Pharmacology of Parkinson's and Alzheimer's Disease

Question 1

What is the central Dopamine pathway and its role in Parkinson’s disease?

Answer 1

The Nigrostriatal pathway: Neurons in the substantia nigra pars compacta project to the dorsal striatum (involved in purposeful movement).

• contains 80% of brain’s dopamine
• degenerates in Parkinson’s disease.

Question 2

What causes idiopathic PD?

Answer 2

degeneration of nigrostriatal system leading to imbalance of DA and ACh in corpus striatum

Question 3

What is Parkinson’s Disease?

Answer 3

PD is a progressive neurological disorder of muscle movement characterized by:

• bradykinesia
• muscle rigidity
• resting tremor
• impairment of postural balance

Question 4

What does the final stage of PD look like?

Answer 4

a rigid, akinetic state in which patients are incapable of caring for themselves.

Question 5

Which neural pathways are involved in the development of PD?

Answer 5

• Indirect pathway (inhibits movement): in PD it is activated
• Direct Pathway (enables movement): in PD it is inhibited
• This results in reduced movement overall

Question 6

Describe the Indirect pathway in detail

Answer 6

Signals from putamen–>globus pallidus externa (GPe)–>subthalamic nuclei (STN)–>globus pallidus interna (GPi)–>thalamus–>cortex
-net effect: reduces excitatory outflow from thalamus to cerebral cortex

Question 7

Describe the direct pathway in detail

Answer 7

Signals from putamen to GPi to thalamus and then to cortex.

-net effect: increase the excitatory outflow from the thalamus to the cortex

Question 8

Degeneration of DA neurons in the substantia nigra results in…

Answer 8

• under stimulation of the direct (movement enabling) pathway and
• under inhibition of the indirect (movement inhibiting) pathway.
• The net result is the paucity (scarcity) of movement.

Question 9

What is the pharmacological strategy for treating PD?

Answer 9

Restoring DA levels in the brain or blocking the effect of ACh

Question 10

What classes of drugs are used for treatment of PD?

Answer 10

DA precursors, DA receptor agonists, inhibitors of DA metabolism, anticholinergic agents, amantadine

Question 11

What are the pharmacological properties of DA precursors?

Answer 11

• Levodopa/Carbidopa
• most effective agent for PD
• DA can’t cross BBB on its own
• Carbidopa inhibits AADC, preventing conversion of Levodopa to DA—> increase bioavailability in CNS
• Restores dopaminergic transmission by enhancing DA synth in surviving neurons of substantia nigra pars compacta

Question 12

What are the pharmacological properties of DA receptor agonists?

Answer 12

• enhance dopaminergic neurotransmission by activating postsynaptic DA receptors
• include ropinirole and pramipexole
• agonists for D2 and D3 receptors
• longer durations of action than levodopa (useful for fluctuations in levodopa use)
• less dyskinesia and motor fluctuations than levodopa therapy
• also used for restless leg syndrome

Question 13

List the drugs that function as inhibitors DA metabolism

Answer 13

MAOIs: selegiline and rasagiline

COMT inhibitors: tolcapone and entacapone

Question 14

What are the pharmacological properties of the MAOIs for PD?

Answer 14

• Selegiline and Rasagiline
• selectively and irreversibly inhibit MAO-B
• can be used alone or can potentiate effectiveness of levodopa therapy
• inhibit metabolism of dopamine in the striatum

Question 15

What are the pharmacological properties of COMT inhibitors for PD?

Answer 15

• Tolcapone and Entacapone
• inhibit COMT–>inhibit metabolism of levodopa and DA
• Tolcapone crosses BBB; Entacapone only in peripheral tissues

Question 16

What are the pharmacological properties of antimuscarinic agents?

Answer 16

• benztropine and Trihexiphenidyl
• block muscarinic receptors and reduce cholinergic tone in the CNS
• Act by modifying activity of striatal cholinergic interneurons that regulate direct and indirect pathways
• reduce tremor more than bradykinesia

Question 17

What is the MOA of amantadine for treatment of PD?

Answer 17

• increases DA release
• blocks cholinergic receptors
• blocks NMDA glutamate receptors (major pathway in PD)
• has little or no effect on tremor but works on bradykinesia and rigidity

Question 18

What is Alzheimer’s disease?

Answer 18

refers to dementia that does not have antecedent causes such as stroke, brain trauma or alcohol
-involves amyloid plaques and neurofibrillary tangles

Question 19

What is the consensus on amyloid plaques in AD?

Answer 19

Aβ accumulation is an upstream event that triggers tau pathology resulting in impaired neuronal function and cell loss.

Question 20

What is the neurochemistry of AD?

Answer 20

• deficiency of acetylcholine

- Atrophy and degeneration of subcortical cholinergic neurons especially those in the nucleus basalis of Meynert (NBM)

Question 21

What is the pharmacological classification of drugs used in the treatment of AD?

Answer 21

• Cholinesterase inhibitors (Rivastigmine, Donepezil, Galantamine)
• NMDA receptor antagonist (Memantine)

Question 22

What are the pharmacological strategies for treating AD?

Answer 22

• improving cholinergic transmission in the CNS

- preventing excitotoxic actions due to overstimulation of NMDA receptors

Question 23

What are the pharmacological properties of Donepezil?

Answer 23

• reversible acetylcholinesterase inhibitor

- metabolized by CYP2D6 and CYP3A4

Question 24

What are the pharmacological properties of Rivastigmine?

Answer 24

• reversible inhibitor of actylcholinesterase

- Also inhibits butyrylcholinesterase

Question 25

What are the pharmacological properties of Galantamine?

Answer 25

• reversible inhibitor of acetylcholinesterase

- metabolized by CYP2D6 and CYP3A4

Question 26

What are the pharmacological properties of Memantine?

Answer 26

• noncompetitive NMDA-type glutamate receptor antagonist

- interacts with Mg2+ binding site of channel to prevent excess activation