Lect. 6 Drugs for Neurodegenerative Diseases

1. DRUGS USED IN DISORDERS OF THE
CENTRAL NERVOUS SYSTEM AND
TREATMENT OF PAIN
Lecture 6:
Drugs for Neurodegenerative Diseases
Marc Imhotep Cray, M.D.

2. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Learning Objectives:
2
PARKINSONISM AND ITS TREATMENT
1. The presentation of Parkinson’s disease and its underlying pathophysiology
2. The functional circuitry of the nigrostriatal system.
3. The major classes of pharmacotherapy for Parkinson’s Disease and the timeline for
their use
4. The indications, mechanism of action, adverse effects and contraindications for the
major classes of drugs used in the treatment of Parkinson’s Disease
5. The type and mechanisms of alternative treatments for Parkinson’s Disease.
PHARMACOLOGY OF STROKE AND ALZHEIMER’S DISEASE
1. The laboratory and clinical tests for ruling out reversible forms of dementia in the
elderly.
2. The drug treatments for the reversible forms of dementia.
3. The current symptomatic and theoretical preventive drug therapies for Alzheimer’s
disease.
4. The theoretical drug therapies for Huntington’s disease and ALS.
5. The preventive and symptomatic drug treatments for cerebrovascular disease.

3. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6Classification Schema:
Drugs for Neurodegenerative Diseases
3
ANTI-PARKINSON DRUGS
Amantadine SYMMETREL
Apomorphine APOKYN
Benztropine COGENTIN
Biperiden AKINETON
Bromocriptine PARLODEL
Carbidopa LODOSYN
Entacapone COMTAN
Levodopa (w/Carbidopa) SINEMET
Pramipexole MIRAPEX
Procyclidine KEMADRIN
Rasagiline AZILECT
Ropinirole REQUIP
Rotigotine NEU PRO
Selegiline (Deprenyl) ELDEPRYL
Tolcapone TASMAR
Trihexyphenidyl ARTANE
ANTI-ALZHEIMER DRUGS
Donepezil ARICEPT
Galantamine RAZADYNE
Memantine NAMENDA
Rivastigmine EXELON
ANTI-MULTIPLE SCLEROSIS DRUGS
Azathioprine IMURAN
Cyclophosphamide CYTOXAN
Dexamethasone DECADRON
Fingolimod GILENYA
Glatiramer COPAXONE
Dalfampridine
Interferon 1a AVONEX
Interferon 1b BETASERON
Natalizumab TYSABRI
Prednisone DELTASONE
ANTI-ALS DRUGS
Riluzole RILUTEK

4. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
CNS Neurodegenerative diseases
4
 Neurodegenerative diseases of CNS include:
 Parkinson’s disease
 Huntington disease
 Alzheimer’s disease
 Multiple Sclerosis (MS)
 Amyotrophic Lateral Sclerosis (ALS)
 These devastating illnesses are characterized by progressive loss of
selected neurons in discrete brain areas, resulting in characteristic
disorders of movement, cognition, or both

5. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Basal Nuclei (Ganglia)
5
COMPONENTS
 Caudate nucleus
 Putamen
 Globus pallidus
GROUPING OF THE BASAL NUCLEI (GANGLIA)
 The striatum consists of caudate nucleus and putamen
 The lentiform nucleus consists of globus pallidus and putamen
 The corpus striatum consists of lentiform nucleus and caudate
nucleus

6. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Striatal (Extrapyramidal) Motor System
6
 Striatal (Extrapyramidal) Motor System plays a role in initiation and
execution of somatic motor activity, especially willed movement
 It is also involved in automatic stereotyped postural and reflex motor
activity (e.g., normal subjects swing their arms when they walk).
 Striatal motor system includes the following structures:
1. Neocortex
2. Striatum (caudatoputamen, or neostriatum)
3. Globus pallidus
4. Subthalamic nucleus
5. Substantia nigra (i.e., pars compacta and pars reticularis)
6. Thalamus (ventral anterior, ventral lateral, and centromedian nuclei)

7. 7
The basal nuclei (ganglia)
Fix JD and Brueckner JK. High yield neuroanatomy 4th ed. 2009.

8. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Motor Tracts, Basal Ganglia, and
Dopamine Pathways
8
 Several major neuronal tracts coordinate somatic motor functions:
 One is the pyramidal tract, whose direct motor component goes
from precentral gyrus through internal capsule and midbrain and
terminates on motor neurons in anterior horn of spinal cord (What
is another name for this tract?)
 Extrapyramidal tracts (e.g., rubrospinal, reticulospinal, and
corticoreticular) are also important for motor control

9. 9
Principal fiber tracts of spinal cord:

10. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Pyramidal System
Lateral (crossed) corticospinal tract
10

11. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Motor Tracts, Basal Ganglia, and
Dopamine Pathways (2)
11
 The basal ganglia (including caudate nucleus, putamen, and globus
pallidus) are subcortical masses found between the cerebral cortex
and thalamus that, together with the substantia nigra, help to
coordinate movement
 A major pathway, the nigrostriatal, originates in substantia nigra and
connects with basal ganglia and other structures
o The substantia nigra receives reciprocal input from these structures plus
others
 Efferent pathways (nigrostriatal) are dopaminergic; afferent input
is from neurons containing 5-HT, GABA, and substance P
 Defects in these pathways lead to motor incoordination or incapacity

12. 12
Horizontal Brain Section Showing Basal Ganglia
Motor Tracts, Basal Ganglia,
and Dopamine Pathways (3)

13. 13
Connections of Basal Ganglia
Motor Tracts, Basal Ganglia,
and Dopamine Pathways (4)

14. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Parkinsonism: Symptoms and Defect
14
 Parkinsonism is a progressive neurodegenerative disease that
adversely affects motor neuron control:
 Major early symptoms are:
 tremor at rest
 bradykinesia (slowness in initiating and carrying out voluntary movements)
 muscle rigidity (cogwheel) and
 flat facial affect
 If untreated, condition worsens, leading eventually to complete
immobility and early mortality
 Prevalence is approximately 2% in persons older than 65 years
 A genetic predisposition seems likely, but environmental factors
(including viral infections and neurotoxins) may play a role

15. 15
Parkinsonism: Symptoms and Defect (2)
 Most distinctive neuropathologic finding is progressive
loss of dopaminergic neurons of the pars compacta of
the substantia nigra
 Projections of dopaminergic neurons from substantia
nigra correlate with motor and cognitive deficits
 Degeneration of dopaminergic neurons in the
nigrostriatal tract causes loss of inhibitory dopamine
action on striatal GABAergic neurons and leads to
excessive cholinergic neuron excitation of these striatal
neurons
 Drugs such as levodopa (increases DA activity) can help
Modifiedfrom:LippincottIllustratedReviews-PharmacologySixthEdition.2015

16. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
16
Clinical Signs of Parkinson’s Disease:

17. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
17
Neuropathology of Parkinson Disease:
 In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in
excitatory cholinergic neurons that oppose action of dopamine
 Many of symptoms of parkinsonism reflect an imbalance between excitatory cholinergic neurons
and diminished number of inhibitory dopaminergic neurons

18. 18
 Treatment aims to replenish dopamine, or at least
to reestablish balance between DA and ACh
influences on striatal neurons
 Dopamine cannot cross the blood-brain barrier,
so its metabolic precursor, levodopa, is used
 Most of an oral dose is rapidly converted to
dopamine by dopa decarboxylase located in
blood vessel walls (thus peripherally)
 Approximately 1% to 5% of the dose crosses
blood-brain barrier, enters metabolic
pathways of dopaminergic neurons, and is
converted to DA
PD Strategy of treatment

19. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Levodopa:
19
Levodopa (L-dopa [Dopar, Larodopa]), the most effective treatment, is
metabolized by dopa decarboxylase to DA, which increases availability
of DA ( the inhibitory transmitter, in the basal ganglia)
 L-Dopa becomes effective in a few weeks, especially for reducing
rigidity and akinesia
o However, L-dopa is rapidly metabolized in peripheral tissues
(bld vessels) , so that only 1% of administered dose reaches
CNS
• Pyridoxine (vitamin B6) increases this metabolism by
activating dopa decarboxylase

20. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Levodopa (2)
20
L-Dopa should be taken on an empty stomach because large, neutral
amino acids will compete with it for absorption from gut and
transport across blood–brain barrier (BBB)
Carbidopa (Sinemet), a peripheral dopa decarboxylase inhibitor
that slows metabolism of L-dopa, is usually combined with L-dopa
 L-dopa dosage can then be reduced by 80% without changing
effectiveness
 Side effects from conversion of L-dopa to DA in periphery are
also reduced

21. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Levodopa (3)
21
 Catechol-O-methyltransferase (COMT) inhibitors prevent
methylation of L-dopa in a side pathway
o This side pathway becomes significant when dopa decarboxylase
is inhibited by carbidopa
i. Entacapone (Comtan) requires frequent dosing but is least
toxic COMT inhibitor
ii. Tolcapone (Tasmar) is longer acting but can cause
fulminating hepatic necrosis
Remember: Entacapone and tolcapone—prevent peripheral L-dopa
degradation to 3-O-methyldopa (3-OMD) by inhibiting COMT

22. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Side effects from L-dopa
22
 Side effects from L-dopa include:
 Nausea, vomiting, and anorexia induced by stimulation of
chemoreceptor trigger zone
 severity of nausea is reduced by gradually increasing t dose into
therapeutic range and by combining L-dopa with carbidopa
 Postural hypotension
 Arrhythmias from actions of DA on the heart
 Choreiform movements due to excessive actions of DA on basal
ganglion
 Psychological disturbances that can lead to insomnia and delirium

23. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
On–Off effects of L-Dopa Tx of PD
23
 On-Off effects often develop after a year or more
 These are indicative of the “wearing-off phenomena” at end of
dosage intervals and erratic effectiveness
 Patients typically have a decline in response after a few years of
therapy

24. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Contraindications for L-dopa:
24
 Contraindications for L-dopa include:
 Treatment with MAO inhibitors, because the combination can
lead to a hypertensive crisis
 Glaucoma, because L-dopa can induce mydriasis
 Psychiatric disorders (PD), especially those disorders being
treated with antipsychotic drugs, which are DA antagonists;
o However, SSRIs or mirtazapine can be tried in PD patients
who are also depressed

25. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
DA receptor agonists: nonselective
25
 DA receptor agonists have effects and side effects that are similar to
L-dopa
 They are often used with L-dopa and carbidopa to reduce the ON–
OFF effects
o However, they are not active in patients who have no response
to L-dopa
i. Bromocriptine (Parlodel) and Pergolide (Permax) are
nonselective DA agonists
 Because they are ergot derivatives, they can cause
pulmonary and retroperitoneal fibrosis

26. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
DA receptor agonists: D2 selective
26
ii. Pramipexole (Mirapex) and ropinirole (Requip) are selective D2-
agonists, which are very effective and have fewer side effects
Pharmacokinetics:
 Pramipexole is cleared by renal tubular secretion
o Its half life is increased by cimetidine, which interferes
with secretion of organic bases (cations)
Remember: Dopamine agonists
Ergots—bromocriptine and pergolide
Non-ergot (preferred) —pramipexole, ropinirole

27. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Anticholinergics:
27
 The anticholinergics (e.g., trihexyphenidyl [Artane]), benztropine
[Cogentin]) reduce cholinergic excitatory tone in basal ganglia
 They are most frequently used in combination with antipsychotic
drugs to reduce extrapyramidal symptoms from antipsychotic
drugs (see note box below)
 Side effects are due to central and peripheral cholinoceptor
blockade
Secondary parkinsonism: Drugs such as the phenothiazines and haloperidol,
whose major pharmacologic action is blockade of dopamine receptors in the
brain, may produce parkinsonian symptoms (also called pseudoparkinsonism).
These drugs should be used with caution in patients with Parkinson’s disease.

28. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Other Drug Used to Tx PD:
28
 Amantadine (Symmetrel) is an antiviral drug (Tx influenza A and rubella) that
reduces symptoms of Parkinson’s disease
 It increases DA release, decrease DA reuptake, blocks ACh receptors, and inhibits
N-methyl-D-aspartic acid (NMDA) glutamate receptors (NMDAR)
 Tolerance to this therapeutic effect often develops within 6 months
 Adverse events ataxia, livedo reticularis
 Selegiline (Eldepryl) blocks conversion of dopamine into 3-MT by selectively inhibiting
MAO-B
 This enzyme metabolizes L-dopa, but not 5-HT or NE
 The selective decrease of DA metabolism enhances effectiveness of L-dopa with
less risk of a hypertensive crisis compared to MAO-A (Metab. 5-HT, EPI, NE)
 It can be used in combination with L-dopa, making it possible to lower the L-
dopa dosage
 Antihistamines, such as diphenhydramine (Benadryl) have some weak
therapeutic effects, which are probably due to anticholinergic actions of these
drugs

29. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Parkinson’s disease Tx approach:
29
 Order of efficacies of available drugs for PD disease is the following:
L-dopa  bromocriptine amantadine  anticholinergics
 A common approach is to use low-efficacy drugs (e.g., selegiline,
amantadine, anticholinergics) during early stages of Parkinson’s
disease and reserve L-dopa with carbidopa and dopaminergic
agonists for later stages

30. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Final Points on PD Tx:
30
 A loss of GABA or increase DA in basal ganglia can lead to the
choreiform movements that are characteristic of Huntington’s
disease
 As a result, L-dopa and anticholinergics are an inappropriate
combination
 Some reduction of symptoms can be induced by DA depleters,
antipsychotics (DA blockers), or cholinesterase inhibitors
 These treatments are largely palliative and do not cure
syndrome (choreiform movements)
Note: METHYLPHENYLTETRAHYDROPYRIDINE (MPTP)-INDUCED PARKINSONISM
MPTP is an analog of meperidine (Demerol). It destroys dopaminergic neurons in
the substantia nigra

31. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
PD treatment strategies encapsulated:
31
Class and Drug Mechanism of Action
Dopamine prodrugs
 Levodopa
 Levodopa + carbidopa
Are rapidly converted to dopamine by dopa
decarboxylase (which is inhibited by
carbidopa)
Direct-acting dopamine agonists
 Bromocriptine, Pergolide, Pramipexole, Ropinirole
Bind to dopamine receptors and mimic the
action of dopamine
Indirect-acting dopamine agonist
 Amantadine
Increases dopamine release and reduces
dopamine reuptake into dopaminergic nerve
terminals of substantia nigra neurons (by
unknown mechanism)
MAOI
 Selegiline
Inhibits only type B isozyme
Muscarinic antagonists:
 Benztropine, Biperiden, Orphenadrine,
Trihexyphenidyl
Have central activity (brain) as anticholinergic
agents
Levodopa, Carbidopa, and Other Drugs

32. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
PD treatment
strategies
summary
schematic
32LE, T et al. First Aid for the USMLE Step 1 2015

33. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Huntington Disease and Tourette
Syndrome
33
 Various tremors (rhythmic oscillations around a joint), tics
(repetitive, sudden, coordinated, abnormal movements), and chorea
(irregular, unpredictable, involuntary muscle jerks) are components
of disorders of coordinated movement
 Gilles de la Tourette syndrome (which includes involuntary
verbal outbursts) is a disorder of unknown cause
 Current therapy consists primarily of haloperidol and other
dopamine D2 receptor antagonists

34. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Huntington Disease and Tourette
Syndrome (2)
34
 Huntington disease is a dominantly inherited disorder
characterized by progressive chorea and dementia
 disorder is traced to a single gene defect on chromosome 4
 It is typically associated with an adult onset and a shortened
lifespan
 GABA and enzymes for ACh and GABA synthesis are deficient in
basal ganglia
 Current therapy consists usually of amine-depleting drugs, such as
tetrabenazine, or haloperidol or other dopamine D2 receptor
antagonists
 adverse drug effects: hypotension, depression, sedation,
restlessness, and parkinsonism are most common

35. 35

36. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Alzheimer Disease: Symptoms, Course,
and Pathology
36
 Alzheimer disease is a neurodegenerative disorder characterized by
progressive impairment of short-term memory and other memory,
language, and thought processes
 Functions are typically lost in reverse order in which they were attained
 In advanced stages, patients cannot perform simple activities of daily
life
 Diagnosis is usually made 3 years or more after symptom onset, and
life expectancy is approximately 7 to 10 years after diagnosis

37. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Alzheimer Disease: Symptoms,
Course, and Pathology (2)
37
 Gross brain atrophy accompanies progression of
disease, with characteristic high numbers of
neuritic plaques (fragments of insoluble amyloid,
type Aβ, protein) and neurofibrillary tangles
(abnormal τ microtubule complexes), particularly in
hippocampus and posterior temporoparietal lobe
areas
 Predisposing factors include aging and genetics,
with a possible contribution from environmental
toxins
 The neurodegeneration results in loss or
dysfunction of neurotransmitter pathways

38. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Alzheimer Disease: Cholinergic
Involvement and Drugs
38
 Although many NT systems become disrupted in Alzheimer disease,
cholinergic pathways become especially damaged
 Functional cholinergic deficits, such as impairment in short-term
memory, become apparent even in early stages of disease
 (SDL, Study NIP, Plates 3-21 , 3-22 and 3-23)
 Medication strategies to ameliorate the decline in cholinergic
function include the administration of precursors (eg, lecithin); direct-
acting cholinergic receptor agonists; and indirect acting
cholinomimetics
 Indirect-acting agents, specifically cholinesterase inhibitors, such
as donepezil, galantamine, and rivastigmine, are currently the
most commonly used

39. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
39

40. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Drugs Used in Multiple Sclerosis (MS)
40
 MS is an autoimmune inflammatory demyelinating disease
of the CNS (effects both sensory and motor function)
 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

41. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
MS Tx-Disease-modifying therapies
41
 Drugs currently approved for MS are indicated to decrease relapse
rates or in some cases to prevent accumulation of disability
 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

42. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
MS Tx-Disease-modifying therapies (2)
42
 Interferon β1a and interferon β1b: The immunomodulatory effects of interferon
help to diminish inflammatory responses that lead to demyelination of the axon
sheaths
 Adverse effects may include depression, local injection site rxns, hepatic
enzyme increases, and flulike symptoms
 Glatiramer: a synthetic polypeptide that resembles myelin protein and may act
as a decoy to T-cell attack
 Adverse effects some patients experience a postinjection reaction that includes
flushing, chest pain, anxiety, and itching
 It is usually self-limiting
 Fingolimod: an oral drug that alters lymphocyte migration, resulting in fewer
lymphocytes in the CNS
 Adverse effects may cause first-dose bradycardia and is associated with an
increased risk of infection and macular edema

43. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
MS Tx-Disease-modifying therapies (3)
43
4. Teriflunomide: an oral pyrimidine synthesis inhibitor that leads to a lower
concentration of active lymphocytes in CNS
 Adverse effects may cause elevated liver enzymes, should be avoided in pregnancy
5. Dimethyl fumarate: an oral agent that may alter cellular response to oxidative
stress to reduce disease progression
 Adverse effects flushing and abdominal pain are most common
6. Natalizumab: a monoclonal antibody indicated for MS in patients who have failed
first-line therapies

44. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
MS-Symptomatic treatment
44
 Many different classes of drugs are used to manage symptoms of MS
such as spasticity, constipation, bladder dysfunction, and depression
 Dalfampridine an oral potassium channel blocker, improves
walking speeds in patients with MS
o First drug approved for this use

45. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
Drugs Used in Tx of Amyotrophic Lateral
Sclerosis (ALS)
45
 ALS is characterized by progressive degeneration of motor neurons,
resulting in inability to initiate or control muscle movement (pure
motor disease (vs MS that is motor and sensory)
 Riluzole an NMDA receptor antagonist, is currently the only drug
indicated for management of ALS
 It is believed to act by inhibiting glutamate release and blocking
sodium channels
 Riluzole may improve survival time and delay need for ventilator
support in patients suffering from ALS

46. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
THE END
46

47. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 6
47
Lectures/discussions to follow:
7. Anesthetics
8. Analgesics
9. Drugs of Abuse
Further study (SDL):
MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders
Companion eNotes: CNS- Central Nervous System Pharmacology
Textbook Reading: Aminoff MJ. Pharmacologic Management of Parkinsonism & Other
Movement Disorders In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 483-98
Online resource center: Medical Pharmacology Cloud Folder