting one of the enzymes, monoamine oxidase, that breaks down dopamine. They may be used alone in early stages of PD or in combination with other drugs as the disease progresses. These drugs are similar to amphetamines as they can interfere with sleep. For this reason, they must be dosed early in the day. Drugs in this category include selegiline (Eldepryl and Zelapar), rasagiline (Azilect), and safinamide (Xadago).
Amantadine, a drug that was originally used to prevent influenza A, was found to also have activity in PD patients. It has some anticholinergic activity, so it must be used with caution in elderly patients. In addition, since amantadine is partly removed from the body by the kidneys, patients with decreased kidney function will need lower daily doses. Amantadine is no longer marketed under the Symmetrel brand, but some doctors and patients may still use that name. There are two once-daily (extended-release) amantadine products, Gocovri and Osmolex ER, which are approved for use in Parkinson’s disease and also for drug-induced extrapyramidal reactions.
Levodopa is a drug that actually increases the amount of dopamine in the brain. Dopamine itself cannot be used for PD because it cannot enter the brain from the systemic circulation. Levodopa is an alteration of the dopamine molecule that can cross the blood–brain barrier into the brain, where it is converted to dopamine. Carbidopa, which accompanies levodopa in the brand-name products Sinemet, Parcopa, Rytary, and the enteric pump product, Duopa, prevents the conversion of levodopa to dopamine until the drug gets into the brain. Levodopa is one of the most important drugs used in managing PD, but it is not without its drawbacks. It has a fairly short duration of action, so it must be dosed several times daily. There are long-acting carbidopa/levodopa preparations, which can be taken twice a day, but the onset of action for long-acting carbidopa/levodopa is delayed, so the patient may need to take an immediate-release tablet early in the morning in order to be able to get moving sooner. In addition, as PD progresses many patients will take both the long-acting drug (two or three times a day) and also several doses of the immediate-release drug during the day.
Levodopa comes in a variety of dosage forms and strengths, with and without carbidopa, and some are extended-release preparations. Entacapone is also included in some products. The pharmacy technician must exercise care to choose the product that precisely matches the one that has been prescribed. Combination and extended-release brands are not interchangeable.
Dopamine agonists are medications that mimic the effects of dopamine on the dopamine receptors in the brain. Since they act in a similar manner to dopamine, they can postpone the need for carbidopa/levodopa. They are often an early choice for younger patients with PD. Dopamine agonists include bromocriptine (Parlodel), pramipexole (Mirapex), ropinirole, and the transdermal patch, rotigotine (Neupro). In addition, the injectable dopamine agonist apomorphine (Apokyn) is used to provide relief from “off episodes,” in which patients become frozen and unable to move. All drugs that increase dopamine activity, including both dopamine agonists and levodopa, have the potential to cause hallucinations, dyskinesias (abnormal movements), and unusual obsessive behavior. Some patients taking these medicines have developed a new compulsion to gamble or obsession with sex. These effects do not happen in most patients with PD using these medicines, but patients should be counseled to report any unusual thoughts or behavior to the doctor. In addition, these medicines have a side effect known as “sleep attacks.” There are reports of patients suddenly, without preliminary drowsiness, falling asleep. Patients should be warned of this possibility, especially if they are still operating automobiles or machinery.
COMT inhibitors (catechol-O-methyl transferase) are also used to extend the activity of dopamine by reducing another enzyme responsible for its break down. Available COMT inhibitors include entacapone, opicapone, and tolcapone. Because tolcapone has been reported to cause liver damage and must be monitored with regular liver enzyme tests, and opicapone has no generic equivalent, entacapone is much more commonly used. These drugs have no direct activity on PD and must always be given along with carbidopa/levodopa. There is a combination product, Stalevo, that combines carbidopa, levodopa, and entacapone into one product for ease of use. COMT inhibitors have the potential to cause diarrhea.
As PD progresses, patients may develop “off spells,” when they become unable to move. Off spells may occur at random or predictable times during the day. Some PD medications are used only for patients who experience off spells. Daily oral istradefylline (Nourianz), an adenosine receptor antagonist, may be added to a patient’s carbidopa/levodopa regimen when off spells become a regular problem. It is not known specifically how this product helps to prevent off spells. Tobacco use may reduce this drug’s effectiveness, so a higher dose may be needed if a patient smokes a pack or more of cigarettes daily. For acute treatment, apomorphine (Apokyn) is an injectable product used for off spells. Because of several problematic side effects, it is not often used. Apomorphine causes severe nausea, and the patient needs to take trimethobenzamide (Tigan) for 3 days before beginning apomorphine therapy to prevent nausea. Most drugs used to treat nausea, such as promethazine and metoclopramide, act against dopamine and make PD symptoms worse, so they should not be used in patients with PD. In addition, the type 3 serotonin (5-HT3) receptor antagonists, such as ondansetron (Zofran), are contraindicated with apomorphine. (These agents are addressed specifically in Chapter 21.) Levodopa inhalation powder (Inbrija) is another product for off spells that is effective within about 10 minutes of use and lasts up to one hour. Patients should inhale the powder slowly through their mouths to avoid gagging and coughing. Istradefylline (Nourianz) is also used for off spells.
Patients with PD will often need other medications to help manage constipation, skin problems, depression, sleep disturbances, and pain. Sometimes an antipsychotic medication is needed to help manage hallucinations or delusions that may occur in PD or with PD medications. Most antipsychotics are not good choices due to their activity against dopamine. Most practitioners prefer to use low doses of quetiapine or sometimes clozapine in patients with PD. Pimavanserin (Nuplazid) is an atypical antipsychotic that is approved only for treatment of hallucinations and delusions associated with PD.
Matilda is a 93-year-old widow who just moved to an assisted-living facility. Matilda is a retired real estate agent. She has three grown sons, eight grandchildren, and two great-grandchildren. Matilda’s sons decided that their mother needed more supervision than they were able to give her and persuaded her to move to the assisted-living home. Matilda had been found wandering in the neighborhood in her housecoat and slippers, and she could not find her way home. She also had her telephone and electricity shut off due to not paying the bills. Matilda’s checkbook was a mess, with some legible writing mixed with unreadable scribbles. Matilda sometimes calls her sons by her husband’s or brothers’ names. She usually does not recognize her grandchildren but is happy to see them when they visit.
From what type of dementia is Matilda likely suffering?
Dementia is a condition in which a person declines in cognitive, or mental, level of functioning. Some of the characteristics of dementia are impairment of memory, especially of recent events; loss of the ability to do everyday cognitive tasks, such as following a grocery list, paying bills, or managing a checkbook; loss of the ability to follow directions; and decline in the ability to name common objects, such as books, paper clips, and shoelaces. The patient with dementia may become confused or lost in a formerly familiar setting. There are several types of dementia, the most common one being Alzheimer’s disease, which is a progressive dementia that ends with the patient being bedfast and unable to walk, talk, or recognize family. Death follows when the patient loses the will to eat or develops an infection such as pneumonia or a urinary tract infection. The duration of the disease varies but averages about 10 years from onset to death. Other types of dementia include vascular dementia, in which the mental decline is due to strokes or other blood vessel disease in the brain; Lewy body dementia, which may exist alone or as part of PD and often includes visual hallucinations (animals, strange people in the house, children playing) and may lead to the patient becoming suspicious of caregivers; and frontotemporal dementia, which involves dramatic changes in personality and the ability to make judgments.
Matilda’s doctor conducted the Mini Mental Status Exam, on which Matilda scored 19 out of a possible 30, indicating that she has significant dementia. Matilda had problems remembering lists, doing subtraction, repeating a phrase, and drawing a geometric figure. What medication(s) might Matilda be taking? What benefits would be expected from them?
Dementia is assessed by tests such as the Mini Mental Status Exam, in which the examiner asks the patient to repeat phrases, name objects, follow commands, and do simple tasks. The score given is an assessment of the severity of the disease. Because of the expected decline, it is better for a patient to be assessed early in the disease so the patient can make decisions about supportive care, living situation, driving, and other important issues.
Dementia cannot be cured. Medication may help to slow the decline and treat behavioral issues. Currently, nearly one-half of elderly people over the age of 85 years have symptoms of cognitive impairment. Studies are ongoing to see if the incidence of dementia can be lowered with interventions made earlier in life. There are suggestions that good nutrition, regular exercise, lifelong learning, and avoiding or managing diabetes, hypertension, and depression may reduce the likelihood of dementia if these changes are made by middle age.
Medications specifically indicated to treat dementia include cholinesterase inhibitors and memantine. (See Medication Table 6-3.) Most of these agents have a formal Food and Drug Administration (FDA) approval only for Alzheimer’s disease, but are usually also useful for Lewy body and vascular dementias. Frontotemporal dementia usually does not respond to medications used for Alzheimer’s disease. In addition, other medications, such as antidepressants, mood stabilizers, sedative-hypnotics, and antipsychotics are used for depression, sleep, and behavioral problems. Usually initial doses used are lower than would be used in a younger person. In addition, the use of antipsychotics is controversial—they help with behavioral problems, such as aggression and hallucinations, but they have been shown to increase the risk of stroke and other events in patients with dementia. In addition, most antipsychotics should be avoided in patients with Lewy body dementia, since they can exacerbate PD symptoms that often accompany that condition.
The effects of plaques and nerve tangles in the brain that are characteristic of Alzheimer’s disease reduce the activity of acetylcholine, causing many symptoms. The cholinesterase inhibitors work by reducing the metabolism of acetylcholine in the brain, thus increasing its activity. Cholinesterase inhibitors have been shown to slow the decline in mental function by at least several months. The drugs, which include donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), should be started at a lower dose and titrated up to the desired dose in order to improve patient tolerance. Common side effects are stomach upset, decreased appetite, and weight loss. These drugs may increase the risk of gastrointestinal (GI) bleeding in patients with ulcers and must be used with care in patients with heart rhythm problems.
Rivastigmine is available as both an oral capsule and a transdermal (patch) system. Namzaric is an oral extended-release combination product containing 10 mg donepezil and varying amounts of memantine. Take care to notice the amount of each ingredient in orders and prescriptions.
What side effects might Matilda experience from her treatment?
Memantine (Namenda) is another drug that may be helpful in patients with dementia. Memantine works by decreasing the activity of N-methyl-D-aspartate (NMDA) receptors in the brain. These receptors are acted on by glutamate, and the result is believed to worsen some of the symptoms of Alzheimer’s disease. Since memantine is mostly eliminated by the kidneys, the dose should be reduced in patients with renal impairment. Memantine has a titration schedule for achieving the desired dosage and is usually well tolerated, but dizziness, headache, constipation, and confusion have been reported in a small percentage of patients.
Herbals and Supplements
Vitamin E and the herb Gingko biloba have been studied to see if they would benefit patients with Alzheimer’s disease. Vitamin E was hypothesized to work as an antioxidant to reduce the advancement of the disease. Gingko biloba, a plant used for centuries in traditional Chinese medicine, was thought to be beneficial by acting to enhance neurotransmitter activity, improve blood circulation in the brain, or other unknown actions. Studies have not shown a clear benefit for either, but some doctors will recommend high doses of vitamin E. A patient with early cognitive impairment may be interested in trying Gingko biloba even though effectiveness has not been established. Although not standard medications, both vitamin E and Gingko biloba still have the potential for side effects and drug interactions.
M. J. is a 72-year-old woman who had seizure onset following a stroke 3 years ago. She had been seizure-free for 17 months, but for the last 3 weeks she has been having one to two brief (lasting about 1 minute) complex partial seizures per week. On questioning, she also complains of worsening heartburn problems for the past 6 weeks, which causes her to wake up at night. She feels tired because of the interruption of her sleep.
M. J. has been taking the following medications: gabapentin 400 mg TID, Lipitor 10 mg daily (for 3 years), Plavix 75 mg daily, Hyzaar 50/12.5 daily, and omeprazole 40 mg daily. Which of M. J.’s medication was prescribed to treat her seizures?
Epilepsy is a condition that is really a collection of disorders. Due to excessive electrical activity in the brain, a person will partially or completely lose consciousness. The person will have either localized movements, such as an arm shaking, or generalized movements, such as arms and legs jerking wildly. Seizures usually last only a few minutes, and the patient regains consciousness but often feels tired or confused for several hours. If a seizure lasts more than a few (eg, 5) minutes, it can become life threatening and needs to be treated as an emergency.
Epilepsy is diagnosed by taking a history from the patient, doing a neurologic examination, and checking an MRI scan and an EEG. The EEG is the most beneficial tool for detecting abnormal brain waves. Often, a neurologist can detect abnormal brain waves when a patient is not having a seizure, but sometimes the brain looks normal at that time.
There are many medications available to reduce the number of seizures a patient has. The goal is to have no seizures and no side effects. Many patients can be treated successfully with the first drug that is tried. Unfortunately, some patients have epilepsy that is more difficult to treat and will have to try several different medications or use two or three medications together. Many epilepsy medications, especially the older ones, are prone to causing drug interactions with other medications. The physician and pharmacist must always check for these interactions. Some medications will decrease the blood levels of the antiepileptic drug, and that could cause the patient to have a seizure.
Some situations that can increase the possibility of having a seizure are missing doses of medicine, not getting enough sleep, stress or infections, and, for women, different phases of the menstrual cycle. Patients with epilepsy, especially when seizures are not well controlled, often have problems with their memory. It is helpful to use a seizure calendar and medication compliance aids, such as pill boxes, to monitor the effectiveness of the medication and improve adherence to therapy. In addition, patients may contact the Epilepsy Foundation for assistance in meeting the challenges of this condition.
Treatment of epilepsy relies on medication. (See Medication Table 6-4.) There has been a dramatic increase in the number of drugs available to treat epilepsy in the past 20 years, but the older drugs are also commonly used. Certain drugs are more effective for particular types of epilepsy. For example, ethosuximide, valproate, and a few others are effective in treating absence seizures, but some other medications, such as carbamazepine and phenytoin, are not—indeed, these drugs can increase the frequency of seizures in these patients.
For about half of patients with epilepsy, the first drug their doctor tries will be effective in controlling their seizures. If the patient tolerates the drug well, treatment can continue with that medication. For many other patients, their epilepsy is more difficult to control and will require trials of different medications and sometimes combinations of medications. Patients with difficult to control seizures often benefit from a referral to a neurologist who specializes in epilepsy.
Many antiepileptic drugs have the potential for drug interactions. These drugs can interact with other antiepileptics and also other medications the patient may take, such as antidepressants and warfarin. The effects of these interactions must be recognized, especially when adding or withdrawing a drug from the patient’s therapy. In addition, some antiepileptics have a narrow range of blood levels between which they are effective but not toxic. Some doctors test the blood of their patients to follow the levels, and others just rely on the patient’s response and monitor for side effects. Patients with particular needs in epilepsy management are women who may become pregnant. Some antiepileptic drugs may reduce the effectiveness of hormone contraceptives or have the potential to cause birth defects. The choice of drugs used to treat epilepsy will depend on issues such as these in addition to patient tolerance and effectiveness of a drug in treating the patient’s seizures.
The following sections discuss medications used to treat epilepsy, some particular features of the medicine, and possible side effects. Some important drug interactions are listed, but a more complete reference should be consulted for a thorough discussion of possible interactions. In general, antiepileptic drugs should be started at low doses and gradually increased to the desired dose to reduce the chance of undesirable effects. Likewise, when taking a patient off an antiepileptic drug, the dose should be lowered gradually—usually over several weeks—to reduce the risk of seizures. In addition, when drugs that have interactions are used together, attention must be paid to the effect that removal of one drug may have on the levels of the continued drug. In addition to all benzodiazepines and barbiturates, some other antiepileptic drugs (eg, pregabalin, lacosamide) are controlled substances.
In status epilepticus (a seizure that lasts for a prolonged period, which, if not treated immediately, can cause brain damage or death), the seizures must be brought under control as quickly as possible. For that reason, IV medications are used. Only a few antiepileptic drugs are available and approved to be used intravenously for status epilepticus. A benzodiazepine, such as lorazepam, diazepam, or midazolam, is used initially, because these drugs work quickly (within a few minutes) by increasing the seizure-suppressing activity of gamma-aminobutyric acid (GABA) in the brain. In addition, the patient is started on another antiepileptic drug—usually phenytoin, fosphenytoin, or a barbiturate—which takes longer to administer and to start working. Clonazepam, a long-acting benzodiazepine, is also used sometimes to prevent seizures. Clonazepam is also frequently used for certain sleep disorders. Clobazam (Onfi) is a benzodiazepine approved for a rare epilepsy condition that begins in children (Lennox-Gastaut syndrome). Midazolam (Nayzilam) and diazepam (Valtoco) nasal sprays can be used for breakthrough seizures and seizure clusters, as can diazepam rectal gel (Diastat).
Sudden withdrawal of a benzodiazepine that a patient has been using for a long time—whether it is being used for epilepsy, sleep, or anxiety—can sometimes precipitate seizures. Withdrawal should be done gradually, reducing the dose over several weeks. All benzodiazepines can depress respirations at high levels, or when used with other central nervous system (CNS) depressants, including alcohol.
LOOK-ALIKE/SOUND-ALIKE—Clonazepam and its brand name, Klonopin, can be confused with clonidine, an autonomic nervous system drug used for cardiovascular disorders.
The main barbiturate used to treat epilepsy is phenobarbital, which is a depressant of the central nervous system. It works by regulating the flow of sodium ions into nerve cells, which slows the conduction of the seizure signals and also enhances GABA, an inhibitory neurotransmitter. It is used for partial seizures and generalized seizures but not for absence seizures. Phenobarbital commonly causes drowsiness. At high doses or in combination with other CNS depressants, such as alcohol, phenobarbital can cause respiratory depression. Phenobarbital has many drug interactions. Primidone (Mysoline) has action resembling that of barbiturates and is, in fact, partially metabolized to a barbiturate.
Phenytoin and Fosphenytoin
Phenytoin is a drug that has been available for many decades. It, too, works by regulating sodium ion flow through openings called gates or channels in nerve cells. It is tricky to dose since the metabolism of this drug may differ greatly from one patient to another. Also, there are many drug interactions with phenytoin, including with other antiepileptic drugs. For this reason, there is no typical dose of this medication. Some patients may take as little as 200 mg daily; others may take 500 mg daily. Many patients tolerate this medication well as long the levels are not too high. At higher blood (serum) phenytoin levels, the patient may have problems walking. The eyes may appear to bounce around (nystagmus). Another unusual effect of this medication is that it may cause increased growth in gum tissue—sometimes to the point of causing the patient to need surgery to free the teeth. Some patients who take phenytoin for a long time may have a coarsening of their facial features. Phenytoin comes in several dosage forms, including capsules, chewable tablets, oral suspension, and IV solution. Phenytoin IV admixtures should only be mixed with normal saline. Adding the drug to dextrose solutions will cause prompt precipitation.
LOOK-ALIKE/SOUND-ALIKE—Cerebyx, the brand name for fosphenytoin, has been confused with Celebrex and Celexa. Fosphenytoin has been misspelled with an initial “ph.” This can cause confusion for hospital staff looking for the drug in dispensing machines.
Many precautions must be taken with IV phenytoin. It is not stable in dextrose solutions and must only be mixed in normal saline solution (and even then carefully examined for precipitation).
IV phenytoin must be administered slowly to avoid problems with the heart and blood pressure. IV phenytoin also can cause serious tissue damage if the drug is accidentally administered out of the vein. For these reasons, fosphenytoin was developed as a prodrug. Fosphenytoin is better tolerated on administration and breaks down in the body to phenytoin.
The dosage schedule for phenytoin varies greatly with the dosage form and must be adjusted when a patient’s therapy is changed from one dosage form or route of administration to another.
Carbamazepine and Oxcarbazepine
Carbamazepine and oxcarbazepine are related drugs that are used for partial seizures. They are also sodium channel regulators. Oxcarbazepine was developed to take advantage of the benefits of carbamazepine but to reduce the side effects and drug interactions. Carbamazepine may also be used for certain neuropathic pain conditions and to stabilize patients with bipolar disorder. Patients beginning carbamazepine must have their blood and liver function checked during the early weeks of therapy. In addition, early side effects include nausea, dizziness, drowsiness, double vision, and problems walking. An occasional unusual side effect of these medications is hyponatremia, or low sodium levels in the blood. Carbamazepine has many drug interactions, mostly due to its activity as an inducer of enzymes in the liver. Use of carbamazepine can cause levels of certain other medications to decrease, requiring a dose adjustment. In fact, carbamazepine induces its own metabolism. Carbamazepine is contraindicated with nefazodone due to reducing nefazodone levels dramatically. Other important interactions are with warfarin, levothyroxine, methadone, phenytoin, and oral contraceptives.
Ethosuximide is an antiepileptic drug that is only used for patients with absence seizures. Its mechanism of action is not clear but may involve regulating ion flow in nerve cells. Absence seizures, also called petit mal seizures, usually occur in children. Characteristically, the child stares or blinks for several moments, and sometimes many times daily. Ethosuximide will not help other types of epilepsy. The most common side effects are nausea and vomiting early in therapy.
Note: Because generalized tonic-clonic seizures are also called grand mal (big sickness) seizures, the lay public often calls less dramatic partial seizures petit mal (little sickness) seizures. This is a misuse of the term. The term petit mal only refers to absence seizures.
Valproic Acid, Valproate Sodium, Divalproex
Valproate sodium and divalproex are variations of the same original drug product, valproic acid. Valproic acid is the most versatile of all the antiepileptic drugs, which is believed to work by enhancing the activity of GABA in the brain. GABA is the main neurotransmitter that inhibits nerve activity, and increasing GABA activity will prevent or reduce seizure activity. Valproic acid can be used for absence, partial, and generalized tonic-clonic seizures. In addition, valproic acid can help to prevent migraine headaches, reduce neuropathic pain, and manage bipolar disorder. Valproic acid has many possible side effects, including nausea and vomiting, weight gain, hair loss, and tremor, and many potential drug interactions. There are many dosage forms, including tablets, capsules, oral solution, and IV preparations. Valproic acid (Depakene) is dosed three times a day and often causes nausea and other GI side effects. Valproate sodium (Depakote) is a twice-daily, long-acting preparation, but divalproex (Depakote ER) is a once-daily dosage formulation.
Technicians must be careful to distinguish the type of valproic acid product ordered to be sure the patient receives the correct one.
What might be causing M. J.’s sudden increase in seizure frequency?
Gabapentin and Pregabalin
Gabapentin (Neurontin) is a usually well-tolerated antiepileptic drug that has few drug interactions. In spite of its name, gabapentin does not increase GABA activity in the brain. It acts by an unknown mechanism. It is also useful in treating neuropathic pain, which is actually its main use. Common side effects include fatigue, dizziness, weight gain, and edema. Pregabalin (Lyrica) is a medication that is similar in activity to gabapentin, and it also can be used for neuropathic pain.
Taking antacids within 2 hours of a dose of gabapentin can reduce the amount absorbed by the body significantly and patients may suffer from seizures. Patients using antacids, especially OTC products that may not be on the medical or pharmacy profile because they were not prescribed by a physician, should be counseled by the pharmacist about timing them so that the gabapentin is taken at least 2 hours after the antacid.
Lamotrigine (Lamictil) works by regulating sodium channels, and it is usually well tolerated and has fewer drug interactions than phenobarbital, phenytoin, carbamazepine, and valproic acid. However, a very important interaction can occur when it is used along with valproic acid. Lamotrigine sometimes causes a serious rash that is potentially life threatening (as well as less serious rashes). To avoid the risk of rash, the starting dose must be very low and gradually increased to the desired dose. Valproic acid reduces the elimination of lamotrigine from the body. For this reason, patients who are taking valproic acid must start lamotrigine at even lower doses and titrate the dosage more slowly. When doses are started low, the side effects of headache, drowsiness, and double vision are less likely to occur or more easily tolerated.
LOOK-ALIKE/SOUND-ALIKE—Lamotrigine and its brand name, Lamictal, have been confused with the antiviral drug lamivudine and with the antifungal drug, Lamisil.
Topiramate and Zonisamide
Topiramate (Topamax) and zonisamide (Zonegran) are medications that work differently than most of the other drugs for epilepsy. Topiramate and zonisamide work by regulating the activity of calcium entering the nerve cells, and they are similar in how they work and in their side effects. They are also potentially useful in a variety of seizure conditions. Zonisamide may cause a reaction in patients who are allergic to sulfa drugs. Other common side effects include dizziness, nausea, and headache. Many patients lose weight when taking these two drugs. They can also occasionally cause kidney stones, so patients should be advised to drink plenty of water while on these medications. Some patients complain of mental slowing and problems finding words. Topiramate and zonisamide may reduce sweating. Since sweating is the way humans cool their bodies, drugs that suppress sweating can cause the body temperature to rise during hot weather or exercise, risking heat stroke. Patients should be advised not to get overheated from exercise or heat exposure.
LOOK-ALIKE/SOUND-ALIKE—Topamax, the brand name for topiramate, is similar to Toprol XL, a medication used for cardiovascular disease.
Tiagabine (Gabitril) is usually considered a second-line option when other medications have been ineffective in treating a patient’s seizures. The way tiagabine works is different from other drugs for epilepsy. It increases the activity of GABA by inhibiting its reuptake into storage sites in nerve cells. Side effects include dizziness, weakness, nervousness, diarrhea, tremor, and depression.
LOOK-ALIKE/SOUND-ALIKE—Tiagabine has been confused with the muscle relaxant drug tizanidine.
Levetiracetam (Keppra) is a popular drug in the treatment of epilepsy due to usually good tolerance, effectiveness, and few drug interactions. Levetiracetam works differently than all of the other antiepileptic drugs, but its exact mechanism is not known. It is usually well tolerated and has few drug interactions because it is mostly removed from the body by the kidneys, rather than primarily through the liver. Common side effects include fatigue, drowsiness, problems with coordination, and occasionally behavior problems. Because of the usually mild side effect profile, the dosage can be titrated to desired levels quicker than with some other medications.
Felbamate (Felbatol) is an antiepileptic drug that may be tried when several others have either not been effective or are not tolerated. Its mechanism of action is unknown. Felbamate is an effective drug but has the rare side effect of causing serious blood and liver problems, which may be fatal. Other more common side effects are nausea and weight loss.2
Lacosamide (Vimpat) is a newer antiepileptic drug whose exact mechanism is uncertain. One facet is believed to be regulation of sodium entrance into nerve cells, which is one factor that controls the transmission of signals through the nerves, but there may also be other areas of activity. Lacosamide is available as a tablet, oral liquid, and IV injection. The dose of lacosamide must be reduced in patients who have severe impairment of their kidney activity. Side effects of lacosamide include nausea, headache, drowsiness, dizziness, double vision, and balance problems; rarely it can cause heart conduction problems and hypersensitivity reactions.
Vigabitrin (Sabril, Vigadrone) is approved for use alone for infantile spasms, and as adjunctive therapy for patients with refractory complex partial seizures. Its mechanism is unknown, but it is believed to increase GABA levels in the brain. Patients must have their vision monitored periodically while on this medication, due to reports of effects on the visual field.
Perampanel (Fycompa) is an antiepileptic drug with a novel mechanism of action—it reduces the activity of glutamate, a CNS-stimulating neurotransmitter, on one type of receptor in the brain. It is approved for partial seizures and primary generalized tonic-clonic seizures. Possible side effects include behavior and psychiatric reactions, drowsiness, and falls. This medication also has the potential for several drug interactions.
Cenobamate (Xcopri) is a new antiepileptic drug that inhibits flow through sodium channels and also enhances GABA activity. It is approved as an add-on treatment for partial seizures. Both initiation and discontinuation must involve careful dose titration. Because of interactions with other medications, doses of other antiepileptic drugs may need to be increased or decreased when cenobamate is added.
Stiripentol and Cannabidiol
The mechanisms of action for stiripentol (Diacomit) and cannabidiol (Epidiolex) are not known. Stiripentol is approved to treat Dravet syndrome. Cannabidiol is approved for both Dravet syndrome and Lennox-Gastaut syndrome. Both are epilepsy syndromes that begin in childhood.
Some antiepileptic drugs are controlled substances under federal law. These include phenobarbital, pregabalin, the benzodiazepines, lacosamide, cenobamate, and cannabidiol. Gabapentin is also a controlled substance in many states and carries special reporting requirements in others.
In addition to medications, there are other approaches to controlling seizures. One is the vagal nerve stimulator, an implantable device that sends electrical impulses to the vagal nerve. This device is controlled with a magnetic wand so that the strength and frequency of the impulses can be adjusted. Another approach for some patients is brain surgery to remove the site in the brain where their seizures start. Surgery can be very effective in improving control of seizures, often leading to a seizure-free life. With both the vagal nerve stimulator and epilepsy surgery, the patient must still take antiepileptic drugs, although sometimes the number of medications can be reduced. For some children with difficult-to-control seizures doctors will prescribe a ketogenic diet, which is a diet very high in fat and protein and extremely low in carbohydrates. This diet has been shown to reduce seizures in many children whose seizures have not responded well to drugs. The ketogenic diet is not a “natural” diet. The child cannot have common foods such as milk, bread, and fruit because of the carbohydrate content. The diet is usually started in the hospital in order to closely monitor the child, including blood tests that are frequently done. It is a difficult diet to follow and some children do not tolerate it, but it is a useful tool for many.
Paula is a 43-year-old woman who has had a diagnosis of multiple sclerosis (MS) for 13 years. Initially she noticed numbness and weakness in her right hand that lasted a week or so and then went away on its own. Eight months later she had an episode of optic neuritis, in which she developed blurring in her right eye that progressed to loss of sight within a few hours. After treatment, her vision came back over the following 2 weeks. An MRI showed abnormal areas in the brain that were suspicious for MS. Since then, she has had a flare-up of neurologic symptoms about once a year. Sometimes it is profound tiredness and weakness that makes her unable to do her job as a hotel manager, and on other occasions she has had numbness and tingling in her feet and lower legs. She has problems with constipation, depression, and occasional muscle spasms. When the numbness is severe, she must use a cane to get around.
MS is a disease that affects nerves, causing a dramatic slowing in the conduction of electrical impulses. It is caused by an inflammatory process that attacks myelin, a protective insulator of the axon of nerve cells. When the myelin is damaged or destroyed, the areas innervated by those nerves lose their function (Figure 6-1). The symptoms of MS vary, depending on which area of the brain is having its myelin attacked. These attacks come and go, with disability followed by recovery, or they continue to progress. Eventually many patients become unable to walk without assistance. Muscle weakness, muscle spasms, problems with constipation, bladder incontinence, and vision problems are common developments.
Can Paula’s physician prescribe a medication or therapy to cure her MS?
The treatment of MS includes treatment of acute exacerbations, the use of disease-modifying therapy to reduce exacerbations, and the use of other medications for symptomatic problems such as pain, spasticity, fatigue, constipation, and urinary problems.
The medications used to treat MS are meant to reduce the number of relapses the patient experiences. These medications are known as immunomodulators. Other medications are used for treatment of the symptoms associated with MS, such as fatigue, depression, constipation, or muscle spasms. None of these medications will cure the disease. (See Medication Table 6-5.)
Sometimes Paula’s symptoms become especially severe. Should her regular medication doses be increased at these times or might something else be added?
For acute exacerbations, high doses of corticosteroids are used, usually intravenously. Methylprednisolone is given IV for 3 to 10 days, and symptoms usually improve after 5 days or so. The main key to management of MS is disease-modifying therapy. Several medications are used for this purpose. The specific mechanisms of action are not known for all of these products but, as a group, they interfere, in different ways, with the immune system’s attack on myelin. The choice of therapy depends on the characteristics of the patient’s disease, such as relapsing or progressive, and how the patient responds and tolerates a medication. A challenge to compliance is that these medications often cause considerable side effects and are inconvenient and expensive. They are intended to reduce the rate of relapses, but the patient may not realize that benefit for a year or more. Interferons (beta1b and beta1a) are one class in this category. Their exact mechanism of action is not known, but they are believed to reduce the immune response that attacks myelin. Interferons are administered either intramuscularly (IM) or subcutaneously. When administered according to direction, which varies by product, they can reduce the rate of MS relapses. However, these medications often cause side effects that discourage compliance, including flu-like symptoms, injection site irritation, and depression. Brand names of interferon drugs include Rebif, Plegridy, Extavia, and Betaseron.
Glatiramer acetate (Copaxone, Glatopa) is an alternative to interferons in many patients and may be better tolerated. Its mechanism is not fully understood, but it may act as a substitute for receptors that are attacked by the immune response in MS. Glatiramer is administered as a daily or three times weekly SUBQ injection, and it must be stored in the refrigerator. Glatiramer is very expensive but is gaining more attention as a useful agent for many MS patients. Some patients (about 10%) may develop flushing and tightness in the chest and difficulty breathing the first time they use this medication, but this reaction usually goes away in about 20 minutes.
Paula became depressed when taking interferons, and glatiramer did not relieve her symptoms. What else can be tried? What makes these treatments different?
Natalizumab (Tysabri), ocrelizumab (Ocrevus), and alemtuzumab (Lemtrada) are monoclonal antibodies that work by preventing white blood cells from attacking myelin in the brain. They are alternatives for patients who continue to have relapses while on other medications. All three are administered as IV infusions, but they have different schedules. These products are usually well tolerated, but patients must be monitored during and after infusions for reactions. Common side effects include headache, fatigue, and nausea. These products, because of their action in reducing the immune response, may increase the patient’s susceptibility to certain infections.
Mitoxantrone (Novantrone) is a chemotherapy drug that is also used for progressing forms of MS and for difficult cases of MS that have not responded well to other medications. It inhibits white blood cell activity in attacking nerve cells. Because of the possible reduced heart function that can be caused by this medication, there is a maximum total lifetime dosage that should not be exceeded. Other side effects include nausea, vomiting, hair loss, and menstrual problems.3 Cladribine (Mavenclad) is another drug that resembles a chemotherapy medication. It has approval for certain MS patients who meet its criteria. This medication is taken orally, and only a few days over the course of two years, but has limitations due to several precautions, including the possibility of causing malignancies.
Mitoxantrone must be prepared with the same precautions as other chemotherapy drugs and is administered every 3 months by IV infusion.
Medications used to manage fatigue, urinary problems, constipation, muscle spasms, depression, and other symptoms of MS are also used to manage these symptoms due to other causes, which are discussed in the appropriate chapters of this text. Dalfampridine (Ampyra) is a medication approved specifically to improve the walking ability of people with MS. It works by blocking potassium channels, which increase nerve signal conduction through axons. Dalfampridine is an oral medication. It is contraindicated in patients who have had seizures and in those who have decreased kidney function.
In addition to medications, patients with MS need to avoid becoming excessively fatigued or overheated. In spite of the difficulties associated with the disease, patients will usually have a normal life expectancy. The degree of disability varies dramatically from one patient to another.
M. K. is a 69-year-old man with metastatic pancreatic cancer. One of the tumors is in the area near his spine, and it is putting pressure on his spinal cord. M. K. describes the pain as feeling like an electric shock; the pain shoots down his legs. He takes extended-release morphine (MS Contin) 30 mg twice daily, which he says works for his abdominal pain but “doesn’t touch” this new pain. He also takes conventional morphine 10 mg every 4 hours as needed for breakthrough pain, Senna Plus, two tablets twice a day for constipation, and Ambien 10 mg as needed at bedtime for sleep.
M. K. has brought in new prescriptions for antidepressants and gabapentin. Is this because his cancer is affecting his mood and causing seizures?
Neuropathic pain is a particular pain condition caused by sensitivity, excessive activity, or damage in nerves. Characteristics of neuropathic pain are numbness, burning, tingling, shooting, and electric shock-like pain. Neuropathic pain can occur due to neuropathies caused by diabetes, nerve pain due to MS, pain in a nerve root due to shingles, and pressure on the spinal cord, such as spinal stenosis. Neuropathic pain can be treated with medications that work on the neurotransmitters that transmit pain signals. Medications that we have already discussed include tricyclic antidepressants (used at low doses); many of the anticonvulsants, such as gabapentin, pregabalin, and carbamazepine; and specific analgesics, such as tramadol and methadone.
Q. Z. is a 23-year-old college student who comes to the pharmacy looking for something to help him sleep. He says it takes an hour for him to fall asleep at night, and sometimes he wakes up in the middle of the night and can’t get back to sleep. Q. Z. is healthy, but says he is worn out trying to keep up with his classes and working part-time. He drinks two or three cups of coffee in the morning and has a couple of Red Bulls in the afternoon to keep going. On days that he isn’t working in the evening, he stays up late playing video games or goes out drinking with his friends. On those nights he might not go to bed until 3:00 or 4:00 a.m. instead of his usual midnight bedtime. Some days he has an 8:00 a.m. class but other days he has later classes and he can sleep in until 10:00 a.m. He wants to know what he can take to help him fall asleep when he wants to every night.
When we think of sleep disorders, we usually think of problems falling asleep. That is the most common problem for Americans, but there are many other conditions that cause problems with the sleep cycle. To begin we should discuss normal sleep. Our bodies react to decreasing amounts of light to increase the production of melatonin in the brain. Melatonin causes us to feel drowsy and fall asleep. In addition there is a circadian rhythm that determines periods of time during the day that we sleep or are alert. When we fall asleep, we initially enter a light sleep, then proceed through deeper phases to deep sleep (phases 3 and 4). Then we enter a lighter sleep in which we do most of our dreaming, the rapid eye movement phase (REM sleep), and then the cycle begins again. We go through this cycle several times every night, with the amount of time in the deep and REM phases changing as the night progresses.
What are some of the factors that might be contributing to Q. Z.’s sleep problems?
People with sleep disorders may have problems falling asleep, problems staying asleep, and problems waking up too early and being unable to go back to sleep. Sleep problems may be transient or temporary—resulting from some change or stress in the patient’s life—or chronic and continuing for a long period of time. Some patients also have unusual behaviors during sleep in which they may walk, cook, eat, or do other activities that are better left to the waking hours. During REM sleep behavior disorder, a patient will thrash around as he acts out his dreams (normally we do not move during dreaming.)
There are many nonpharmacologic interventions that can improve the ability to fall asleep and stay asleep. In general, these methods are known as good sleep hygiene. Some of these strategies include maintaining constant times for going to bed and rising, avoiding drinking caffeine or alcohol in the evening, using the bedroom only for sleep and intimacy (ban the TV, computer, etc.), eliminating sources of light in the bedroom, avoiding long naps during the day, and exercising daily but not within 2 hours of bedtime. In addition, counseling, such as cognitive behavioral therapy (CBT), in which the patient brings to light worries that interfere with sleep and develops techniques to deal with them, is helpful for many people. Comfortable bedding and cool room temperature also enhance sleep. In older people, who do not sleep as deeply as the young, increasing the skin temperature very slightly—using a warm bath or electric blanket or mattress pad—may improve sleep structure.
For insomnia, which is the inability to fall asleep or stay asleep, there are several OTC medications that are effective short term. These are in two categories: antihistamines and melatonin. The first-generation antihistamines cause drowsiness as an expected side effect and are also marketed for insomnia. These products include doxylamine and diphenhydramine. Diphenhydramine is the “PM” of medications such as Tylenol PM and Advil PM. Side effects include dry mouth, constipation, and possible hangover feeling the next morning. In older people these drugs should be avoided as they can also cause urinary retention and confusion, which older people are more sensitive to.
When Q. Z. tells the pharmacist about his problem, will she tell him he needs to see a doctor if he wants things to improve or are there any OTC remedies she can recommend?
Melatonin is a synthetic form of the natural product produced in our brains that makes us sleepy. When taken about an hour before the usual bedtime, melatonin can help a patient become drowsy and fall asleep. Patients, especially elderly ones, should try a low dose initially (i.e., cutting the tablet in half). Melatonin may also be helpful in people who expect to experience jet lag while traveling or after returning home. One prescription sleep aid, ramelteon (Rozerem) acts on melatonin receptors in the brain to produce sleep.
If OTC remedies do not help Q. Z., what might his doctor prescribe to help him sleep? Is there any reason for him not to take them every night for the rest of his life?
Most of the prescription medications stimulate GABA receptors to cause drowsiness. These include the benzodiazepines—flurazepam and temazepam, quazepam, and triazolam. Benzodiazepines can be habit forming, and they also can cause drowsiness during the next day. For this reason, they are less safe to use in older patients. These medications have fallen from favor in recent years due to the availability of nonbenzodiazepines that also stimulate GABA receptors, such as zolpidem, zaleplon, and eszopiclone. These medications are shorter acting than benzodiazepines and can be used to help a patient fall asleep initially, or for a patient who has problems getting back to sleep during the night. Side effects include headache, dry mouth, strange behavior during sleep, and weight gain (zolpidem).
Of the prescription sleep medications, all of the ones that are benzodiazepines (or act on benzodiazepine receptors) are controlled substances under federal law. These include estazolam, eszopiclone (Lunesta), zaleplon (Sonata), zolpidem (Ambien), quazepam (Doral), temazepam (Restoril), and flurazepam. Drugs specifically approved for insomnia that are not controlled substances include doxepin (Silenor) and the antidepressants suvorexant (Belsomra) and lemborexant (Dayvigo), both of which block orexin, an alertness chemical in the brain, and ramelteon (Rozerem), which acts on melatonin receptors. Antidepressants that are often used off-label for sleep, such as trazodone, amitriptyline, doxepin, and mirtazapine, are not controlled substances either. Many antihistamines used for insomnia, such as diphenhydramine and doxylamine, are available in OTC products.
Other prescription medications used to help with sleep are usually in the category of sedating antidepressants. These include trazodone, mirtazapine, doxepin, and amitriptyline. These medications are discussed thoroughly in Chapter 7. (See Medication Table 6-6.)
Restless legs syndrome (RLS) is a condition in which a patient feels the need to move his or her legs after going to bed, to relieve crawling or tingling feelings in the legs. (One patient said it felt like he needed to ride a bicycle in bed.) This condition is sometimes associated with iron deficiency anemia or pregnancy, but more often the problem is unexplainable. When iron levels are low, an iron supplement will often improve the symptoms. Otherwise, some nonpharmaceutical approaches are to take a walk or exercise early in the evening and take a warm bath before bed. Medications that are used to treat PD, such as ropinirole and pramipexole, taken at bedtime are the choice agents. As carbidopa/levodopa may cause rebound restlessness later in the night, other alternatives are benzodiazepines, gabapentin, and opioids.
Obstructive sleep apnea is another condition that interferes with a person’s ability to get a good night’s sleep and can have serious health consequences. It is caused when tissue in the throat relaxes during sleep, closing the airway. The sleeper often snores, stops breathing for several seconds, and then resumes breathing with a snort. This pattern prevents the patient from getting into the restful phases of deep sleep, and the patient often is tired the next day. Sleep apnea contributes to poor control of diabetes and high blood pressure, and the tiredness during the day can lead to accidents. It is diagnosed when a sleep study shows that the patient has periods during sleep in which he or she does not breathe for extended lengths of time. Sleep apnea is managed with machines that force air into the lungs during sleep, and, alternatively, it may be managed with oral appliances that are made by dentists. For patients who have excessive drowsiness during the day, medications such as methylphenidate, modafinil (Provigil), armodafinil (Nuvigil), and solriamfetol (Sunosi) may be used.
There are many other rare sleep disorders, such as narcolepsy and non-24-hour sleep-wake disorder. There are some medications that are specifically directed at these conditions, and are only available through specialty pharmacies. Two such medications are sodium oxybate (Xyrem) for narcolepsy and tasimelteon (Hetlioz) for non-24-hour sleep-wake disorder. Patients must be enrolled in the Risk Evaluation and Mitigation Strategies (REMS) program by their physicians, and the medications are shipped to them at home.
The central nervous system is complex and is connected to every part of the body in some way. This means there are many different kinds of malfunctions that can occur and many different conditions that can result. Some of these can be completely relieved, while others can be treated to lessen their impact on the patient’s daily life. Often, multiple therapies, including medications and other treatments, must be tried and/or continued before the patient’s condition improves.
No greater than 75 mg orally 2 times daily or 50 mg orally 3 times daily and increased to a maximum dose of 600 mg/day in divided doses
CV, Rx only
Alcohol should be avoided with administration of pregabalin
Rufinamide (roo FIN a mide)
40 mg/mL oral suspension; 200 mg, 400 mg tablets
400–800 mg/day orally in 2 equally divided doses; increase by 400–800 mg/day every 2 days to a maximum dose of 3,200 mg/day in 2 equally divided doses
Abrupt discontinuation should be avoided; nonhormonal forms of contraception are recommended during use for female patients
Stiripentol (stir ee PEN tol)
Capsules 250 mg, 500 mg
Powder for oral suspension packets 250 mg, 500 mg
Dose by weight, 50 mg/kg/day, in 2 or 3 divided doses; take with a meal
For Dravet syndrome. monitor weight and growth
Tiagabine hydrochloride (ty AG a been)
2 mg, 4 mg, 12 mg, 16 mg tablet
Adjunct therapy for patients taking enzyme-inducing antiepileptics: 4 mg orally once a day; may increase dosage by 4–8 mg/day at weekly intervals to a maximum dose of 56 mg/day (given in 2–4 divided doses); lower doses are used in patients who are not taking enzyme-inducing drugs
Modification of concomitant antiepilepsy drugs is not necessary, unless clinically indicated
Topiramate (toe PYRE a mate)
Topamax, Eprotia, Trokendi XR
Topamax: 15 mg, 25 mg capsule; 25 mg, 50 mg, 100 mg, 200 mg tablet; Topiragen: 25 mg, 50 mg, 100 mg, 200 mg tablet (all forms also available generic)
Titrated over 6 weeks to maximum dose of 200 mg orally twice daily
May decrease effectiveness of estrogen-containing oral contraceptives with concurrent use
Valproate (val PROE ate) sodium, valproic (val PROE ik) acid, divalproex (dye val PRO ex) sodium
Depakene, Depakote, Depakote ER, Depakote Sprinkles, Depakote DR
Injection solution (albumin free) 8.8 mcg, 22 mcg, and 44 mcg autoinjectors and prefilled syringes
Titrate to 22 mcg or 44 mcg 3 times/week
Rebif is to be administered SUBQ at the same time of day on the same 3 days each week, rotating injection sites; may premedicate with an analgesic
125 mcg/0.5 mg in single-dose pens or syringes; 63 mcg and 94 mcg prefilled pens
Titrate to 125 mcg every 14 days
May premedicate with an analgesic on treatment days
Interferon (in ter FEER on) beta-1b
Injection powder for reconstitution, with diluent (containing albumin)
0.25 mg every other day; titrate dose
Gradual dose titration, analgesics, and/or antipyretics may help decrease flu-like symptoms on treatment days
Injection powder for reconstitution, with diluent (containing albumin preservative free)
0.25 mg every other day; titrate dose
Patient should be well hydrated
Cladribine (KLAD ri been)
Tablets 10 mg
Two yearly treatment courses; 2 cycles/course; cumulative dose 3.5 mg/kg
Do not use during pregnancy; dose should be given at least 3 hours before or after any other oral medication; hands must be dry when taking drug; wash hands well after taking
Mitoxantrone (mye toe ZAN trone)
Injection solution: 2 mg/mL; add to D5W or NS for infusion
12 mg/m2 every 3 months
Maximum lifetime cumulative dose: 140 mg/m2
Dimethyl fumarate (dye METH il FU mar ate)
Delayed-release capsules 120 mg, 240 mg
120 mg twice daily for 7 days, then 240 mg twice daily
Flushing is a common side effect; take with food, or take up to 325 mg non-enteric-coated aspirin 30 minutes before dose to reduce flushing
Diroximel fumarate (dir OX i mel FU mar ate)
Delayed-release capsules 231 mg
231 mg twice daily for 7 days, then 462 mg twice daily
Avoid administration with a high-fat, high-calorie meal, avoid co-administration with alcohol; flushing is a common side effect; take with food, or take up to 325 mg non-enteric-coated aspirin 30 minutes before dose to reduce flushing
Fingolimod (fing GO li mod)
Capsules 0.25 mg, 0.5 mg
Adults: 0.5 mg daily
Children under 10 years and less than 40 kg: 0.25 mg orally daily
Monitor patient for 6 hours after first dose for bradycardia, blood pressure, pulse; contraindicated with recent MI, unstable angina, stroke, TIA, Class III or IV heart failure
Siponimod (si PON i mod)
Tablets 0.25 mg and 2 mg
Genotype determines dose target; titrate from 0.25 mg daily to 1 mg or 2 mg daily dose
Contraindicated with MI, unstable angina, stroke, TIA, Class III or IV heart failure in last 6 months; contraindicated in CYP2C9*3/*3 genotype
Teriflunomide (te ri FLU no mid)
Tablets 7 mg and 14 mg
7 mg or 14 mg daily
Exclude pregnancy before starting therapy; use effective contraception during use; check liver function before and every month during treatment for 6 months
Alemtuzumab (al em TUZ you mab)
Injection solution 12 mg/1.2 mL (10 mg/mL); add 12 mg to 100 mL NS or D5W; gently mix, infuse over 4 hours
First course: 12 mg/day on 5 consecutive days
Second: 12 mg/day on 3 consecutive days, 12 months after first course; repeat, if needed, 12 months later
Premedicate with corticosteroids before infusion for the first 3 days of each treatment course; administer antivirals for herpes prophylaxis and continue for 2 months after completion; monitor vital signs during infusion, watch patient for at least 2 hours after infusion
Natalizumab (na ta LIZ you mab)
Injection solution: 300 mg/15 mL; add to 100 mL NS for infusion
300 mg infused over 1 hour every 4 weeks
Access to this medication is restricted; treatment must be reauthorized every 6 months; watch patient for 1 hour after infusion
Ocrelizumab (ok ri LIZ you mab)
Injection solution 300 mg/10 mL; add 300 mg to 250 mL NS for infusion; duration 2.5 hours or longer
Add 600 mg to 500 mL NS for infusion; duration 3.5 hours or longer
Start: 300 mg IV infusion; repeat in 2 weeks; 600 mg IV infusion every 6 months thereafter
Only FDA-approved disease-modifying therapy for primary-progressive MS; premedicate with corticosteroid and antihistamine before infusion; observe patient for 1 hour after infusion
Dalfampridine (dal FAM pri deen)
Extended-release tablets 10 mg
10 mg twice daily
For improvement in walking for adults with MS; contraindicated in patients with history of seizures and CrCl 50 mL/min
D5W = dextrose 5% in water; FDA = U.S. Food and Drug Administration; IM = intramuscular; IV = intravenous; MI = myocardial infarction; NS = normal saline; SUBQ = subcutaneous; TIA = transient ischemic attack.