PHARMACOLOGY OF HUNTINGTON DISEASE, MULTIPLE SCLEROSIS AND AMYOTROPHIC LATERAL SCLEROSIS

Question 1

What are the pathophysiological features of HD? (it is characterized by…; genetic characteristics, progression)

Answer 1

• characterized by chorea (involuntary muscle movements) and dementia
• autosomal dominant disorder
• memory of family and friends normally remains intact initially
• progressive disease: fatal in 15-20 years due to total immobility, can’t communicate, total disability
• symptoms develop as movement disorder, personality changes, or both

Question 2

What is the principal pathologic feature of HD?

Answer 2

• severe degeneration of basal ganglia and frontal cerebral cortex
• basal ganglia degeneration–> enlarged lateral ventricles

Question 3

True or False: in HD, loss of medium spine neurons (MSN) causes abnormal DA, glutamate, and GABA transmission;
GABA suppresses involuntary movements in healthy individuals

Answer 3

True

Question 4

HD impacts the direct and indirect pathways. Which one is normally affect first?

Answer 4

-the globus pallidus externa’s (indirect pathway) medium spiny neurons are normally affected before the globus pallidus interna’s (direct pathway)

Question 5

In most patients, chorea is the predominant clinical feature. However, in some cases, ____ is the predominant feature.

Answer 5

rigidity

Question 6

Describe the relationship between Early HD, Late HD, and the direct and indirect pathways

Answer 6

• in early HD, the indirect pathway is inhibited, resulting in excessive movement
• in late HD, both the direct and indirect pathways breakdown, resulting in inhibited movement

Question 7

What is the pharmacological strategy for treatment of HD?

Answer 7

-no cure, so symptomatic treatment is used for patients who are depressed, irritable, paranoid, anxious, or psychotic

Question 8

Which drugs are used for treatment of HD?

Answer 8

-Vesicular Monoamine Transporters such as tetrabenazine and deutetrabenazine

Question 9

Why is Tetrabenazine used?

Answer 9

• acts by inhibiting VMAT2—>presynaptic depletion of catecholamines
• reversible inhibitor of transporter
• causes 23.5% decrease in chorea

Question 10

What is Multiple Sclerosis (MS)?

Answer 10

• -demyelinating inflammatory disease of the CNS
• may be episodic or progressive
• complex genetic disease with multiple allelic variants
• autoimmune component

Question 11

What are the common initial presentations of MS?

Answer 11

weakness, numbness, tingling, unsteadiness of limb, spastic paraparesis (partial paralysis of both legs), retrobulbar optic neuritis, diplopia, sphincter disturbance leading to urinary urgency

Question 12

MS attacks are classified based on ____ and _____

Answer 12

type and severity

Question 13

What are the 3 types of MS?

Answer 13

• Relapsing-remitting: comes and goes; in 85% of younger patients
• Secondary progressive: progressive neurological deterioration after long period of relapsing-remitting disease
• Primary progressive: found in 15% of patients; steadily progressive from onset and disability develops at early stage

Question 14

True or False: Pathological features of MS include inflammatory demyelination, axonal injury, and development of CNS lesions

Answer 14

True

Question 15

What pathological feature occurs in the white matter of the brain, spinal cord, and optic nerve in MS?

Answer 15

demyelination and reactive gliosis (abnormal change in glial cells)

Question 16

Describe the pathogenesis of MS (think autoimmune)

Answer 16

activity of inflammatory mediators –> apoptosis of oligodendrocytes (produce myelin sheath) and damage to the myelin sheath of axon

Question 17

What is the pharmacological strategy for treating MS?

Answer 17

resolving acute attacks, reducing recurrences, and slowing progression of disease
-Major target: alter immune response by modifying inflammatory process that causes myelin sheath damage

Question 18

What drugs can be used for the acute attacks of MS?

Answer 18

corticosteroids like dexamethasone and methylprednisolone

Question 19

What is ALS?

Answer 19

• Amyotrophic lateral sclerosis
• disorder of motor neurons in ventral horn of spinal cord (lower motor neurons) and cortical neurons that provide afferent input (upper motor neurons)

Question 20

What clinical features characterize ALS?

Answer 20

rapidly progressing weakness, muscle atrophy and fasciculations(involuntary muscle contractions), spasticity, dysarthria, dysphagia, respiratory problems

Question 21

What are occasional effects of ALS?

Answer 21

cognitive decline (dementia), pseudobulbar effect (laughing uncontrollably), or parkinsonism

Question 22

Is ALS fatal?

Answer 22

Yes, it is a progressive and fatal disorder with most patients dying of respiratory compromise and pneumonia after 2-3 years

Question 23

What is the principal pathologic feature of ALS?

Answer 23

lower and upper motor neuron degeneration

-includes axonal degeneration and secondary demyelination

Question 24

What are the two hypotheses about the origin of ALS?

Answer 24

• Dying-forward hypothesis: ALS is a diorder of corticomotor neurons; anterograde degeneration of anterior horn cells via glutamate excitotoxicity
• Dying back hypothesis: ALS begins within muscle cells or at NMJ; retrograde

Question 25

What is the pharmacological strategy for treating ALS?

Answer 25

symptomatic treatment; not curative

Question 26

Which drugs are used in treatment of ALS?

Answer 26

Riluzole and Edaravone

Question 27

How does Riluzole work?

Answer 27

• inhibits glutamate release from motor neurons

- blocks postsynaptic NMDA and Kainate receptors and inhibits voltage-dependent sodium channels

Question 28

How does Edaravone work?

Answer 28

• free radical scavenger and peroxyl radical induced peroxidation systems
• potent antioxidant; prevents oxidative stress from inducing motor neuron death in ALS patients