11.4: Drugs Used in the Treatment of Multiple Sclerosis
By the end of this section, you should be able to:
- 11.4.1 Identify the characteristics of drugs used to treat multiple sclerosis.
- 11.4.2 Explain the indications, actions, adverse reactions, contraindications, and interactions of drugs used to treat multiple sclerosis.
- 11.4.3 Describe the nursing implications of drugs used to treat multiple sclerosis.
- 11.4.4 Explain the client education related to drugs used to treat multiple sclerosis.
Interferons
Interferons are proteins that are released in response to pathogens. Synthetic interferons have been made to resemble naturally occurring ones. These agents are important for treating viral infections, neoplasms, and autoimmune diseases such as MS. They have antiviral, antiproliferative, and immunomodulatory actions and should be used early in the disease because they have been shown to modify disease progression and reduce relapse rates. Interferon drugs are available as interferon beta-1a (given intramuscularly) and interferon beta-1b (given subcutaneously). This classification reduces the severity of symptoms and decreases the number of lesions detected with MRI. There are different mechanisms of action for interferons, including inhibition of the growth of some cells, changes in cell surface antigen expression, and induction to lymphocytic cytotoxicity.
Table 11.14 lists common interferons and typical routes and dosing for adult clients.
| Drug | Routes and Dosage Ranges |
|---|---|
|
Interferon beta-1a
( Avonex ) |
30 mcg intramuscularly weekly or 7.5 mcg intramuscularly weekly, then increase dose by 7.5 mcg each week until 30 mcg once weekly is reached. |
|
Interferon beta-1b
( Betaseron ) |
0.0625 mg subcutaneously every other day; gradually increase dose by 0.0625 mg every 2 weeks to a maximum dose of 0.25 mg every other day. |
Adverse Effects and Contraindications
Avonex is produced by recombinant DNA technology using genetically engineered Chinese hamster ovary cells into which the human interferon beta gene has been introduced. Betaseron is manufactured by bacterial fermentation of a strain of Escherichia coli that possesses the gene for human interferon beta. In addition, the medication contains mannitol and albumin. Anyone with a hypersensitivity to any of these three components could develop angioedema or anaphylaxis (DailyMed, Betaseron , 2023).
Flu-like symptoms on treatment days are common when first started. Symptoms experienced are fever, chills, myalgia, malaise, and sweating. These usually diminish over time. The symptoms can be minimized by starting with a low dose and then slowly titrating up to the full dose or by giving an analgesic/antipyretic medication before taking the interferon. Neutralizing antibodies can form against synthetic agents. This will decrease the drug’s effectiveness but also increase the risk of anaphylaxis.
Drug-induced lupus erythematous has been reported. Clinical manifestations include rash, polyarthritis, nephritis, and serositis. If this occurs, the drug should be stopped. Interferon beta can injure the liver by causing an asymptomatic increase in circulating liver enzymes. Liver function tests must be monitored routinely. If liver injury is evident, the dose can be decreased or a temporary interruption of treatment could be tried. When the liver function returns to baseline, treatment can resume with continued careful monitoring (DailyMed, Betaseron , 2023).
Transient injection site reactions include redness, pain, swelling, itching, or a lump. Injection site necrosis can occur with this drug, and some lesions have extended to the fascia overlying the muscle. Some have developed injection site abscesses and cellulitis, but this is usually the result of poor technique.
With interferon alpha, clients can develop subclinical hypothyroidism. It first causes inflammation of the thyroid (thyroiditis) that causes a short period of hyperthyroidism followed by hypothyroidism. Symptoms of heart failure can be exacerbated. Although these drugs have no direct-acting cardiac toxicity properties, they can trigger symptoms to arise.
Other immunosuppressive agents may increase the toxic effects of both immunosuppressives and elevate the risk of serious infection. Infections are related to the immunosuppressant effects. Many of these are opportunistic and are produced by microbes that do not normally cause infections unless the host is immunocompromised. Live vaccines should be avoided due to increased risk of vaccine-related infections. If needed, clients should receive them at least 4–6 weeks before starting therapy, especially the varicella-zoster virus (VZV) vaccine if one did not have chickenpox. Overall, the immunosuppression decreases the body’s response to vaccines and renders them useless (DailyMed, Betaseron , 2023).
Table 11.15 is a drug prototype table for interferons featuring interferon beta-1b. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
Interferons (biologic or synthetic) Mechanism of Action Enhances suppressor T-cell activity Reduces pro-inflammatory cytokine production Down-regulates antigen presentation Inhibits lymphocyte trafficking from crossing the blood–brain barrier and reaching neurons of the CNS |
Drug Dosage
0.0625 mg subcutaneously every other day; gradually increase dose by 0.0625 mg every 2 weeks to a maximum dose of 0.25 mg every other day. |
|
Indications
Relapsing forms of MS (CIS, RRMS, SPMS) Therapeutic Effects Decreases frequency and severity of relapse reactions Reduces development and size of brain lesions |
Drug Interactions
Hypersensitivity to albumin, mannitol, or E. coli –derived products Chemotherapeutic agents Bone marrow suppressing drugs Live vaccines Food Interactions No significant interactions |
|
Adverse Effects
Flu-like symptoms (fever, chills, headache, myalgia) Injection site reactions Infection Anaphylaxis Neutralizing antibodies Depression/suicidal ideations/psychosis Hepatotoxicity Leukopenia/neutropenia/lymphopenia Thrombocytopenia Drug-induced lupus erythematous Hyperthyroidism/hypothyroidism (interferon alpha) |
Contraindications
Hypersensitivity to interferon beta, any ingredient within the drug, or albumin Caution: Heart failure Psychiatric conditions Thyroid disorder Depression Immunocompromised clients Active liver disease |
Nursing Implications
The nurse should do the following for clients who are taking interferons:
- Closely examine the injection sites for redness, swelling, and/or tenderness.
- Explain to the client the importance of avoiding contact with infected or sick people.
- Monitor the following lab studies before starting the medication and periodically throughout therapy: complete blood cell count (CBC) with differential, thyroid function, and liver function tests.
- Assess for any signs of infection or excessive bleeding or easy bruising.
- Emphasize to the client to avoid injuries and apply direct pressure to the affected area for several minutes.
- Teach the client signs and symptoms of hypo- and hyperthyroidism.
- Medicate with analgesics-antipyretics on injection days to decrease flu-like symptoms.
- Evaluate for any indication of depression or suicidal ideations.
- Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.
Client Teaching Guidelines
The client taking an interferon should:
- Report any signs of infection, such as a fever or sore throat.
- Avoid injuries. If one occurs, direct pressure should be applied to the affected area to control bleeding.
- Promote a balance of rest and exercise.
- Have the ability to correctly reconstitute and prepare the medication using aseptic technique.
- Rotate injection sites with each injection. The same site should not be used two consecutive times.
- Use proper technique in administering a subcutaneous injection.
- Notify the provider of feelings of depression or suicidal thoughts.
- Notify the provider of right upper quadrant pain, jaundice, dark urine, anorexia, fatigue, and clay-colored stools.
- Take an analgesic-antipyretic on the days of treatment to minimize the flu-like symptoms.
- Immediately contact the provider with the first signs of a rash.
- Contact the provider if any signs of thyroid dysfunction, such as temperature intolerances, change in weight, or level of energy, occur.
The client taking an interferon should not:
- Overexert themselves; they should take rest periods between activities.
- Spend time with individuals who are actively sick or spend time in crowds.
- Receive live vaccines while on therapy or within 3 months of stopping therapy.
- Inject in a site that is red, bruised, infected, scabbed, broken, or has lumps.
Immunomodulators
Immunomodulators work by blocking the activity of specific cytokines, which promote autoimmune reactions and inflammation in MS. Immunomodulators are used for treating relapsing forms of MS (RRMS and active SPMS) and reducing the frequency of relapses and slowing down the accumulation of disabilities. Common immunomodulators include:
- Teriflunomide: An active metabolite of leflunomide, which is a drug that was previously approved to treat rheumatic arthritis. It inhibits dihydroorotate dehydrogenase. The overall result is a reduction of the number of activated lymphocytes in the CNS. This can reduce or prevent the number of relapses a client experiences (DailyMed, Teriflunomide , 2023).
- Monomethyl fumarate: This drug inhibits immune processes that damage the brain and spinal cord; it also has antioxidant properties. Monomethyl fumarate comes in a delayed-release capsule. Certain lab tests must be obtained before initiating this drug, including CBC with differential, liver enzymes, and total bilirubin levels. A CBC with differential also needs to be obtained 6 months after the start of the medication and then every 6–12 months thereafter. Adverse reactions associated with this drug include flushing, anaphylaxis, angioedema, progressive multifocal leukoencephalopathy (PML), herpes zoster, lymphopenia, and hepatotoxicity. A non-enteric coated aspirin (325 mg or less) may be taken 30 minutes before taking the drug to reduce the incidence or severity of flushing. For the remaining adverse reactions, the drug is held and appropriate treatment given (DailyMed, Bafiertam , 2023).
- Glatiramer acetate: This drug is thought to curb the body’s attack of the myelin covering by acting as a decoy to T-cell attack. Also, it induces and activates suppressor T cells in the periphery, which modifies the immune process. This drug does not cause many of the bone suppression reactions or flu-like symptoms similar to the other immunomodulators. It can cause postinjection reactions including flushing, urticaria, chest tightness, palpitations, or dyspnea. These should last only a few minutes and subside spontaneously. If symptoms last longer or are more intense, the client must notify the provider immediately (DailyMed, Glatiramer Acetate , 2023).
The medication must be stored in the refrigerator. Before administration, allow the medication to stand at room temperature for 20 minutes. Syringes are single-use only—any unused portion must be discarded. Injection is subcutaneously in the arms, abdomen, hips, or thighs. Injection sites should be rotated to prevent lipoatrophy (localized loss of fat tissue). Clients who have hypersensitivity to mannitol should avoid this drug because mannitol is part of the drug mixture.
Table 11.16 lists common immunomodulators and typical routes and dosing for adult clients.
| Drug | Routes and Dosage Ranges |
|---|---|
|
Teriflunomide
( Aubagio ) |
7 mg or 14 mg orally daily. |
|
Monomethyl fumarate
( Bafiertam ) |
95 mg orally twice daily for 7 days, then 2 95 mg capsules orally twice daily. |
|
Glatiramer acetate
( Copaxone ) |
20 mg subcutaneously once daily. |
Adverse Effects and Contraindications
Teriflunomide is very hepatoxic throughout therapy. If the alanine aminotransferase (ALT) amount is three times the upper normal limit on two consecutive tests, the drug must be immediately stopped, and an accelerated elimination procedure will begin. This procedure includes the administration of cholestyramine or activated charcoal for 11 days. In addition, this drug is highly teratogenic, and a negative pregnancy test must be obtained before therapy. The client should avoid pregnancy and speak with their provider if they are planning on becoming pregnant. Teriflunomide is eliminated very slowly and can take months to be fully leave the body.
Clients should be screened for latent tuberculosis (TB) before beginning therapy with immunomodulators because they have been found to activate latent TB, causing an active TB infection to develop. If found to be positive, the client must be treated for the active TB before initiating immunomodulators.
This group of drugs can cause peripheral neuropathy—either mononeuropathy or polyneuropathy. Risk factors include being older than 60 years of age, concurrent neurotoxic medications, and diabetes. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome has been associated with the use of this drug and is characterized by multiorgan hypersensitivity. DRESS can include symptoms like fever, rash, enlarged lymph nodes, facial swelling, hepatitis, nephritis, myocarditis, or myositis. Blood pressure should be checked before therapy and periodically throughout. An elevated blood pressure should be properly managed.
Concurrent use of drugs that have immunosuppressive and/or bone marrow suppressive properties should be avoided because it can increase the risk of infections. Teriflunomide can decrease the peak international normalized ratio (INR) by 25% in clients taking warfarin. Close monitoring of the INR is warranted to evaluate for warfarin dose adjustments to maintain therapeutic levels. This drug can also reduce the effectiveness of some oral contraceptives; therefore, a second barrier backup plan should be in place. In addition, the HMG-Co-A reductase inhibitors are prevented from being metabolized and can build up in the body. Live vaccines should be avoided because they can increase the risk of infection. These vaccines should be held until 6 months after immunomodulators have been discontinued.
Table 11.17 is a drug prototype table of immunomodulators featuring teriflunomide. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
Immunomodulator (synthetic) Mechanism of Action Inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis |
Drug Dosage
7 or 14 mg orally daily. |
|
Indications
Relapsing forms of MS (CIS, RRMS, SPMS) Therapeutic Effects Reduces the number of activated lymphocytes in the CNS |
Drug Interactions
Other drugs that cause immunosuppressive effects Other hepatotoxic drugs Oral contraceptives Warfarin HMG-Co-A reductase inhibitors Live vaccines Food Interactions No significant interactions |
|
Adverse Effects
Elevated blood pressure Anaphylaxis/angioedema Hepatotoxicity Bone marrow suppression Infections Stevens–Johnson syndrome DRESS Peripheral neuropathy |
Contraindications
Hypersensitivity Pregnancy/breastfeeding Active acute or long-term infections Severe hepatic impairment Immunocompromise |
Nursing Implications
The nurse should do the following for clients who are taking immunomodulators:
- Monitor the following lab values at baseline and routinely during therapy: ALT, aspartate aminotransferase (AST), serum bilirubin levels, CBC with differential.
- Observe for any signs and symptoms of infection and teach the client ways to prevent infection.
- Teach clients of reproductive age that they should use an effective contraceptive barrier.
- Monitor temperature and blood pressure during therapy.
- Perform a tuberculin skin test or interferon-gamma release assay (IGRA) to rule out latent TB before drug therapy is initiated.
- Obtain a pregnancy test before the start of treatment.
- Observe for any skin rashes/reactions.
- Monitor for any signs of bleeding, such as multiple bruises, hematuria, blood in the stool, or epistaxis.
- Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.
Client Teaching Guidelines
The client taking an immunomodulator should:
- Notify the health care provider if manifestations of liver injury occur, such as dark urine, clay-colored stools, right upper quadrant pain, or jaundice.
- Contact provider immediately with any evidence of infection, such as fever or sore throat.
- Notify the provider if they want to get pregnant because this drug can be harmful to the fetus.
- Monitor their blood pressure periodically because hypertension may occur.
- Immediately contact the provider for any signs of urticaria, rash, fever, dyspnea, wheezing, or swelling of the eyes, throat, or tongue.
- Inform the provider if experiencing bilateral numbness or tingling of hands or feet.
The client taking an immunomodulator should not:
- Get pregnant or breastfeed while on this medication.
- Stay for long periods when there are crowds because of their decreased white blood cell count and immune response.
- Participate in activities that could cause injury and bleeding because of bone marrow suppression.
FDA Black Box Warning
Teriflunomide
Clients who take teriflunomide risk severe to fatal acute liver injury and embryofetal toxicity.
Monoclonal Antibodies
Monoclonal antibodies are derived from a single B-cell source. Cloning of individual B lymphocytes results in the production of biologically identical antibody molecules. These drugs must be administered intravenously because they are proteins and would get destroyed in the GI system if taken orally. A mouse or hamster is injected with the human antigen for the rodent to produce the desired antibody. Once the antigen is administered, the rodent’s immune system mounts a response. Its B lymphocytes are stimulated to produce a specific antibody against that particular antigen. The B lymphocytes are extracted from the animal’s spleen. The antibodies can then be isolated and prepared for clinical use. Because these antibodies originate from one single cell line, it is possible to design them to suppress specific components of the immune system responsible for causing tissue damage in certain conditions. The generic names of the monoclonal antibodies end in “-mab.”
- Alemtuzumab: This agent is generally reserved for people who have had inadequate responses to two or more MS therapies. Due to its safety profile, this drug is only available through a restricted distribution program. Prescribers must be certified with the program by completing training. Clients must enroll and comply with ongoing monitoring requirements, and pharmacies must be authorized to dispense to certified facilities (DailyMed, Lemtrada , 2023).
- Ocrelizumab: This agent is indicated as a monotherapy for treating relapsing forms of MS including CIS, RRMS, and SSMS. In contrast to alemtuzumab and natalizumab, this medication is also used in the treatment of PPMS. This drug is administered via IV infusion and targets circulating CD20 markers on B lymphocytes, which produce antibodies. Clients must be premedicated with steroids and an antihistamine before each infusion to reduce infusion-related reactions. They also must be monitored during and for at least 1 hour after infusion; however, clients must be aware that reactions can occur up to 24 hours after the dose was received (DailyMed, Ocrevus , 2023).
- Natalizumab: This drug is indicated as a monotherapy for treating relapsing forms of MS including CIS, RRMS, and SSMS. This drug prevents cells of the immune system from entering the brain and spinal cord. It is very effective but is mainly used in clients who have failed first-line therapies. Only prescribers registered in the MS TOUCH Prescribing Program may prescribe this drug. Clients must read the medication guide and sign the enrollment form. The mechanism of action for natalizumab is different and complex compared with alemtuzumab. Overall, this drug demonstrates reduction of leukocyte migration into the brain and reduction of plaque formation. This results in an increase of the number of circulating leukocytes. The drug does not affect the absolute neutrophil count (DailyMed, Tysabri , 2023).
Table 11.18 lists common monoclonal antibodies and typical routes and dosing for adult clients.
| Drug | Routes and Dosage Ranges |
|---|---|
|
Alemtuzumab
( Lemtrada ) |
Intravenous (IV) infusion over 4 hours for 2 or more treatment courses:
First course: 12 mg daily on 5 consecutive days (60 mg total). Second course: 12 mg daily on 3 consecutive days (36 mg total) 12 months after the first treatment. Subsequent treatment courses: 12 mg daily on 3 consecutive days as needed at least 12 months after the last dose course. |
|
Ocrelizumab
( Ocrevus ) |
300 mg IV infusion, followed 2 weeks later with a second 300 mg IV infusion.
Subsequent doses: 600 mg IV infusion every 6 months. |
|
Natalizumab
( Tysabri ) |
300 mg IV over 1 hour every 4 weeks. |
Adverse Effects and Contraindications
Alemtuzumab must be administered in a certified health care setting with appropriate equipment to manage anaphylaxis or other serious infusion reactions, such as myocardial ischemia, myocardial infarction, ischemic/hemorrhagic stroke, and cervicocephalic arterial dissection. These can occur following any of the doses being given. To reduce infusion-related adverse effects, clients should be premedicated with high-dose corticosteroids for the first 3 days of each treatment course. They can also receive antihistamines and/or antipyretics before the dose. Additionally, antiviral agents should be administered for herpetic prophylaxis starting on the first day of dosing and continue for a minimum of 2 months after completion of alemtuzumab dosing or until the CD4+ lymphocyte count is less than 200 cells/microliter.
Some autoimmune disorders caused by alemtuzumab include immune thrombocytopenia (spontaneous bleeding, petechiae, heavy menstrual bleeding, hemoptysis), glomerular nephropathies (edema, decreased urine output, hematuria), autoimmune hemolytic anemia (chest pain, jaundice, dark urine, tachycardia), and thyroiditis.
Clients of childbearing age should consistently use effective contraception during therapy and for 4 months after a course of treatment. This drug can cause fetal harm.
A few infections caused by alemtuzumab include hepatitis, human papilloma virus (HPV), TB, and fungal infections, especially oral and vaginal candidiasis. Any client with active disease of these infections should not take the monoclonal antibodies. Pregnant or breastfeeding clients should avoid monoclonal antibodies.
The FDA recommends that 6 weeks before starting therapy, clients should be vaccinated for VZV. No live-virus vaccines should be received after starting monoclonal antibodies.
Oletuzemab can cause immune-mediated colitis characterized by diarrhea (DailyMed, Ocrevus , 2023). Other ADRs, contraindications, and cautions are similar to alemtuzumab.
Table 11.19 is a drug prototype table for monoclonal antibodies featuring alemtuzumab. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
Monoclonal antibodies (biologic) Mechanism of Action Targets CD52 protein, a cell surface antigen present on lymphocytes, natural killer cells, monocytes, and macrophages; after binding on the cell surface of lymphocytes, an antibody-dependent cellular cytolysis occurs |
Drug Dosage
IV infusion over 4 hours for 2 or more treatment courses: First course: 12 mg daily on 5 consecutive days (60 mg total). Second course: 12 mg daily on 3 consecutive days (36 mg total) 12 months after the first treatment. Subsequent treatment courses: 12 mg daily on 3 consecutive days as needed at least 12 months after the last dose course. |
|
Indications
Reduces frequency and severity of relapses in RRMS and SSMS Therapeutic Effects Depletes circulating T and B lymphocytes after each treatment course, resulting in less myelin sheath being destroyed |
Drug Interactions
Antineoplastics Immunosuppressive/immunomodulators Food Interactions No significant interactions |
|
Adverse Effects
Nasopharyngitis/URI/sinusitis Infusion reactions Stroke Increased risk of thyroid cancer and cutaneous melanomas Autoimmune disorders PML |
Contraindications
Hypersensitivity or anaphylactic reaction to alemtuzumab or any of its components HIV infection Active infection Pregnancy Active hepatitis B History of life-threatening infusion reactions Caution: Viruses Preexisting or ongoing malignancy |
Nursing Implications
The nurse should do the following when administering monoclonal antibodies:
- Obtain and analyze CBC with differential, serum creatinine levels, thyroid function, and urine cell count before therapy and then regularly until 48 months after last infusion.
- Obtain urine protein to creatinine ratio before the start of therapy.
- Assess client during and for 2 hours after each infusion, including vital signs, to identify any infusion-related adverse effects.
- Educate client regarding the drug’s increased risk of malignancies, including thyroid cancer, melanoma, and lymph disorders.
- Teach client signs and symptoms of hypothyroidism and hyperthyroidism.
- Perform a tuberculin skin test and HPV screening.
- Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.
Client Teaching Guidelines
The client taking a monoclonal antibody should:
- Be compliant related to the required monthly laboratory testing.
- Complete any necessary immunizations at least 6 weeks before treatment starting.
- Be screened for TB and HPV (if applicable).
- Understand clinical manifestations related to certain autoimmune disorders caused by therapy, such as hematuria, hemoptysis, easy bruising, petechiae, edema, decreased urine output, spontaneous bleeding, abdominal pain, and jaundice.
- Be able to differentiate manifestations related to hypo- and hyperthyroidism.
- Be able to verbalize possible signs/symptoms of stroke, such as facial droop, dysarthria, unilateral weakness, or sudden severe headache.
- Notify the provider with any indication of infection, such as fever, fatigue, sore throat, enlarged lymph nodes, or coughing.
The client taking a monoclonal antibody should not:
- Stop drugs abruptly because symptoms will quickly reoccur.
- Overexert themselves; they should take rest periods between activities.
- Engage in activities that could cause injury.
FDA Black Box Warning
Monoclonal Antibodies
Alemtuzumab may cause life-threatening autoimmune conditions, such as immune thrombocytopenia, serious infusion reactions resulting in anaphylaxis, potential fatal strokes, and an increase risk of malignancies.
Natalizumab may cause increased risk of PML, which is a potentially fatal viral infection of the brain.
Sphingosine 1-Phosphate Receptor Modulators
Sphingosine 1-phosphate (S1P) receptor modulators regulate immune activity by specifically blocking the activity of S1P receptors found on the surface of lymphocytes. This prevents the lymphocytes from leaving the lymph nodes and entering the bloodstream, thus reducing their activity in the CNS. S1P receptor modulators are oral drugs prescribed for RRMS and active SPMS. There are currently three drugs on the market that fit into this category. This chapter will only focus on siponimod fumaric acid ( Mayzent ) because there are very few differences among them. The drug is associated with a CYP2C9 genotype variant that alters the dose.
Adverse Effects and Contraindications
Initiation of S1P drug therapy results in a decrease in heart rate, for which monitoring is recommended. The nurse should administer the first dose in a setting in which resources to appropriately manage symptomatic bradycardia are available. Before dosing and at the end of the observation period, an ECG should be obtained for all clients. Observation of clients overnight is necessary if they are at higher risk of symptomatic bradycardia, heart block, prolonged QTc interval, or if taking drugs with known risk of torsades de pointes. If post-dose symptomatic bradycardia occurs, appropriate management should be initiated, beginning with continuous ECG monitoring and continuing until the symptoms have resolved.
Another adverse effect is macular edema. Fundoscopic examinations are essential before and 3–4 months after the treatment has been started. They are also performed again whenever a client reports visual disturbances. Diabetes mellitus and uveitis increase the risk of macular edema.
S1P receptor modulators may also cause fetal harm. Advise clients of childbearing age of the potential risk to a fetus and to use an effective method of contraception during treatment and for 10 days after stopping the drug.
Furthermore, siponimod fumaric acid can cause an increase in blood pressure readings. Blood pressure should be monitored routinely, and any significant changes should be reported to the provider. Suspicious skin lesions should be evaluated because the risk of basal cell carcinoma and melanoma is increased in clients being treated with siponimod fumaric acid.
There have been reported cases of posterior reversible encephalopathy syndrome (PRES) in clients receiving an S1P receptor modulator. This is caused by swelling and narrowing of the blood vessels within the brain. If a client complains of a sudden onset of a severe headache, altered mental status, vision changes, or seizure activity, the provider should promptly schedule a complete physical and neurological examination and consider an MRI. Symptoms are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, the drug should be discontinued.
Before initiation of treatment with siponimod fumaric acid, clients should be tested to determine their CYP2C9 genotype. Substantially elevated siponimod plasma levels may occur in clients who are homozygous for CYP2C9*3, so its use is contraindicated in these individuals.
This therapy can cause a dose-dependent reduction in peripheral lymphocyte count to 20%–30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. It is important not to start therapy in clients with active infection.
Avoid live vaccines during therapy and for 4 weeks after to prevent the possibility of developing an infection. Concurrently taking antineoplastics or immunosuppressive or immune-modulating therapies can elevate the client’s risk of infection. Class Ia or Class III antiarrhythmic drugs should be avoided due to the increased risk of prolongation of the QTc interval. The administration of drugs that slow the heart rate or decrease atrioventricular conduction (e.g., beta blockers, digoxin, diltiazem, or verapamil) can intensify the risk of dysrhythmias or atrioventricular block or can exacerbate manifestations of heart failure. Monitor for the development of severe increase in disability following drug discontinuation and begin appropriate treatment as needed.
Table 11.20 is a drug prototype table for S1P receptor modulators featuring siponimod fumaric acid. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
S1P receptor modulator Mechanism of Action: Modulates its role in immune cell trafficking through sequestration of autoreactive lymphocytes in the lymphoid organs to reduce their recirculation and subsequent infiltration into the CNS |
Drug Dosage
The dosage has a 5-day titration schedule: First 2 days: 0.25 mg orally daily. Day 3: 0.5 mg orally daily. Day 4: 0.75 mg orally daily. Day 5 and maintenance dose: 1.25 mg orally daily. |
|
Indications
Reduces relapse in RRMS and SPMS Reduces symptoms in CIS Therapeutic Effects Regulates lymphocyte traffic by preventing lymphocytes from lymphoid organs from entering the lymphatic circulation, presumably limiting inflammatory cell migration into the CNS |
Drug Interactions
Hepatotoxic drugs Class Ia or Class III antiarrhythmic drugs Antineoplastics Immunosuppressive or immune-modulating therapies Live vaccines Drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers, digoxin, diltiazem, or verapamil) Food Interactions No significant interactions |
|
Adverse Effects
Headache Cough/influenza/sinusitis Bradycardia/AV block Hypertension Heart failure Hepatotoxicity Severe increase in disability with MS exacerbations when discontinued Infections PML Macular edema PRES Skin malignancies Decline in pulmonary function |
Contraindications
CYP2C9 genotype In the past 6 months:
Caution: Bradydysrhythmias/AV conduction delays Elevated blood pressure Liver injury |
Nursing Implications
The nurse should do the following when administering S1P receptor modulators:
- Before starting treatment, obtain serum transaminases (ALT and AST), total bilirubin, CBC, and pulmonary function (e.g., spirometry) if indicated.
- Before starting treatment, determine whether clients are taking drugs that could slow their heart rate or atrioventricular (AV) conduction. Obtain cardiologist consultation before concomitant use with other drugs that decrease heart rate.
- Monitor all clients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly heart rate and blood pressure measurement. Provider must assess for elevated blood pressures. Clients should know ahead of time they will be in the office for a minimum of 6 hours.
- Perform a thorough skin assessment periodically for signs of malignancy, such as asymmetry, indistinct borders, color variations, and increased size and elevation of any lesions.
- Assess for any neurological changes that could be related to PRES.
- Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.
Client Teaching Guidelines
The client taking an S1P receptor modulator should:
- Call provider with any dizziness, lightheadedness, shortness of breath, and fatigue.
- Notify the provider with any visual changes.
- Inform the provider of manifestations related to liver injury, such as jaundice, nausea, right upper quadrant pain, dark urine, and clay-colored stools.
- Implement measures to avoid being exposed to infection. Contact provider if signs/symptoms of infection are present.
- Limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor.
The client taking an S1P receptor modulator should not:
- Stop drugs abruptly because symptoms will quickly reoccur.
- Ignore any suspicious skin changes, such as a newly developed lesion, change of appearance in a mole, a new darkened area on their skin, a sore that does not heal, or growths on their skin.
- Chew, split, break, or crush medication.
Muscle Relaxants
Muscle spasticity is the result of damage to neurons within the CNS rather than injury to the peripheral structures. Clients often report stiffness and/or heavy muscles, difficulty with movement, and pain. Because the nerve damage originates in the CNS, the risk of this becoming permanent is high. Spasticity results in the excessive stimulation of muscles (hypertonia) in opposing muscle groups at the same time. The different types and brands of skeletal muscle relaxants work in different ways to affect muscle function. Most are CNS depressants and prevent the nerves from sending pain signals to the brain. They have no direct effect on skeletal muscle. Other actions may include the blockage of nerve impulses that cause increased muscle tone and contraction (Cleveland Clinic, 2023).
Centrally Acting Muscle Relaxant
Along with treating spasticity, baclofen is helpful in treating pain from trigeminal neuralgia that occurs in MS. This drug is available in oral and intrathecal (within the spine) forms and can be administered through an implantable delivery pump for treating central spasticity. The drug has no direct effect on skeletal muscle; therefore, it does not reduce muscle strength.
Peripherally Acting Muscle Relaxant
Dantrolene acts peripherally on the muscle itself. The drug inhibits the release of calcium from the sarcoplasmic reticulum directly within skeletal muscle cells. This action prevents the muscle fibers from contracting. Dantrolene does not interfere with neuromuscular transmission but does impair muscle strength. This drug is also used in the treatment and prevention of malignant hyperthermia (manages muscle contraction and rigidity). This agent is not therapeutic for treating muscle spasms associated with muscle injury or rheumatic disorders (DailyMed, Dantrolene, 2022).
Table 11.21 lists common muscle relaxants and typical routes and dosing for adult clients.
| Drug | Routes and Dosage Ranges |
|---|---|
|
Baclofen
( Lioresal ) |
Oral:
Start at low doses and increase gradually until optimum effect is achieved. Initial dose: 5 mg orally 3 times daily. Usually, the drug is increased by 5 mg every 3 days until desired effect is obtained. Average dose range: 40–80 mg daily. Maximum dose: 80 mg daily.
Intrathecal pump: Start with a 100 mcg IV bolus. Maintenance therapy is individualized; generally, 300–800 mcg daily. |
|
Dantrolene sodium
( Dantrium ) |
25 mg daily for 7 days, then 25 mg 3 times daily for another 7 days.
Increase by 25 mg every 7 days until the maximum of 100 mg 3 times daily is reached. |
Adverse Effects and Contraindications
The most common adverse effects for baclofen are related to CNS depression. Constipation and urinary retention are linked to CNS depression of the parasympathetic nervous system reflexes. This slows down peristalsis and relaxes the detrusor muscle of the bladder. Baclofen crosses the placenta and enters breast milk, so a fetus/infant may develop CNS depression.
Cardiac concerns, such as heart failure and arrhythmias, result from the depression of the normal reflex arcs. This drug could exacerbate heart failure due to depressed muscle function caused by these drugs.
If the oral version of baclofen is stopped too quickly, this can cause the development of psychoses, visual hallucinations, and seizures. The drug should be tapered off over a 1- to 2-week period. Abrupt withdrawal of the intrathecal route can be more dangerous. Possible reactions include high fever, altered mental status, rebound spasticity, and muscle rigidity that could lead to muscle breakdown (rhabdomyolysis).
Blocking the spasticity associated with movement, posture, or balance results in loss of these functions. This places clients at high risk for falls.
Some common adverse reactions for dantrolene include diarrhea and abdominal cramps. Clients with respiratory depression must be closely monitored because this can be exacerbated by muscular weakness. Dose-related hepatotoxicity is the most serious adverse effect. Baseline liver enzymes should be obtained and monitored periodically throughout treatment. If clients show no response within 45 days of initiating this drug, it should be stopped to prevent damage to the liver. Caution should be used in all clients older than 35 years of age due to their increased risk of potentially fatal hepatocellular disease. Supplemental estrogen increases the incidence of hepatocellular toxicity. This drug should be discontinued at the first indication of hepatic impairment (DailyMed, Baclofen , 2023).
Table 11.22 is a drug prototype table for muscle relaxants featuring baclofen. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
Centrally acting muscle relaxant Mechanism of Action Inhibits GABA receptors located on the spinal cord Restricts calcium influx, reducing presynaptic neurotransmitter release in the excitatory spinal pathways Reduces nerve impulse transmission from the spinal cord to the skeletal muscle, resulting in decreased muscle spasticity |
Drug Dosage
Oral: Start at low doses and increase gradually until optimum effect is achieved. Initial dose: 5 mg orally 3 times daily. Usually, the drug is increased by 5 mg every 3 days until desired effect is obtained. Average dose range: 40–80 mg daily. Maximum daily dose: 80 mg. Intrathecal pump: Start with a 100 mcg IV bolus. Maintenance therapy is individualized; generally, 300–800 mcg daily. |
|
Indications
Reversible muscle spasticity associated with neuromuscular diseases such as MS and spinal cord injuries Therapeutic Effects Suppresses hyperactive reflexes involved in regulating muscle movement Alleviates signs and symptoms of spasticity, especially reducing discomfort and rigidity |
Drug Interactions
Agents that cause CNS depression Alcohol Anticholinergic agents Food Interactions No significant interactions |
|
Adverse Effects
Weakness/drowsiness/fatigue Confusion/headache/insomnia Nausea/vomiting/constipation Urinary retention Hypotension Arrhythmias |
Contraindications
Hypersensitivity to drug or any of its ingredients Caution: Skeletal muscle spasms resulting from rheumatic disorders Spasticity that contributes to locomotion, upright position, or balance Pregnancy and breastfeeding Older adults History of schizophrenia or psychosis Heart failure BPH |
Nursing Implications
The nurse should do the following for clients who are taking muscle relaxants:
- Assess alertness, orientation, and affect.
- Evaluate muscle strength before and after administration of medication.
- Auscultate bowel sounds and monitor bowel movements due to constipation and to avoid a fecal impaction.
- Obtain baseline liver function tests and serum BUN/creatinine levels and assess these levels periodically during therapy to assess for changes.
- Ensure safety precautions are in place to prevent falls because of fatigue, weakness, and confusion.
- Provide additional measures to relieve discomfort such as heat, rest, NSAIDs, and positioning to augment effects of the drug.
- Emphasize to the client/caregiver that the drug must be gradually discontinued over a 1- to 2-week period.
- Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.
Client Teaching Guidelines
The client taking a muscle relaxant should:
- Eat plenty of fruits, vegetables, and whole grains to prevent or reduce constipation.
- Drink at least 6–8 8-oz of water daily to promote regular bowel movements.
- Have a clear understanding of the baclofen pump if applicable, such as frequent monitoring, adjusting the dose, and programming the unit, to avoid complications.
- Report painful or frequent urination, constipation, headache, insomnia, or excessive fatigue.
- Understand various nonpharmacological comfort measures to use, such as heat, rest, or position change, to help relieve discomfort.
- Notify provider if signs or symptoms of liver dysfunction appear, such as right upper quadrant pain, jaundice, dark urine, and clay-colored stools.
The client taking a muscle relaxant should not :
- Chew, break, or crush extended-release capsules.
- Rise or change positions quickly due to possible orthostatic hypotension.
- Drive or engage in potentially hazardous tasks that require alertness and focus until the effects of the drug are known.
- Stop the drug abruptly, to prevent negative effects.
FDA Black Box Warning
Muscle Relaxants
Dantrolene sodium can cause severe to fatal hepatotoxicity, especially if taking greater than 800 mg/day.
Baclofen: Abrupt discontinuation of baclofen can cause high fever, altered mental status, and muscular changes that can result in organ failure and death.
Gamma-Aminobutyric Acid Structural Analogs
Seizures may be slightly more common in people with MS due to the way the condition affects the brain. MS damages several parts of the brain, which can lead to disruptions in signal transmission. The scar tissue of an MS lesion creates a barrier to the transmission of nerve signals down a path. The flow of the nerve signals gets redirected. If the lesions create enough barriers, the result is an abnormal discharge of excessive electrical energy from the nerve cells of the brain. Clinical manifestations vary depending on the area of the brain affected.
There are various forms of seizures. Some stimulate motor nerves, whereas others affect autonomic and sensory nerves (Moreo & Benbadis, 2019). The form a particular seizure takes depends on the cell location that initiated the electrical discharge and the neural pathways stimulated by that initial impulse. In general, the three main categories of seizures are generalized, focal, and combined. The combined form is referred to as a focal to bilateral seizure where the impulse initiated in one area of the brain and then spread to both hemispheres (secondary generalized seizure). For a more detailed discussion on the different types of seizures and their treatment, refer to Anticonvulsant Drugs and Drugs to Treat Epilepsy, Migraine Headaches, and Intracranial Emergencies.
Drugs used for seizures do not treat the underlying cause but simply control the seizure activity and modulate the inhibitory neurotransmitter GABA.
- Gabapentin: FDA-approved agent used as an adjunct in treating focal seizures. It is believed to enhance the release of GABA. It does not bind directly to GABA receptors. It is also helpful in the treatment of central pain caused by damage to the brain and/or spinal cord. In addition, it is used in the management of postherpetic neuralgia and restless leg syndrome. It is important to know that the forms of gabapentin indicated for these last two conditions are not equivalent with each other or that which is used for seizures (DailyMed, Gabapentin, 2023).
- Pregabalin: A pproved as an adjunct in treating focal seizures, it is also FDA-approved for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia along with fibromyalgia. This drug has a high binding affinity for voltage-gated calcium channels in the cerebrovascular system. It does not bind to GABA or benzodiazepine receptors; therefore, its effect is indirect. Pregabalin is regulated under the Controlled Substances Act. It is listed as a Schedule V agent (DailyMed, Pregabalin, 2022).
Table 11.23 lists common GABA structural analogs and typical routes and dosing for adult clients.
| Drug | Routes and Dosage Ranges |
|---|---|
|
Gabapentin
( Neurontin ) |
300 mg 3 times daily. Increase at weekly intervals as necessary. Maximum dose: 3600 mg daily. |
|
Pregabalin
( Lyrica ) |
Immediate release:
300–600 mg daily in divided doses.
Controlled release: 165 mg daily. |
Adverse Effects and Contraindications
Hypersensitivity reactions have occurred with GABA structural analogs. Angioedema is characterized by swelling of the face, tongue, lips, gums, throat, and larynx. The drug should immediately be discontinued at the first sign of angioedema or other hypersensitivity reaction, such as hives, rash, wheezing, or dyspnea. Weight gain, due to an increased appetite, can be significant; some clients gain 7% or more in a few months. There is a possibility of rhabdomyolysis, so clients should be taught to let the provider know if muscle pain/tenderness occurs. Decreased sperm counts, reduced sperm motility, and increased sperm abnormalities can occur in male clients taking the drug. Clients may develop a low platelet count (thrombocytopenia).
Also, it has been reported pregabalin causes subjective effects similar to diazepam, increasing the risk of physical dependence. To avoid withdrawal symptoms, such as headache, diarrhea, or insomnia, the drug should be discontinued over at least 1 week.
CNS depressants and alcohol can increase the depressant effects of pregabalin. Taking angiotensin-converting enzyme (ACE) inhibitors concurrently increases the risk of swelling and hives. If taking thiazolidinediones with pregabalin, there is a higher chance of weight gain or swelling of one’s hands or feet.
Table 11.24 is a drug prototype table for GABA structural analogs featuring pregabalin. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.
|
Drug Class
GABA structural analogs/antiseizure Mechanism of Action: Binds with calcium channels on nerve terminals and can thereby inhibit neuronal calcium influx, thus decreasing the release of several neurotransmitters that may underlie seizure activity |
Drug Dosage
Immediate release: 300–600 mg orally daily in divided doses. Controlled release: 165 mg orally daily. |
|
Indications
Focal seizures Neuropathic pain Therapeutic Effects Modulates the calcium function in neurons, leading to a decrease in cellular excitation |
Drug Interactions
CNS depressants (benzodiazepines, opioids) Alcohol ACE inhibitors Thiazolidinediones (rosiglitazone/pioglitazone) Food Interactions No significant interactions |
|
Adverse Effects
CNS depression Dizziness/confusion/headaches Angioedema Increased suicidal ideations Thrombocytopenia Peripheral edema/weight gain Euphoria Decreased male fertility |
Contraindications
Hypersensitivity Caution: Clients with a history of substance or alcohol use disorders Class III/IV heart failure |
Nursing Implications
The nurse should do the following for clients who are taking GABA structural analogs:
- Ensure the client is taking an additional antiseizure medication because these are used only as adjuncts.
- Instruct the client not to break, chew, or crush the extended-release forms.
- Watch for any mood or personality changes and signs of suicidal ideation.
- Assess for seizure activity and ensure seizure precautions are in place.
- Evaluate for CNS depression to maintain client safety.
- Monitor weight and presence of peripheral edema.
- Emphasize to client not to stop drug abruptly.
- Assess client for muscle pain or tenderness.
- Monitor platelet count and creatinine kinase enzymes if muscle pain occurs.
- Evaluate history of drug use disorder or drug misuse.
- Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.
Client Teaching Guidelines
The client taking a GABA structural analog should:
- Sit or lie down if excessive fatigue occurs and wait until it subsides.
- Weigh themselves at the same time each day and notify provider if they gain more than 2 pounds within 24 hours.
- Know there is a risk of dependence.
- Immediately stop the drug if any manifestations of hypersensitivity arise to prevent reaction from worsening.
- Be aware of the increased risk of suicidal thoughts and behavior.
- Notify the provider if they are experiencing muscle discomfort.
- Contact the health care provider if they notice easy bruising, prolonged bleeding, or anemia.
- Use condoms to prevent pregnancy.
The client taking a GABA structural analog should not:
- Stop drugs abruptly when discontinuing because there is a risk of precipitating seizures with sudden withdrawal.
- Drink alcohol due to additive sedative effects and risk for injury.
- Drive or perform tasks requiring alertness, coordination, or physical dexterity until the effects of the drug are known.
- Engage in activities or tasks that have a high risk of bleeding.