Alzheimer's Disease Medications Quiz

Pharmacology-Stage (4)

• Lecture 2: Drugs for Neurodegenerative Diseases (Part 2)
• Date: 2/10/2024

Drugs Used in Alzheimer's Disease

• Alzheimer's disease (AD): A progressive dementia with no known cause or cure.
• Distinct from vascular dementia, which is associated with brain infarction, stroke, trauma, or alcohol.
• Characterized by brain shrinkage and loss of neurons, primarily in the hippocampus and basal forebrain.
• Has a devastating impact on cognitive, emotional, and physical function of patients and their families.

Alzheimer's Symptoms

• Confusion with time and location
• Withdrawal from social activities
• Difficulty completing familiar tasks
• Difficulty solving problems
• Poor judgment
• Trouble with images and spaces
• Misplacing items
• Memory loss
• Unfounded emotions
• Difficulty with words

Dementia of the Alzheimer Type Distinguishing Features

• Accumulation of senile plaques (β-amyloid accumulations)

• Formation of numerous neurofibrillary tangles

• Loss of cortical neurons, especially cholinergic neurons

• Deficit in cholinergic neurotransmission due to neuron destruction, causing acetylcholine production deficiency.

Pharmacologic Intervention

• Palliative
• Modest short-term benefit
• Current therapies aim to improve cholinergic transmission within the CNS or prevent excito-toxic actions resulting from overstimulation of N-methyl-D-aspartic acid (NMDA)-glutamate receptors.

1) Acetylcholinesterase Inhibitors

• Donepezil, Galantamine, Rivastigmine, and Tacrine
• Linked to progressive loss of cholinergic neurons and memory loss.
• Treatment aims to improve cholinergic neurotransmission.
• Does not affect the underlying neurodegenerative process; disease is fatal.

Tacrine (Cognex®)

• First centrally-acting cholinesterase inhibitor approved.
• Lower bioavailability and shorter half-life than donepezil, requiring multiple daily administrations.
• Significant hepatotoxicity and peripheral cholinergic side effects (diarrhea, nausea, urinary incontinence).
• Withdrawn from the market due to adverse effects.

Donepezil (Aricept®)

• Reversible cholinesterase inhibitor selectively inhibiting cholinesterase in the CNS and increasing acetylcholine levels in the cerebral cortex.
• Well absorbed after oral administration and crosses the blood-brain barrier (BBB).
• Long half-life (approximately 70 hours), allowing once-daily administration.
• Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps.
• Unlike tacrine, it is not associated with hepatotoxicity.

Rivastigmine (Exelon®)

• Newer, centrally acting, reversible cholinesterase inhibitor available as a transdermal formulation.
• Significantly delays global cognitive impairment in AD.
• Transdermal formulation provides 24-hour administration and increases patient compliance.
• No interactions with drugs that alter P450-dependent enzyme activity.

Galantamine (Razadyen®)

• Newer, centrally acting, competitive reversible cholinesterase inhibitor.
• May also act as an allosteric modulator of nicotinic receptors, increasing cholinergic neurotransmission.
• Discovered from daffodil extracts.
• Shown to slow the progression of AD(like rivastigmine).
• Common side effects include nausea, diarrhea, vomiting, anorexia, tremors, bradycardia and muscle cramps.

1) Memantine (Namenda®)

• N-methyl-D-aspartic acid (NMDA) - glutamate receptor antagonist.
• A new mechanism of action for dementia of AD treatment.
• Normal glutamate stimulation is critical for memory formation; however, overstimulation leads to excito-toxic effects.
• Memantine assists in preventing neuronal damage through reduced glutamate receptor overstimulation.
• Helps prevent programmed cell death.
• NMDA-glutamate receptor antagonists are neuroprotective. They help prevent neuronal loss following injuries.

2) Caprylidene (Axona®)

• New approach to treat AD developed as medical food.
• Metabolism into ketone bodies that the brain uses for energy when glucose processing is impaired.
• MRI scans reveal a significant decrease in glucose uptake by the brain.
• Replaces depleted glucose levels to treat age-associated memory impairment and AD.

Drugs Used in Multiple Sclerosis (MS)

• Autoimmune inflammatory demyelinating disease of the CNS.
• Variable course; may be acute or chronic (relapsing or progressive).
• Course of disease spans 10 to 20 years.
• Affected areas' neurologic symptoms are varied and depend on affected brain areas, including pain, spasticity, weakness, ataxia, fatigue, speech and vision problems, gait issues, and bladder dysfunction.
• Many experience relapses and remissions.

Disease-Modifying Therapies

• Drugs aim to reduce relapse rates and prevent disability accumulation.
• Primary target: Modify the immune response and limit white blood cell-mediated inflammation that damages myelin sheaths and reduces axonal communication.

1) Interferon β-1b and Interferon β-1a (Betaseron®)

• Interferon β-1b is the first drug to demonstrate an ability to stop or reverse MS progression in some cases. Immunomodulatory effects help diminish the inflammatory responses leading to axon sheath demyelination.
• Clinical trials showed decreased relapse frequency and reduced new MRI lesions in ambulatory, relapsing-remitting MS patients, who had at least two exacerbations over the past two years.

2) Interferon β-1a

• Approved for relapsing forms of MS, acting as an immunomodulator.

3) Peginterferon β-1a

• PEGylated derivative of interferon β-1a (for longer duration).

2) Glatiramer (Copaxone®)

• Synthetic polypeptide mimicking myelin basic protein.
• Acts as a decoy to T-cell attack.
• Reduced relapse episodes in clinical trials.

3) Fingolimod (Gilenya®)

• Oral drug altering lymphocyte migration for lower levels in the CNS of MS patients.
• Sphingosine-1-phosphate receptor modulator.
• Reduces the number of lymphocytes in peripheral blood and lymph node egress.
• May cause first-dose bradycardia, infections, macular edema.

4) Teriflunomide (Aubagio®)

• Oral pyrimidine synthesis inhibitor.
• Reduces active immune cell proliferation, especially T and B-cells that attack nerves in the CNS.
• Potential hepatic toxicity (elevated liver enzymes).

5) Dimethyl fumarate (Tecfidera®)

• Oral agent altering cellular response to oxidative stress to reduce disease progression.
• Unknown mechanism of action but involves the mono-methyl fumarate (MMF) metabolite and the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which regulates the cellular response to oxidative stress
• Flushing and abdominal pain are common adverse effects.

6) Dalfampridine (Ampyra®)

• New drug for MS to improve walking speed by blocking potassium channels. Enhances conduction in damaged nerves to improve walking speed.

7) Mitoxantrone (Novantrone®)

• An anti-neoplastic agent for treating MS.
• Reduces the activity of T cells, B cells, and macrophages that attack the myelin sheaths

8) Monoclonal Antibodies

• Reserved for patients who haven't responded to other therapies.

1) Ocrelizumab

• First agent approved for primary progressive forms of MS.

2) Natalizumab (Tysabr®)

• Monoclonal antibody blocking lymphocyte adhesion pathways into the CNS.
• The presence of lymphocytes is linked to immune processes contributing to MS pathology.
• Significant toxicity as progressive multifocal leukoencephalopathy (PML).

Daclizumab

• Monoclonal preparation targeting Interleukin-2 (IL-2) receptor.
• Blocking Interleukin-2 receptor blocks lymphocyte activation.

Alemtuzumab

• CD52-directed cytolytic monoclonal antibody for relapsing MS.
• Reserved for patients who did not respond to other treatments due to potential life-threatening adverse effects.

Drugs Used in Amyotrophic Lateral Sclerosis (ALS)

• Progressive degeneration of motor neurons, causing muscle wasting, weakness, and respiratory failure, ultimately leading to death within 2-5 years.
• Unknown cause but evidence suggests a defect in superoxide dismutase (an enzyme that removes superoxide radicals).

1) Riluzole (Rilutek®)

• First drug specifically approved for ALS.
• Oral NMDA receptor antagonist.
• Mechanism unclear, but believed to limit glutamate release, reduce sodium channel activity (protects motor neurons from neurotoxins like glutamate),and limit oxidative stress.
• May improve survival time, prolonging time before tracheotomy and life by approximately 3 months.

2) Edaravone (Radicava®)

• Intravenous free radical scavenger and antioxidant reducing neuronal damage from oxidative stress.
• Effective in slowing ALS progression.
• Officially FDA-approved for ALS treatment.

Anti-spastic Agents for MS & ALS

• Used for skeletal muscle spasms resulting from injury or neurologic diseases.

1) Baclofen (Lioresal®)

• GABAB receptor agonist to lessen motor excitability.
• Reduces spasticity, pain, clonus, muscle rigidity.
• Available in oral, injectable, intrathecal infusion formulations.

2) Methocarbamol

• CNS depressant with sedative and musculoskeletal relaxant properties.
• Mechanism of action is not precisely understood.

3) Carisoprodol (Soma®)

• Short-term muscle spasm treatment.
• Major metabolite is meprobamate (an older, barbiturate-like tranquilizer).

4) Tizanidine (Zanaflex®)

• Centrally acting alpha2-adrenoceptor agonist.
• Reduces spasticity by inhibiting motor neuron impulses via presynaptic inhibition without affecting muscle strength.

5) Dantrolene (Dantrium®)

• Blocks calcium release in muscle fibers, decoupling excitation-contraction and relaxing skeletal muscle directly.
• Used for malignant hyperthermia triggered by halogenated anesthetics, neuroleptic malignant syndrome (associated with high-potency antipsychotics), and spasticity from various neurological disorders.

6) Botulinum toxin A (Botox®)

• Used for cosmetic purposes, also approved for treating upper-limb spasticity in stroke patients, cervical dystonia, and related PD symptoms, strabismus, and blepharospasm.
• Blocks acetylcholine release at the neuromuscular junction.
• Treating urinary incontinence resulting from detrusor overactivity (patients with spinal cord injury or MS).

Test your knowledge on various medications used to treat Alzheimer's disease and related dementias. This quiz covers drug mechanisms, side effects, and forms of administration. Assess your understanding of donepezil, tacrine, rivastigmine, and more.