NCLEX: Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases: DRUGS USED IN ALZHEIMER’S DISEASE

Focus topic: Drugs for Neurodegenerative Diseases

Dementia of the Alzheimer type has three distinguishing features: 1) accumulation of senile plaques (β-amyloid accumulations), 2) formation of numerous neurofibrillary tangles, and 3) loss of cortical neurons, particularly cholinergic neurons. Current therapies aim to either improve cholinergic transmission within the CNS or prevent excitotoxic actions resulting from overstimulation of NMDA-glutamate receptors in selected areas of the brain. Pharmacologic intervention for Alzheimer’s disease is only palliative and provides modest short-term benefit. None of the available therapeutic agents alter the underlying neurodegenerative process.

Drugs for Neurodegenerative Diseases

Drugs for Neurodegenerative Diseases

A. Acetylcholinesterase inhibitors

Focus topic: Drugs for Neurodegenerative Diseases

Numerous studies have linked the progressive loss of cholinergic neurons and, presumably, cholinergic transmission within the cortex to the memory loss that is a hallmark symptom of Alzheimer’s disease. It is postulated that inhibition of acetylcholinesterase (AChE) within the CNS will improve cholinergic transmission, at least at those neurons that are still functioning. The reversible AChE inhibitors approved for the treatment of mild to moderate Alzheimer’s disease include donepezil [doe-NE-peh-zil], galantamine [ga-LAN-ta-meen], and rivastigmine [ri-va-STIG-meen]. All of them have some selectivity for AChE in the CNS, as compared to the periphery. Galantamine may also augment the action of acetylcholine at nicotinic receptors in the CNS. At best, these compounds provide a modest reduction in the rate of loss of cognitive functioning in Alzheimer patients. Rivastigmine is the only agent approved for the management of dementia associated with Parkinson’s disease and also the only AChE inhibitor available as a transdermal formulation. Rivastigmine is hydrolyzed by AChE to a carbamylate metabolite and has no interactions with drugs that alter the activity of CYP450 enzymes. The other agents are substrates for CYP450 and have a potential for such interactions. Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps.

B. NMDA receptor antagonist

Focus topic: Drugs for Neurodegenerative Diseases

Stimulation of glutamate receptors in the CNS appears to be critical for the formation of certain memories. However, over stimulation of glutamate receptors, particularly of the NMDA type, may result in excitotoxic effects on neurons and is suggested as a mechanism for neurodegenerative or apoptotic (programmed cell death) processes. Binding of glutamate to the NMDA receptor assists in the opening of an ion channel that allows Ca2+ to enter the neuron. Excess intracellular Ca2+ can activate a number of processes that ultimately damage neurons and lead to apoptosis. Memantine [meh-MAN-teen] is an NMDA receptor antagonist indicated for moderate to severe Alzheimer’s disease. It acts by blocking the NMDA receptor and limiting Ca2+ influx into the neuron, such that toxic intracellular levels are not achieved. Memantine is well tolerated, with few dose-dependent adverse events. Expected side effects, such as confusion, agitation, and restlessness, are indistinguishable from the symptoms of Alzheimer’s disease. Given its different mechanism of action and possible neuroprotective effects, memantine is often given in combination with an AChE inhibitor.

Drugs for Neurodegenerative Diseases: DRUGS USED IN MULTIPLE SCLEROSIS

Focus topic: Drugs for Neurodegenerative Diseases

Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the CNS. The course of MS is variable. For some, MS may consist of one or two acute neurologic episodes. In others, it is a chronic, relapsing, or progressive disease that may span 10 to 20 years. Historically, corticosteroids (for example, dexamethasone and prednisone) have been used to treat acute exacerbations of the disease. Chemotherapeutic agents, such as cyclophosphamide and azathioprine, have also been used.

[sociallocker]

A. Disease-modifying therapies

Focus topic: Drugs for Neurodegenerative Diseases

Drugs currently approved for MS are indicated to decrease relapse rates or in some cases to prevent accumulation of disability. The major target of these medications is to modify the immune response through inhibition of white blood cell–mediated inflammatory processes that eventually lead to myelin sheath damage and decreased or inappropriate axonal communication between cells.

  • Interferon β1a and interferon β1b: The immunomodulatory effects of interferon [in-ter-FEER-on] help to diminish the inflammatory responses that lead to demyelination of the axon sheaths. Adverse effects of these medications may include depression, local injection site reactions, hepatic enzyme increases, and flulike symptoms.
  • Glatiramer: Glatiramer [gluh-TEER-a-mur] is a synthetic polypeptide that resembles myelin protein and may act as a decoy to T-cell attack. Some patients experience a postinjection reaction that includes flushing, chest pain, anxiety, and itching. It is usually self-limiting.
  • Fingolimod: Fingolimod [fin-GO-li-mod] is an oral drug that alters lymphocyte migration, resulting in fewer lymphocytes in the CNS. Fingolimod may cause first-dose bradycardia and is associated with an increased risk of infection and macular edema.
  • Teriflunomide: Teriflunomide [te-ree-FLOO-no-mide] is an oral pyrimidine synthesis inhibitor that leads to a lower concentration of active lymphocytes in the CNS. Teriflunomide may cause elevated liver enzymes. It should be avoided in pregnancy.
  • Dimethyl fumarate: Dimethyl fumarate [dye-METH-il FOO-marate] is an oral agent that may alter the cellular response to oxidative stress to reduce disease progression. Flushing and abdominal pain are the most common adverse events.
  • Natalizumab: Natalizumab [na-ta-LIZ-oo-mab] is a monoclonal antibody indicated for MS in patients who have failed first-line therapies.
  • Mitoxantrone: Mitoxantrone [my-toe-ZAN-trone] is a cytotoxic anthracycline analog that kills T cells and may also be used for MS.

B. Symptomatic treatment

Focus topic: Drugs for Neurodegenerative Diseases

Many different classes of drugs are used to manage symptoms of MS such as spasticity, constipation, bladder dysfunction, and depression. Dalfampridine [DAL-fam-pre-deen], an oral potassium channel blocker, improves walking speeds in patients with MS. It is the first drug approved for this use.

Drugs for Neurodegenerative Diseases: DRUGS USED IN AMYOTROPHIC LATERAL SCLEROSIS

Focus topic: Drugs for Neurodegenerative Diseases

ALS is characterized by progressive degeneration of motor neurons, resulting in the inability to initiate or control muscle movement. Riluzole [RIL-ue-zole], an NMDA receptor antagonist, is currently the only drug indicated for the management of ALS. It is believed to act by inhibiting glutamate release and blocking sodium channels. Riluzole may improve survival time and delay the need for ventilator support in patients suffering from ALS.

[/sociallocker]

FURTHER READING/STUDY:

Resources:

 

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.