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19 Cards in this Set

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Nervous System- Multiple Sclerosis, ALS, and Alzheimer’s Drugs by Schriefer
Nervous System- Multiple Sclerosis, ALS, and Alzheimer’s Drugs by Schriefer
Multiple Sclerosis (MS)
a disease of the central nervous system in which neurons become demylinated resulting in motor, sensory, and other problems.

Multiple areas of CNS are affected leading to multiple deficits (many symptoms)
Sclerosis refers to plaque (scar) formation leading to disability
Chronic: life-long disease
Progressive: usually increases in severity over time

Types:
Benign
Relapsing-remitting: fluctuating course of exacerbations (attacks) and remissions
Secondary progressive
Primary progressive
Causes and sx of MS
Causes:
Autoimmune disease – there is a cell mediated autoimmune attack against myelin
Viral agent
Genetic predisposition

Sx:
Motor (movement) symptoms
Ataxia: trouble moving and loss of coordination, i.e., walking
Loss of balance: increased risk of falling
Paralysis: inability to move
spasticity: muscle cramps or spasms
Tremor: shaking of extremities, especially upper limb

Sensory symptoms
Visual deficits (blurred, reduced, or double vision): usually FIRST symptom to occur
Loss of sensation in limbs; Parethesias: tingling in extremities
Pain, Vertigo

Fatigue or weakness most common sx
Specific treatment of disease process...

interferons. how do they work? how are they different?
Interferons – interferon beta-1b (Betaseron) and two versions of interferon beta-1a (Avonex and Rebif)

Mechanism of action – uncertain but beneficial effects may be due to immunomodulatory actions. One thought is that INFs decrease antigen presentation in the CNS, which appears to limit immune attack on myelin.

Pharmacokinetics – the major difference between the two interferons are pharmacokinetic (due to slight structural differences).
-Betaseron (1b) and Rebif (1a) are given by alternate day sc. Injections, while Avonex is given by weekly im. Injection.
adverse, therapeutic
Adverse reactions:
flu-like symptoms (muscle ache, fever, chills, asthenia)
Injection site reactions
Antibody formation (can limit effectiveness of drug)
Depression

Therapeutic use:
Used to decrease the frequency and severity of exacerbations in patients with relapsing forms of MS. Uncertain whether they actually slow the progression of the disease.
Glatiramer (Copaxone)
a synthetic compound which resembles a component of myelin
Mechanism of action

Since drug resembles a component of myelin, it’s thought that it may protect myelin by acting as a “decoy” attracting immune cells away from myelin

Pharmacokinetics: Must be given by sc. Injection, once daily

Adverse reactions: Generally well tolerated.
The most common side effects are:
Injection site reactions
Flushing, chest tightness or pain, shortness of breath (within 15 min)
Joint pain; Muscle stiffness

Therapeutic use: Approved for the treatment of relapsing-remitting MS. Has been shown to decrease the rate of relapse.
Mitoxantrone (Novantrone)
a cancer chemotherapeutic agent recently approved to treat advanced MS
Acts by suppressing immune attack on myelin

Common side effects include nausea, bladder infections, mouth sores, and loss of menstrual cycle. Patients should only receive the drug for 2-3 years due to a cumulative effect on cardiac conduction
Natalizumab (Tysabri)
A recombinant humanized MAB

Binds to a specific site on an adhesion molecule on activated lymphocytes and monocytes. This blocks adhesion and prevents leukocyte entry into CNS, therby decreasing immune attack on myelin.

Adverse reactions:
Minor – headache, fatigue etc.
Allergic reactions and antibody formation may limit usefulness
*Progressive multifocal leukoencephalopathy

Therapeutic use: Monotherapy in pts who don’t respond to other drugs. Due to risk of PML, only available in special centers to registered pts.

LAST RESORT!
Sx tx:

Anti-inflammatory steroids
used for management of acute symptoms because they close damaged blood brain barrier and reduce inflammation in the CNS, e.g., methylprednisolone, dexamthasone, prednisone, betamethasone, prednisolone
Sx tx:

Anti-depressants
both SSRIs (e.g., fluoxetine [Prozac]) and tricyclics (e.g., amitriptyline [Elavil]) are used to treat depression associated with MS. Amitriptyline (and carbamazepine [Tegretol]) are used to treat neuralgia associated with damaged nerves. Imipramine used to treat urinary incontinence.
sxtx:

Anti-spasmodics
a variety of drugs are used to relieve spasms, cramping, and muscle tightness caused by spasticity in MS, including benzodiazepines such as clonazepam (Klonopin) and dizaepam (Valium), baclofen (Lioresal; central GABAB agonist), tizanidine (Zanaflex; central α2 agonist) and dantrolene (Dantrium).
Miscellaneous
Amantadine for tremors and fatigue
Meclizine (Antivert) for vertigo
Oxybutanin (Ditropan) for urinary incontinence
Carbamazepine (Tegretol) and phenytoin for neuralgia
Miscellaneous
Amantadine for tremors and fatigue
Meclizine (Antivert) for vertigo
Oxybutanin (Ditropan) for urinary incontinence
Carbamazepine (Tegretol) and phenytoin for neuralgia
Amyotrophic Lateral Sclerosis (ALS)

name THE drug and how it works
A progressive degenerative disease of motor neurons (MS does sensory and motor). Glutamate “excitotoxicity” may be responsible for the disease b/c they're burning out the motor neurons

Riluzole (Rilutek) is the first (and, so far, only) drug approved for the specific treatment of ALS
Pharmacology
Riluzole is a voltage-gated sodium channel blocker which is thought to act by inhibiting glutamate release
Adverse reactions
Therapeutic use
Asthenia, dizziness, vertigo
Nausea, diarrhea, vomiting
*Circumoral parethesias (tingling lips)
*SGPT elevation (monitor liver chemistry – may require DC)

Therapeutic use: Has been shown to increase survival in ALS patients but not increase strength or neurological function
non-specific tx of ALS
Non-specific therapy consist of baclofen for spasticity and gabapentin to slow decline in muscle strength
Alzheimer’s Disease
A progressive, neurodegenerative disease, occurring later in life. It is the most common type of senile dementia, characterized by cognitive deficits, behavioral disorders, and mood changes.
what drugs do we use?
Acetylcholinesterase inhibitors:
Donepezil (Aricept)
Galantamine (Razadyne; formerly Reminyl)
Tacrine (Cognex)
Rivastigmine (Exelon) (oral and patch)

*more central and less peripheral activity (less side fx)

MOA – the cognitive deficits of the disease are thought to be related, in part, to degeneration of cholinergic neurons in the cortex and hippocampus resulting in deficient cholinergic neurotransmission.
Acetylcholinesterase inhibitors increase cholinergic activity by decreasing metabolism of Ach. Benefit is modest (< 10% improve) and short-lived.
Memantine (Namenda)
recently approved to treat Alzheimer’s in U.S.
MOA – memantine is a “use-dependent” NMDA (glutamate) receptor antagonist. The theory behind its action in Alzheimer’s is that it blocks glutaminergic overstimulation of NMDA receptors, which can be toxic to neurons which are important in learning and memory, but allows low levels of receptor activation.

Adverse effects: Dizziness, headache, constipation, and confusion. Is generally well tolerated.

Therapeutic use : Provides modest benefit by appearing to slow progression of the disease. Can be used with cholinesterase inhibitors to improve their effectiveness. May also be useful in the treatment of neurodegeneration associated with ALS, Parkinson’s disease, and epilepsy.
SSRI, Gingko, Estrogen and AD
SSRI’s and atypical antipsychotics useful for depression and agitation.

Gingko has been shown to modestly improve memory in some Alzheimer’s patients.

Estrogen may increase risk.