Ms Als Alzheimers 2009

Neuropharmacology – 2009 John Schriefer, Ph.D. DRUG TREATMENT OF MULTIPLE SCLEROSIS, ALS and ALZHEIMER’S Objectives: The student shall be able to: 1.

describe the basic defect in MS and how this relates to symptoms of the disease.

2.

list drugs used for the specific treatment of MS and explain their proposed mechanisms.

3.

explain the difference between the interferons.

4.

list the side effects of glatiramer, interferon beta-1a and beta-1b, mitoxantrone, and natalizumab.

5.

describe the effect of anti-interferon antibodies on interferon therapy.

6.

name drugs used to treat specific symptoms associated with MS.

7.

name the drug used to treat ALS and describe its proposed mechanism.

8.

describe the hepatic complications of riluzole therapy.

9.

describe the rationale for using acetylcholinesterase inhibitors in the treatment of Alzheimer’s.

10.

recognize the acetylcholinesterase inhibitors used to treat Alzheimer’s.

11.

describe the mechanism of action of memantine.

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DRUG TREATMENT OF MULTIPLE SCLEROSIS AND ALS I.MULTIPLE SCLEROSIS (MS)- A disease of the central nervous system in which neurons become demylinated resulting in motor, sensory and other problems. A.General disease characteristics 1.Multiple areas of CNS are affected leading to multiple deficits (many symptoms) 2.Sclerosis refers to plaque (scar) formation leading to disability 3.Chronic: life-long disease 4.Progressive: usually increases in severity over time 5.Types: benign relapsing-remitting: fluctuating course of exacerbations (attacks) and remissions secondary progressive primary progressive Figure 1 – Plaques at many sites – the diagnostic hallmark of multiple sclerosis – are illustrated here in paraventricular regions of the frontal lobe and in the central nervous system. The protective myelin sheath, produced by oliqodendrocytes and schwann cells, is destroyed and plaque forms, in part as a result of abnormal immune system activity. An inflammatory response causes edema and decreased nerve conduction. Astrocytes, lymphocytes, and macrophages may further disrupt demyelinated axons.

Figure 1 – Plaques at many sites – the diagnostic hallmark of multiple sclerosis – are illustrated here in paraventricular regions of the frontal lobe and in the central nervous The protective myelin 6.Cause of MS system. sheath, produced by oliqodendrocytes and schwann cells, is destroyed and plaque forms, in part as a result of abnormal immune system activity. An inflammatory response causes edema and decreased nerve conduction. Astrocytes, lymphocytes, and macrophages may further disrupt demyelinated

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c.paralysis: inability to move d.spasticity: muscle cramps or spasms e.tremor: shaking of extremities, especially upper limb 2.Sensory symptoms a.visual deficits (blurred, reduced, or double vision): usually first symptom to occur b.loss of sensation in limbs c.parethesias: tingling in extremities d.pain e.vertigo 2.Other symptoms a.fatigue or weakness: most common symptoms b.constipation c.loss of bladder or bowel control d.sexual dysfunction e.speech problems f.cognitive problems g.emotional problems C.Drug Treatment 1.Specific treatment of disease process a.Interferons - Interferon (INF) beta-1b (Betaseron) and two versions of interferon beta-1a (Avonex and Rebif) 1.Mechanism of action - Uncertain but beneficial effects may be due to immunomodulatory actions. IFN B’s decrease antigen presentation within the CNS. Appear to limit immune attack on myelin. 2.Pharmacokinetics - The major difference between the two interferons are pharmacokinetic (due to slight structural differences). Betaseron and Rebif are given by alternate day sc. injections, while Avonex is given by weekly im. injection. 3.Adverse reactions - Flu-like symptoms (muscle ache, fever, chills, asthenia) injection site reactions antibody formation (can limit effectiveness of drug) depression 4.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.

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b.Glatiramer (Copaxone) - A synthetic compound which resembles a component of myelin. 1.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. 2.Pharmacokinetics - must be given by sc. injection, once daily 3.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 4.Therapeutic use - Approved for the treatment of relapsingremitting MS. Has been shown to decrease the rate of relapse. b.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. d.

Natalizumab (Tysabri) – a recombinant humanized monoclonal antibody. 1.

Mechanism of action – binds to the α4 – subunit of the cell surface adhesion molecule α4B1 integren expressed on activated lymphocytes and monocytes. This blocks cell adhesion and prevents leukocyte migration across the BBB, interrupting immune attack on myelin.

2.

Kinetics – must be given IV every 4 weeks

3.

Adverse effects – headache, fatigue, arthralgia, abdominal pain, infection, rash and depression (all only slightly higher than placebo). Allergic reactions and neutralizing antibodies are possible. 3/3000 patients during trials developed progressive multifocal leukoencephalopathy (PML). 6

4.

Therapeutic use – approved for use as monotherapy only in patients who don’t respond to other therapies. Due to risk of PML, only registered centers are allowed to administer drug and patients must be registered in a follow-up program.

2.Symptomatic treatment a.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 b.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. c.

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 diazepam (Valium), baclofen (Lioresal), tizanidine (Zanaflex), and dantrolene (Dantrium).

d.

miscellaneous - amantadine for tremors and fatigue - meclizine (Antivert) for vertigo - oxybutanin (Ditropan) for urinary incontinence - carbamazepine (Tegretol) and phenytoin for neuralgia

II AMYOTROPHIC LATERAL SCLEROSIS (ALS) - A progressive degenerative disease of motor neurons. Glutamate "excitotoxicity" may be responsible for the disease. A. Riluzole (Rilutek) is the first (and, so far, only) drug approved for the specific treatment of ALS. 1.Pharmacology - Riluzole is a voltage-gated sodium channel blocker which is thought to act by inhibiting glutamate release. 2.Pharmacokinetics - orally effective - half-life ~ 12 hours - highly bound to plasma proteins - hepatic metabolism (some metabolites active) and renal excretion 7

3.Adverse Reactions - asthenia, dizziness, vertigo - nausea, diarrhea, vomiting - circumoral parethesias - SGPT elevation (monitor liver chemistry - may require DC) 4.Therapeutic use - has been shown to increase survival in ALS patients but not increase strength or neurological function. B. Non-specific therapy consists of baclofen for spasticity and gabapentin to slow decline in muscle strength. III.

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. Drug therapy A.

Acetylcholinesterase inhibitors donepezil (Aricept) galantamine (Razadyne) rivastigmine (Exelon) (oral and patch) tacrine (Cognex) 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 and short-lived. Less than 10% of patients are improved; some question whether they should be used.

B.

Memantine (Namenda) approved to treat Alzheimer’s 1.

MOA – memantine is a “use-dependent” NMDA 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.

2.

Adverse effects – dizziness, headache, constipation, and confusion. Is generally well tolerated.

3.

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 8

neurodegeneration associated with ALS, Parkinson’s disease, and epilepsy. C.

SSRIs and atypical antipsychotics useful for depression and agitation. Estrogen may worsen Alzheimer’s in women.

D.

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

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