Drugs for Parkinson's & Alzeheimer's

Question 1

neurodegenerative diseases characterized
by progressive loss of neuronal function in a particular part of the CNS

Answer 1

• Parkinson’s Disease (PD)
• Alzheimer’s Disease (AD)
• Multiple Sclerosis (MS)
• Huntington’s Disease (HD)
• Amyotrophic Lateral Sclerosis (ALS)

Question 2

AKA paralysis aitans, shaking palsy

Answer 2

Parkinson’s disease

Question 3

Clinical syndrome that comprises main features of PD

Answer 3

1. BRADYKINESIA (slowness or poverty of movement)
2. RIGIDITY (inability to initiate movements)
3. RESTING TREMOR (involuntary trembling when a limb is at rest)
4. Abnormalities in posture and gait.

Question 4

Etiology and Pathogenesis of PD

Answer 4

DEGENERATION OF DOPAMINERGIC
NEURONS that arise in the substantia
nigra and project to the other structures
of the basal ganglia.

Basal ganglia is a group of subcortical
nuclei responsible for motor function,
procedural and habit learning, eye
movement, cognition, and emotion

Cholinergic neurons in the basal ganglia do not appear to be damaged in PD, however it is postulated that the symptoms of the disease arise because of the LACK OF INHIBITORY CONTROL of the EXCITATORY CHOLINERGIC FUNCTIONS
→ excitation of cholinergic neurons are linked to
inhibitory control to DA neurons

Question 5

Drug treatment for PD

Answer 5

Levodopa

Question 6

Pharmacokinetics of Levodopa

Answer 6

In tissues:
- Metabolized by LAAD (l-amino acid
-decarboxylase) to DA
- COMT to 3OMD (3-O-methyldopa)
→ When metabolized, its bioavailability is
greatly reduced

Exhibits extensive first-pass metabolism
(only about 1% of the administered dose of
levodopa reaches the brain tissue).

Question 7

MOA of Levodopa

Answer 7

taken up by dopaminergic neurons in the striatum and is converted to DA by AADC

it increases concentration of DA in the brain and is the main treatment used to alleviate motor dysfunction in patients with PD.

Question 8

Adverse effects of Levodopa

Answer 8

• Nausea and vomiting (80%)
• Orthostatic hypotension (25%)
• Cardiac dysrhythmias (10%)
  *Psychotic effects
• excessive DA concentrations in the mesolimbic and mesocortical pathways.
• Dyskinesia (30%) Aka: Peak-dose dyskinesia
• occurs during long-term (2-5 years) of therapy as a result of excessive DA concentrations in the striatum.

Manifestations:
Patients appear as if they are chewing
food while lips their lips are protruded.
Flinging movements of the arms and legs.

Management:
→ Reduce dose however therapeutic effect
of Levodopa is compromised.

Question 9

Drugs that can increase dopamine levels when combined with Levodopa

Answer 9

Carbidopa
Entacapone
Tolcapone

Question 10

What does Carbidopa do

Answer 10

It is a false substrate of LAAD thus it increases the amount of levodopa that enters the brain since it reduces the conversion of levodopa to DA

*does not cross the BBB hence it does not inhibit the formation of DA in the brain

Question 11

What does Entacapone do

Answer 11

Inhibits the peripheral COMT thus increasing the amount of levodopa that enters the brain

Question 12

What does tolcapone do

Answer 12

Inhibits the central COMT thus increasing the amount of levodopa that enters the brain

Question 13

Drugs that increase the DA levels

Answer 13

SELEGILINE
RASAGILINE
AMANTADINE

Question 14

MOA of Amantadine

Answer 14

1. Increases release of DA from nigrostriatal
   neurons.
2. Inhibits reuptake of DA.

*this drug is an antiviral agent better tolerated than levodopa and dopamine agonists but is less effective in the treatment of PD

Question 15

Dopamine Receptor Agonists

Answer 15

Ergot Alkaloids
BROMOCRIPTINE
PERGOLIDE

Non Ergot Alkaloids
PRAMIPEXOLE
ROPINIROLE
ROTIGOTINE
APOMORPHINE

Acetylcholine receptor antagonists
BIPERIDEN
BENZTROPINE
TRIHEXYPHENIDYL
- these are more effective in reducing tremors and relieves muscle rigidity but not akinesea

Question 16

MOA of Dopamine Receptor Agonists

Answer 16

Directly activates Dopamine-2 receptors in the striatum even in the absence of endogenous DA

Question 17

Most common type of dementia.

Characterized as a severe, chronic, progressive,
irreversible neurodegenerative and incurable
disorder with memory loss, cognition impairment,
abnormalities in behavior, and personality changes
as the main clinical manifestations.

Characterized by NEURONAL DEATH

Answer 17

Alzheimer’s Diseases

Question 18

Neuropathological hallmarks of AD

Answer 18

Reduction of Acetylcholine - Loss of cholinergic tone and Ach levels in the brain
is hypothesized to be responsible for the gradual cognitive decline.

Increased Glutamate Neurotransmission - Neuronal excitotoxicity from excessive
N-Methyl-D-Aspartate (NMDA) receptor
activation leads to neuronal damage and loss.

Deposition of Amyloid plaques/ Neuritic plaques

Aggregation of Neurofibrillary Tangles

Question 19

Drugs centrally acting on Ache inhibitors

Answer 19

TACRINE (withdrawn because of liver toxicity)
DONEPEZIL
RIVASTIGMINE
GALANTAMINE

They slow the loss of cognitive function temporarily but does not delay AD progression

Question 20

MOA of Memantine

Answer 20

Non-competitive antagonist at NMDA receptors; cannot prevent neuronal loss, worsening of dementia, and modify AD progression.

Question 21

Deposition of Amyloid plaques or Neuritic plaques

Answer 21

Accumulation of Amyloid β (Aβ) is postulated to be the primary cause of AD.

The misfolded sticky proteins are insoluble
aggregates and are neurotoxic.

Research shows that Aβ build-up enhances the activity of glutamate.

*No currently approved drugs are know to target this cause

Question 22

Aggregation of Neurofibrillary Tangles (NFTs)

Answer 22

Also known as hyperphosphorylated tau proteins cause neuronal death.

No currently approved drugs are known to target this cause.