NCLEX: Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents: ACETAMINOPHEN

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Acetaminophen [a-SEET-a-MIN-oh-fen] (N-acetyl-p-aminophenol or APAP) inhibits prostaglandin synthesis in the CNS. This explains its antipyretic and analgesic properties. Acetaminophen has less effect on cyclooxygenase in peripheral tissues (due to peripheral inactivation), which accounts for its weak anti-inflammatory activity. Acetaminophen does not affect platelet function or increase bleeding time. It is not considered to be an NSAID.

A. Therapeutic uses

Acetaminophen is a suitable substitute for the analgesic and antipyretic effects of NSAIDs for those patients with gastric complaints/ risks, in those whom a prolongation of bleeding time is not desirable, as well as those who do not require the anti-inflammatory action of NSAIDs. Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or chickenpox (due to the risk of Reye syndrome with aspirin).

B. Pharmacokinetics

Acetaminophen is rapidly absorbed from the GI tract. A significant first-pass metabolism occurs in the luminal cells of the intestine and in the hepatocytes. Under normal circumstances, acetaminophen is conjugated in the liver to form inactive glucuronidated or sulfated metabolites. A portion of acetaminophen is hydroxylated to form N-acetyl-p-benzoquinoneimine, or NAPQI, a highly reactive metabolite that can react with sulfhydryl groups and cause liver damage. At normal doses of acetaminophen, NAPQI reacts with the sulfhydryl group of glutathione, which is produced by the liver, forming a nontoxic substance. Acetaminophen and its metabolites are excreted in urine. The drug is also available in intravenous and rectal formulations.

C. Adverse effects

At normal therapeutic doses, acetaminophen is virtually free of significant adverse effects. With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and NAPQI reacts with the sulfhydryl groups of hepatic proteins, forming covalent bonds. Hepatic necrosis, a very serious and potentially life-threatening condition, can result. Patients with hepatic disease, viral hepatitis, or a history of alcoholism are at higher risk of acetaminophen-induced hepatotoxicity. [Note: N-acetylcysteine, which contains sulfhydryl groups to which the toxic metabolite can bind, is an antidote in cases of overdose. Acetaminophen should be avoided in patients with severe hepatic impairment.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents: DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

DMARDs are used in the treatment of RA and have been shown to slow the course of the disease, induce remission, and prevent further destruction of the joints and involved tissues. When a patient is diagnosed with RA, DMARDs should be started within 3 months to help stop the progression of the disease at the earlier stages. NSAIDs or corticosteroids may also be used for relief of symptoms if needed.

A. Choice of drug

No one DMARD is efficacious and safe in every patient, and trials of several different drugs may be necessary. Monotherapy may be initiated with any of the DMARDs (methotrexate, leflunomide, hydroxychloroquine, or sulfasalazine) for patients with low disease activity. For patients with moderate to high disease activity or inadequate response to monotherapy, combination DMARD therapy (usually methotrexate based) or use of anti-TNF drugs (adalimumab, certolizumab, etanercept, golimumab, and infliximab) may be needed. For patients with more established disease, use of other biologic therapies (for example, abatacept, rituximab) can be considered. Most of these agents are contraindicated for use in pregnant women.

B. Methotrexate

Methotrexate [meth-oh-TREX-ate], used alone or in combination therapy, has become a mainstay of treatment in patients with rheumatoid or psoriatic arthritis. Methotrexate is a folic acid antagonist that inhibits cytokine production and purine nucleotide biosynthesis, leading to immunosuppressive and anti-inflammatory effects. Response to methotrexate occurs within 3 to 6 weeks of starting treatment; it can also slow the appearance of new erosions within involved joints. The other DMARDs can be added to methotrexate therapy if there is partial or no response to maximum doses of methotrexate. Doses of methotrexate required for RA treatment are much lower than those needed in cancer chemotherapy and are given once a week, thereby minimizing adverse effects. The most common side effects observed after methotrexate treatment of RA are mucosal ulceration and nausea. Cytopenias (particularly depression of the WBC count), cirrhosis of the liver, and an acute pneumonia-like syndrome may occur with chronic administration. [Note: Taking leucovorin (folinic acid) once daily after methotrexate reduces the severity of adverse effects. Folic acid taken on off-days is widely used.] Periodic liver enzyme tests, complete blood counts, and monitoring for signs of infection are recommended.

C. Hydroxychloroquine

Hydroxychloroquine [hye-drox-ee-KLOR-oh-kwin] is used for early, mild RA, often combined with methotrexate. This agent is also used in the treatment of lupus and malaria. Its mechanism of action in autoimmune disorders is unknown, and onset of effects takes 6 weeks to 6 months. Hydroxychloroquine has less effects on the liver and immune system than other DMARDs; however, it may cause ocular toxicity, including irreversible retinal damage and corneal deposits. It may also cause CNS disturbances, GI upset, and skin discoloration and eruptions.

D. Leflunomide

Leflunomide [le-FLOO-no-mide] is an immunomodulatory agent that preferentially causes cell arrest of the autoimmune lymphocytes through its action on dihydroorotate dehydrogenase (DHODH). Activated proliferating lymphocytes require constant DNA synthesis to proliferate. Pyrimidines and purines are the building blocks of DNA, and DHODH is necessary for pyrimidine synthesis. After biotransformation, leflunomide becomes a reversible inhibitor of DHODH. Leflunomide is approved for the treatment of RA. It can be used as monotherapy or in combination with methotrexate. The most common adverse effects are headache, diarrhea, and nausea. Other untoward effects are weight loss, allergic reactions, including a flu-like syndrome, skin rash, alopecia, and hypokalemia. It is not recommended in patients with liver disease, because of a risk of hepatotoxicity. Monitoring parameters include signs of infection, complete blood counts, and liver enzymes.

E. Minocycline

Minocycline [mi-noe-SYE-kleen], a tetracycline antibiotic, is considered to be a DMARD. Although minocycline has been shown to be effective in the treatment of early RA, it is generally not utilized as first-line therapy. Minocycline can be used as monotherapy or in combination with other DMARDs.

F. Sulfasalazine

Sulfasalazine [sul-fa-SAH-la-zeen] is also used for early, mild RA in combination with methotrexate and/or hydroxychloroquine. Onset of activity is 1 to 3 months, and it is associated with leukopenia. Its mechanism of action in treating RA is unclear.

G. Glucocorticoids

Glucocorticoids are potent anti-inflammatory drugs that are commonly used in patients with RA to provide symptomatic relief and bridge the time until DMARDs are effective. Timely dose reductions and cessation are necessary to avoid adverse effects associated with long-term use.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents: BIOLOGIC THERAPIES IN RHEUMATOID ARTHRITIS

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

IL-1 and TNF-α are proinflammatory cytokines involved in the pathogenesis of RA. When secreted by synovial macrophages, IL-1 and TNF-α stimulate synovial cells to proliferate and synthesize collagenase, thereby degrading cartilage, stimulating bone resorption, and inhibiting proteoglycan synthesis. The TNF-α inhibitors (adalimumab, certolizumab, etanercept, golimumab, and infliximab) have been shown to decrease signs and symptoms of RA, reduce progression of structural damage, and improve physical function. Clinical response can be seen within 2 weeks of therapy. As with DMARDs, the decision to continue or stop a biological agent can often be made within 3 months after initiation of therapy. If a patient has failed therapy with one TNF-α inhibitor, a trial with a different TNF-α inhibitor or a non-TNF biologic therapy (abatacept, rituximab, tocilizumab, tofacitinib) is appropriate. TNF-α inhibitors can be administered with any of the other drugs for RA, except for the non-TNF biologic therapies (due to increased risk of infection).

Patients receiving TNF-α inhibitors are at increased risk for infections (tuberculosis and sepsis), fungal opportunistic infections, and pancytopenia. Live vaccinations should not be administered while on TNF-α inhibitor therapy. These agents should be used very cautiously in those with heart failure, as they can cause and/or worsen preexisting heart failure. An increased risk of lymphoma and other cancers has been observed with the use of TNF-α inhibitors. Characteristics of the TNF-α inhibitors and other biologic therapies are outlined below.

A. Adalimumab

Adalimumab [a-dal-AYE-mu-mab] is a recombinant monoclonal antibody that binds to TNF-α, thereby interfering with endogenous TNF-α activity by blocking its interaction with cell surface receptors. This agent is indicated for treatment of moderate to severe RA, either as monotherapy or in combination with methotrexate. It is also indicated for psoriatic arthritis, ankylosing spondylitis, and Crohn disease. Adalimumab is administered subcutaneously weekly or every other week. It may cause headache, nausea, agranulocytosis, rash, reaction at the injection site, or increased risk of infections, such as urinary tract infections, upper respiratory tract infections, and sinusitis.

B. Certolizumab pegol

Certolizumab [ser-toe-LIZ-oo-mab] is a unique TNF-α blocker that contains a Fab fragment of a humanized antibody and is a potent neutralizer of TNF-α biological actions. It is combined with polyethylene glycol (pegylated) and is administered every 2 weeks via subcutaneous injection. It has similar indications to adalimumab. Adverse effects are similar to other TNF-α inhibitors.

C. Etanercept

Etanercept [ee-TAN-er-cept] is a genetically engineered, soluble, recombinant, fully human receptor fusion protein that binds to TNF-α, thereby blocking its interaction with cell surface TNF-α receptors. This agent is approved for use in patients with moderate to severe RA, either alone or in combination with methotrexate. It is also approved for use in ankylosing spondylitis and psoriasis. The combination of etanercept and methotrexate is more effective than methotrexate or etanercept alone in retarding the RA disease process, improving function, and achieving remission. Etanercept is given subcutaneously twice a week. The drug is generally well tolerated. As with all TNF-α inhibitors, it can increase the risk for infections, malignancy, and new or worsening heart failure.

D. Golimumab

Golimumab [goe-LIM-ue-mab] neutralizes the biological activity of TNF-α by binding to it and blocking its interaction with cell surface receptors. This compound is administered subcutaneously once a month in combination with methotrexate or other nonbiologic DMARDs. Golimumab may increase hepatic enzymes. Reactivation of hepatitis B may occur in chronic carriers. As with other TNF-α inhibitors, this drug may increase the risk of malignancies and serious infections.

E. Infliximab

Infliximab [in-FLIX-i-mab] is a chimeric monoclonal antibody composed of human and murine regions. The antibody binds specifically to human TNF-α and inhibits binding with its receptors. Infliximab is approved for use in combination with methotrexate in patients with RA who have had inadequate response to methotrexate monotherapy. This agent is not indicated for monotherapy, as this leads to the development of anti-infliximab antibodies, resulting in reduced efficacy. Additional indications include plaque psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, and Crohn disease. Infliximab is administered as an IV infusion every 8 weeks. Infusion site reactions, such as fever, chills, pruritus, and urticaria, may occur. Infections (for example, pneumonia, cellulitis, and activation of latent tuberculosis), leukopenia, and neutropenia have also been reported.

F. Abatacept

T lymphocytes need two interactions to become activated: 1) the antigen-presenting cell (that is, macrophages or B cells) must interact with the receptor on the T cell and 2) the CD80/CD86 protein on the antigen-presenting cell must interact with the CD28 protein on the T cell. Abatacept [a-BAT-ah-cept] is a soluble recombinant fusion protein that competes with CD28 for binding on CD80/CD86 protein, thereby preventing full T-cell activation. This agent is indicated for patients with moderate to severe RA who have had an inadequate response to DMARDs or TNF-α inhibitors. Abatacept is administered as an IV infusion every 4 weeks. Common adverse effects include headache, upper respiratory infections, nasopharyngitis, and nausea. Concurrent use with TNF-α inhibitors is not recommended due to increased risk of serious infections.

G. Rituximab

B lymphocytes are derived from the bone marrow and are necessary for efficient immune response. In RA, however, B cells can perpetuate the inflammatory process in the synovium by 1) activating T lymphocytes, 2) producing autoantibodies and rheumatoid factor, and 3) producing proinflammatory cytokines, such as TNF-α and IL-1. Rituximab [ri-TUK-si-mab] is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes, resulting in B-cell depletion. This agent is indicated for use in combination with methotrexate for patients with moderate to severe RA who have had an inadequate response to TNF-α inhibitors. Rituximab is administered as an intravenous infusion every 16 to 24 weeks. To reduce the severity of infusion reactions, methylprednisolone is administered 30 minutes prior to each infusion. Infusion reactions (urticaria, hypotension, and angioedema) are the most common complaints with this agent and typically occur during the first infusion.

H. Tocilizumab

Tocilizumab [toe-si-LIZ-ue-mab] is a monoclonal antibody that inhibits the actions of IL-6 by blocking the IL-6 receptor. Tocilizumab is administered as an intravenous infusion every 4 weeks. The drug can be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs for patients with moderate to severe RA.

I. Tofacitinib

Janus kinases are intracellular enzymes that modulate immune cell activity in response to the binding of inflammatory mediators to the cellular membrane. Cytokines, growth factors, interferons, ILs, and erythropoietin can lead to an increase in Janus kinase activity and activation of the immune system. Tofacitinib [toe-fa-SYE-ti-nib] is an oral inhibitor of Janus kinases indicated for the treatment of moderate to severe RA in patients who have had an inadequate response or intolerance to methotrexate. Metabolism of tofacitinib is mediated primarily by CYP3A4, and dosage adjustments may be required if the drug is taken with potent inhibitors or inducers of this isoenzyme. Hemoglobin concentrations must be greater than 9 g/dL to start tofacitinib and must be monitored during therapy due to the risk for anemia. Likewise, lymphocyte and neutrophil counts should be checked prior to initiation of therapy and monitored during treatment. Tofacitinib treatment may also increase the risk for secondary malignancy, opportunistic infections, renal, or hepatic dysfunction.

J. Anakinra

IL-1 is induced by inflammatory stimuli and mediates a variety of immunologic responses, including degradation of cartilage and stimulation of bone resorption. Anakinra [an-a-KIN-ra] is an IL-1 receptor antagonist. Anakinra treatment leads to a modest reduction in the signs and symptoms of moderate to severe RA in patients who have failed one or more DMARDs. This agent is associated with neutropenia and is infrequently used in the treatment of RA.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents: DRUGS USED FOR THE TREATMENT OF GOUT

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Gout is a metabolic disorder characterized by high levels of uric acid in the blood (hyperuricemia). Hyperuricemia can lead to deposition of sodium urate crystals in tissues, especially the joints and kidney. Hyperuricemia does not always lead to gout, but gout is always preceded by hyperuricemia. The deposition of urate crystals initiates an inflammatory process involving the infiltration of granulocytes that phagocytize the urate crystals. The cause of hyperuricemia is an imbalance between overproduction of uric acid and/or the inability of the patient to excrete it via renal elimination. Most therapeutic strategies for gout involve lowering the uric acid level below the saturation point (6 mg/dL), thus preventing the deposition of urate crystals. This can be accomplished by interfering with uric acid synthesis or increasing uric acid excretion.

A. Treatment of acute gout

Acute gout attacks can result from a number of conditions, including excessive alcohol consumption, a diet rich in purines, and kidney disease. NSAIDs, corticosteroids, or colchicine are effective alternatives for the management of acute gouty arthritis. Indomethacin is considered the classic NSAID of choice, although all NSAIDs are likely to be effective in decreasing pain and inflammation. Intraarticular administration of corticosteroids (when only one or two joints are affected) is also appropriate in the acute setting, with systemic corticosteroid therapy for more widespread joint involvement. Patients are candidates for prophylactic urate-lowering therapy if they have more than two attacks per year or they have chronic kidney disease, kidney stones, or tophi (deposit of urate crystals in the joints, bones, cartilage, or other body structures).

B. Treatment of chronic gout

Urate-lowering therapy for chronic gout aims to reduce the frequency of attacks and complications of gout. Treatment strategies include the use of xanthine oxidase inhibitors to reduce the synthesis of uric acid or use of uricosuric drugs to increase its excretion. Xanthine oxidase inhibitors (allopurinol, febuxostat) are first-line urate-lowering agents. Uricosuric agents (probenecid) may be used in patients who are intolerant to xanthine oxidase inhibitors or fail to achieve adequate response with those agents. [Note: Initiation of urate-lowering therapy can precipitate an acute gout attack due to rapid changes in serum urate concentrations. Medications for the prevention of an acute gout attack (low-dose colchicine, NSAIDs, or corticosteroids) should be initiated with urate-lowering therapy and continued for at least 6 months.]

C. Colchicine

Colchicine [KOL-chi-seen], a plant alkaloid, is used for the treatment of acute gouty attacks. It is neither a uricosuric nor an analgesic agent, although it relieves pain in acute attacks of gout.

  • Mechanism of action: Colchicine binds to tubulin, a microtubular protein, causing its depolymerization. This disrupts cellular functions, such as the mobility of granulocytes, thus decreasing their migration into the affected area. Furthermore, colchicine blocks cell division by binding to mitotic spindles.
  • Therapeutic uses: The anti-inflammatory activity of colchicine is specific for gout, usually alleviating the pain of acute gout within 12 hours. [Note: Colchicine must be administered within 36 hours of onset of attack to be effective.] NSAIDs have largely replaced colchicine in the treatment of acute gouty attacks for safety reasons. Colchicine is also used as a prophylactic agent to prevent acute attacks of gout in patients initiating urate-lowering therapy.
  • Pharmacokinetics: Colchicine is administered orally and is rapidly absorbed from the GI tract. Colchicine is recycled in the bile and is excreted unchanged in feces or urine.
  • Adverse effects: Colchicine may cause nausea, vomiting, abdominal pain, and diarrhea. Chronic administration may lead to myopathy, neutropenia, aplastic anemia, and alopecia. The drug should not be used in pregnancy, and it should be used with caution in patients with hepatic, renal, or cardiovascular disease. Dosage adjustments are required in patients taking CYP3A4 inhibitors, like clarithromycin, itraconazole, and protease inhibitors. For patients with severe renal impairment, the dose should be reduced.

D. Allopurinol

Allopurinol [al-oh-PURE-i-nole], a xanthine oxidase inhibitor, is a purine analog. It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase.

  • Therapeutic uses: Allopurinol is an effective urate-lowering therapy in the treatment of gout and hyperuricemia secondary to other conditions, such as that associated with certain malignancies (those in which large amounts of purines are produced, particularly after chemotherapy) or in renal disease.
  • Pharmacokinetics: Allopurinol is completely absorbed after oral administration. The primary metabolite is alloxanthine (oxypurinol), which is also a xanthine oxidase inhibitor with a half-life of 15 to 18 hours. Thus, effective inhibition of xanthine oxidase can be maintained with once-daily dosage. The drug and its active metabolite are excreted in the feces and urine. The dosage should be reduced if the creatinine clearance is less than 50 mL/min.
  • Adverse effects: Allopurinol is well tolerated by most patients. Hypersensitivity reactions, especially skin rashes, are the most common adverse reactions. The risk is increased in those with reduced renal function. Because acute attacks of gout may occur more frequently during the first several months of therapy, colchicine, NSAIDs, or corticosteroids can be administered concurrently. Allopurinol interferes with the metabolism of 6-mercaptopurine, the immunosuppressant azathioprine, and theophylline, requiring a reduction in dosage of these drugs.

E. Febuxostat

Febuxostat [feb-UX-oh-stat], a xanthine oxidase inhibitor, is structurally unrelated to allopurinol; however, it has the same indications. In addition, the same drug interactions with 6-mercaptopurine, azathioprine, and theophylline apply. Its adverse effect profile is similar to that of allopurinol, although the risk for rash and hypersensitivity reactions may be reduced. Febuxostat does not have the same degree of renal elimination as allopurinol and thus requires less adjustment in those with reduced renal function.

F. Probenecid

Probenecid [proe-BEN-a-sid] is a uricosuric drug. It is a weak organic acid that promotes renal clearance of uric acid by inhibiting the urateanion exchanger in the proximal tubule that mediates urate reabsorption. At therapeutic doses, it blocks proximal tubular reabsorption of uric acid. Probenecid blocks the tubular secretion of penicillin and is sometimes used to increase levels of β-lactam antibiotics. It also inhibits the excretion of methotrexate, naproxen, ketoprofen, and indomethacin. Probenecid should be avoided if the creatinine clearance is less than 50 mL/min.

G. Pegloticase

Pegloticase [peg-LOE-ti-kase] is a recombinant form of the enzyme urate oxidase or uricase. It acts by converting uric acid to allantoin, a water-soluble nontoxic metabolite that is excreted primarily by the kidneys. Pegloticase is indicated for patients with gout who fail treatment with standard therapies such as xanthine oxidase inhibitors. It is administered as an IV infusion every 2 weeks.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents: DRUGS USED TO TREAT HEADACHE

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

The most common types of headaches are migraine, tension-type, and cluster headaches. Migraine can usually be distinguished from cluster headaches and tension-type headaches by its characteristics. Migraines, for example, present as a pulsatile, throbbing pain, whereas cluster headaches present as excruciating, sharp, steady pain. This is in contrast to tension-type headaches, which present as dull pain, with a persistent, tightening feeling in the head. Patients with severe migraine headaches report one to five attacks per month of moderate to severe pain, usually unilateral. The headaches significantly affect quality of life and result in considerable health care costs. Management of headaches involves avoidance of headache triggers (for example, alcohol, chocolate, and stress) and use of abortive treatments for acute headaches, as well as prophylactic therapy in patients with frequent or severe migraines.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

A. Types of migraine

There are two main types of migraine headaches. The first, migraine without aura, is a severe, unilateral, pulsating headache that typically lasts from 2 to 72 hours. These headaches are often aggravated by physical activity and are accompanied by nausea, vomiting, photophobia (hypersensitivity to light), and phonophobia (hypersensitivity to sound). The majority of patients with migraine do not have aura. In the second type, migraine with aura, the headache is preceded by neurologic symptoms called auras, which can be visual, sensory, and/or cause speech or motor disturbances.  Most commonly, these prodromal symptoms are visual (flashes,zigzag lines, and glare), occurring approximately 20 to 40 minutes before headache pain begins. In the 15% of migraine patients whose headache is preceded by an aura, the aura itself allows diagnosis. The headache in migraines with or without auras is similar. Women are threefold more likely than men to experience either type of migraine.

B. Biologic basis of migraine headaches

The first manifestation of migraine with aura is a spreading depression of neuronal activity accompanied by reduced blood flow in the most posterior part of the cerebral hemisphere. This hypoperfusion gradually spreads forward over the surface of the cortex to other contiguous areas of the brain. The vascular alteration is accompanied by functional changes. The hypoperfusion persists throughout the aura and well into the headache phase. Patients who have migraine without aura do not show hypoperfusion. However, the pain of both types of migraine may be due to extracranial and intracranial arterial vasodilation, which leads to release of neuroactive molecules, such as substance P, neurokinin A, and calcitonin gene– related peptide.

C. Symptomatic treatment of acute migraine

Acute treatments can be classified as nonspecific (symptomatic) or migraine specific. Nonspecific treatment includes analgesics such as NSAIDs and antiemetics (for example, prochlorperazine) to control vomiting. Opioids are reserved as rescue medication when other treatments of a severe migraine attack are not successful. Specific migraine therapy includes triptans and ergot alkaloids, which are 5-HT1B/1D receptor and 5-HT1D receptor agonists, respectively. It has been proposed that activation of 5-HT1 receptors by these agents leads either to vasoconstriction or to inhibition of the release of pro-inflammatory neuropeptides on the trigeminal nerve innervating cranial blood vessels.

  • Triptans: This class of drugs includes almotriptan [al-moe- TRIP-tan], eletriptan [el-e-TRIP-tan], frovatriptan [froe-va-TRIPtan], naratriptan [nar-a-TRIP-tan], rizatriptan [rye-za-TRIP-tan], sumatriptan [soo-ma-TRIP-tan], and zolmitriptan [zole-ma-TRIPtan]. Sumatriptan was the first available triptan, and is the prototype of this class. These agents rapidly and effectively abort or markedly reduce the severity of migraine headaches in about 70% of patients. The triptans are serotonin agonists, acting at a subgroup of serotonin receptors found on small peripheral nerves that innervate the intracranial vasculature. The nausea that occurs with dihydroergotamine and the vasoconstriction caused by ergotamine (see below) are much less pronounced with the triptans. Sumatriptan is given subcutaneously, intranasally, or orally (sumatriptan is also available in a combination product with naproxen). Zolmitriptan is available orally and by nasal spray. [Note: All other agents are taken orally.] The onset of the parenteral drug sumatriptan is about 20 minutes, compared with 1 to 2 hours when the drug is administered orally. The drug has a short duration of action, with an elimination half-life of 2 hours. Headache commonly recurs within 24 to 48 hours after a single dose of drug, but in most patients, a second dose is effective in aborting the headache. Frovatriptan is the longest-acting triptan, with a half-life of more than 24 hours. Individual responses to triptans vary, and a trial of more than one triptan may be necessary before treatment is successful. Elevation of blood pressure and other cardiac events have been reported with triptan use. Therefore, triptans should not be administered to patients with risk factors for coronary artery disease without performing a cardiac evaluation prior to administration. Other adverse events with the use of triptans include pain and pressure sensations in the chest, neck, throat, and jaw. Dizziness and malaise have also been seen with the use of triptans.
  • Ergot alkaloids: Ergotamine [er-GOT-a-meen] and dihydroergotamine [dye-hye-droe-er-GOT-a-meen], a semisynthetic derivative of ergotamine, are ergot alkaloids approved for the treatment of migraine headaches. The action of the ergot alkaloids is complex, with ability to bind to 5-HT1 receptors, α receptors, and dopamine receptors. 5-HT1 receptors located on intracranial blood vessels are targets that cause vasoconstriction with the use of these agents. Ergotamine is currently available sublingually and is mostly effective when used in the early stages of the migraine. It is also available as an oral tablet or suppository containing both ergotamine and caffeine. Ergotamine is used with strict daily and weekly dosage limits due to its ability to cause dependence and rebound headaches. Dihydroergotamine is administered intravenously or intranasally and has an efficacy similar to that of sumatriptan. The use of dihydroergotamine is limited to severe cases of migraines. Nausea is a common adverse effect. Ergotamine and dihydroergotamine are contraindicated in patients with angina and peripheral vascular disease because they are significant vasoconstrictors.

D. Prophylaxis for migraine headache

Therapy to prevent migraine is indicated if the attacks occur two or more times a month and if the headaches are severe or complicated by serious neurologic signs. β-Blockers are the drugs of choice for migraine prophylaxis. Propranolol and other β-blockers, such as metoprolol, atenolol, and nadolol, have been shown to be  effective. The calcium channel blocker verapamil is an alternative. Anticonvulsants (divalproex) and antidepressants (tricyclics) have also shown effectiveness in preventing migraine. Antidepressants are especially useful for migraine prophylaxis in patients with comorbid depression.

E. Drugs for tension and cluster headache

Analgesics such as NSAIDs (for example, naproxen and ibuprofen), acetaminophen, and aspirin are used for symptomatic relief of tension headaches. Acetaminophen and/or aspirin may also be combined with caffeine. [Note: Caffeine is believed to increase the central effectiveness of acetaminophen and aspirin.] Butalbital, a barbiturate, in combination with acetaminophen or aspirin with or without caffeine is also used in tension headaches. Inhalation of 100% oxygen and triptans (especially sumatriptan) are used as first-line abortive strategies for cluster headache.

Anti-inflammatory, Antipyretic, and Analgesic Agents






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