For pharmacy students

1. Drugs used for Neuro-
Degenerative disorders
By : Kirankumar Solanki

2. What are neurodegenerative disorders?
 As a rule, dead neurons in the adult central
nervous system (CNS) are not replaced, nor can
their terminals regenerate when their axons are
interrupted.
 Therefore any pathological process causing
neuronal death generally has irreversible
consequences.
 In neurodegenerative disorders, The nerve cells
in your brain gets dysfunctional or they
degenerate due to misfolding of proteins,
oxidative stress or excitotoxicity.
 In our syllabus we have two NDDs
◦ Alzheimers Disease
◦ Parkinsons Disease

3. MECHANISMS OF NEURONAL DEATH
 Protein misfolding
◦ Many chronic neurodegenerative diseases involve the misfolding of
normal or mutated forms of physiological proteins. Examples include
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis and many less common diseases.
◦ Misfolded proteins are normally removed by intracellular degradation
pathways, which may be altered in neurodegenerative disorders.
◦ Misfolded proteins tend to aggregate, initially as soluble oligomers,
later as large insoluble aggregates that accumulate intracellularly or
extracellularly as microscopic deposits, which are stable and resistant
to proteolysis.
◦ Misfolded proteins often present hydrophobic surface residues that
promote aggregation and association with membranes.
◦ The mechanisms responsible for neuronal death are unclear, but
there is evidence that both the soluble aggregates and the
microscopic deposits may be neurotoxic.

4. Protein misfolding

5. EXCITOTOXICITY
 Despite its important role as a
neurotransmitter, glutamate is highly toxic to
neurons, a phenomenon dubbed
excitotoxicity.
 A low concentration of glutamate applied to
neurons in culture kills the cells, and the
finding in the 1970s that glutamate given
orally produces neurodegeneration in vivo
caused considerable alarm because of the
widespread use of glutamate as a 'taste-
enhancing' food additive.
 Calcium overload is the essential factor in
excitotoxicity.

6. Steps involved in
excitotoxicity
 Glutamate activates NMDA, AMPA and
metabotropic receptors present on synapse.
 Activation of AMPA receptors depolarises the
cell, which unblocks the NMDA channels,
permitting Ca2+ entry.
 Depolarisation also opens voltage-activated
calcium channels, releasing more glutamate.
 Metabotropic receptors cause the release of
intracellular Ca2+ from the endoplasmic reticulum.
Na+ entry further contributes to Ca2+ entry by
stimulating Ca2+/Na+ exchange.
 Depolarisation inhibits or reverses glutamate
uptake, thus increasing the extracellular
glutamate concentration.

7.  Rise in Ca2+ affects many processes,
the chief ones relevant to neurotoxicity
are:
◦ increased glutamate release
◦ activation of proteases (calpains) and
lipases, causing membrane damage.
◦ activation of nitric oxide synthase; while
low concentrations of nitric oxide are
neuroprotective, high concentrations in
the presence of reactive oxygen species
generate peroxynitrite and hydroxyl free
radicals, which damage many important
biomolecules, including membrane lipids,
proteins and DNA

8. ALZHEIMER'S DISEASE
 Loss of cognitive ability with age is considered to be a
normal process whose rate and extent is very variable.
 AD refers to dementia that does not have an predefined
cause, such as stroke, brain trauma or alcohol. Its
prevalence rises sharply with age, from about 5% at 65 to
90% or more at 95.
 AD can be characterized by impaired cognition, behavior &
functional status and it can be fatal.
 Until recently, age-related dementia was considered to
result from the steady loss of neurons that normally goes
on throughout life, possibly accelerated by a failing blood
supply associated with atherosclerosis.
 AD is associated with brain shrinkage and localised loss of
neurons.
 The loss of cholinergic neurons in the hippocampus and
frontal cortex is a feature of the disease, and is thought to
underlie the cognitive deficit and loss of short-term

9. Cholinesterase
inhibitors

10. Cholinesterase Inhibitors
 Carbamates: They are cholinergic agents that
reversibally deactivates the AchE enzyme
which is responsible for metabolism of Ach.
 Uses
◦ They are used to improve memory in AD, also
used in treatment of glucoma.
◦ They are useful in improving muscle strength in
Myasthesia gravis.
◦ To treat dementia related to AD & (Parkinson’s
disease)PD.
◦ To treat mild to moderate confusion.
 Acridines (eg-Tacrine) are specifically used to
treat the symptoms related to AD.

11. Cholinesterase Inhibitors-
Adverse effects
◦ Increase sweating
◦ Loss of bladder
control
◦ Muscle weakness
◦ Tightness of chest
◦ Irregular heart beat
◦ Blurred vision
◦ Abdominal cramps
◦ Watering in mouth
◦ Decrease in pupil
size
◦ Increase urination
◦ Loss of appetite
◦ Weakness
◦ Drowsiness
◦ Shakiness
◦ Abdominal Pain
◦ Unsteadiness
◦ Diarrhea

12.  Antipsychotics like atypical
neuroleptics are used to supress the
symptoms related to AD.
 They act on D2 dopamine receptor.
 Anti-Depressants like Selective
Serotonine Reuptake Inhibitors
(SSRIs) are also used in some cases
to relieve AD related symptoms.
 In newer approach Drugs like
Memantine are used which is more
effective.

13.  Memantine
 It is an NMDA rec. antagonist.
 It reduces the prolonged influx of Ca
ions particularly from extra synaptic
receptors.
 This leads to reduction in
excitotoxicity.
 This drug is particularly used to treat
symptoms of AD.
 It can show Confusion, Dizziness,
Drowsiness, Insomnia, Agitation as its
adverse effects.

14. PARKINSON'S DISEASE
 Parkinson's disease is a chronic, progressive
disorder of movement that occurs mainly in
the elderly.
 It generally occurs due to imbalance in NTs
like dopamine, GABA & Ach.
 The chief symptoms are:
◦ tremor at rest, usually starting in the hands ('pill-
rolling' tremor), which tends to diminish during
voluntary activity.
◦ muscle rigidity, detectable as an increased
resistance in passive limb movement.
◦ suppression of voluntary movements
(hypokinesis), due partly to muscle rigidity and
partly to an inherent inertia of the motor system,
which means that motor activity is difficult to stop
as well as to initiate.

15.  The most prominent pathological
findings in Parkinson’s disease are
◦ Degeneration of the darkly pigmented
dopamine neurons in the substantia nigra.
◦ Loss of dopamine in the neostriatum.
◦ The presence of intracellular inclusion
bodies known as Lewy bodies.

16. Treatment of PD

17.  We know that PD is generally occur
due to loss of dopaminergic neurons
and increase in activity of NTs like
Ach.
 So based on the mechanism of action
drugs used for parkinsonism are
broadly classified as
1. Drugs enhancing Dopaminergic activity
and
2. Drugs affecting Cholinergic system

20. Drugs enhancing Dopaminergic
activity
 Dopamine precursors (Levodopa)
◦ Levodopa is the biochemical precursor of
dopamine
◦ It is used to elevate dopamine levels in the
neostriatum of parkinsonian patients.
◦ Dopamine itself does not cross the blood-
brain barrier and therefore has no CNS
effects.
◦ However, levodopa, as an amino acid, is
transported into the brain by amino acid
transport systems where it is converted to
dopamine by the enzyme L-aromatic amino
acid decarboxylase.

21. Levodopa in combination with carbidopa
 If levodopa is administered alone, it is
extensively metabolized by L-aromatic
amino acid decarboxylase in the liver,
kidney, and gastrointestinal tract.
 To prevent this peripheral metabolism,
levodopa is co-administered with
carbidopa, a peripheral decarboxylase
inhibitor.
 The combination of levodopa with
carbidopa lowers the necessary dose of
levodopa and reduces peripheral side
effects associated with its administration.

22. Levodopa in combination with carbidopa

24. Dopaminergic agonists
 These agents binds to the D2 receptor
and increases the dopamine action.
 They are used to treat PD as well as
hyperprolectinemia.
 Postural hypotension, abdominal
cramps, Dyskinesia, Hallusinations,
Confusion, weakness are some of
their side effects.
 Eg. Bromocriptine, Ropinirole

25. Drugs inhibiting dopamine metabolism
 MAO-B Inhibitors
◦ They selectively blocks the Mono amine
oxidase-B which is responsible for
Dopamine metabolism.
◦ They are used in early stages of PD, &
also in treatment of Depression &
Dementia.
◦ Insomnia and anxiety are their side
effects.
◦ Eg. Selegline

26. Drugs inhibiting dopamine metabolism
 COMT Inhibitors
◦ They selectively and reversiblly blocks the
catechol-o-methyl transferase enzyme
and blocks the dopamine metabolism.
◦ They are used to reduce “wearing off”
symptoms of PD.
◦ Dyskinesia, Confusion and Hypotension
are their side effects.
◦ Eg. Entacapone, Tolcapone.

27. Dopamine facilitators
 They facilitates (helps to increase) the
release of dopamine from dopaminergic
neurons.
 They are also used for reducing “wearing
off” symptoms in PD. (“Wearing off”
phenomenon – gradual worsening of
symptoms as medication begins to lose
effectiveness, despite maximal doses)
 Hypotension, Constipation,
Hallusinations & insomnia are their side
effects.
 Eg. Amantadine.

28. Drugs affecting brain cholinergic system
 Central anti-cholinergics
◦ They reduces the increased cholinergic
activity during PD.
◦ Used to treat symptoms of PD or to
reduce the involuntary movements due to
side effects of some psychiatric drugs.
◦ Blurred vision, Hallucinations, and urine
retention are some of their side effects.
◦ Eg. Trihexyphenidyl, procyclidine.

29. Drugs affecting brain cholinergic system
 Anti-Histamines
◦ They inhibit histamine rec. as well as
NMDA rec.
◦ Used to relieve pain & discomfort caused
by strain, sprain and other muscle injuries.
◦ Eg. Orphenadrine, Promethazine.