Drugs for Parkinson’s disease
1. Parkinson's disease
- neurological disorder that results in a progressive loss of coordination and movement.
- neurons responsible for coordinating movement are located in a part of the brain called the striatum, which receives information from two major sources
- neocortex: relays sensory information & plans for future action
- substantia nigra: sends dopamine that helps to coordinate all of the inputs
- Parkinson’s disease develops when the neurons connecting the substantia nigra to the striatum progressively degenerate
- Dopaminergic neurons that originate in the substantia nigra
- exert inhibitory effects on GABA neurons located in the striatum
- too little dopamine results in more GABA
- causing increased inhibition of the thalamus & reduced excitatory input to the motor cortex
- exert inhibitory effects on the excitatory cholinergic neurons in the striatum
Without sufficient levels of dopamine the production of acetylcholine is increased, which triggers a chain of abnormal signaling leading to impaired mobility.
Ultimately this imbalance between inhibitory and excitatory activities leads to the manifestation of typical clinical symptoms that include
- resting tremor
- rigidity
- postural instability
- slowed movement.
The pharmacological therapy for Parkinson’s disease is aimed at
- replenishing dopamine levels
- mimicking dopamine’s action
- antagonizing the excitatory effects of cholinergic neurons.
2. Dopaminergic neuron
Inside this dopaminergic neuron, dopamine is synthesized in a two-step process
- starting with the amino acid tyrosine.
- First, with the help of enzyme tyrosine hydroxylase (TH), tyrosine gets converted to L-dopa, also known as levodopa.
- Second, the L-dopa formed by tyrosine hydroxylation is quickly decarboxylated by aromatic L-amino acid decarboxylase (AADC), to the neurotransmitter dopamine.
- Dopamine is then loaded into synaptic vesicles
- released by physiological stimuli into the extracellular space where it can bind to dopamine receptors that are expressed on the postsynaptic neuron
- excess dopamine in the synapse is reuptaken back into the neuron, or into glial cells
- metabolized by Monoamine Oxidase (MAO) and Catechol-O-methyltransferase (COMT).
- MAO enzyme exists in two forms: type A and type B
- found in the glial cells is the MAO type B
3. Drug
a. Levodopa
- Problem: peripheral metabolism
- Two major enzymes in periphery, which cause breakdown of levodopa before it can reach the brain
- Peripheral dopa- decarboxylase (DDC): converts levodopa to dopamine
- Catechol- O- methyltransferase (COMT): converts levodopa to 3-O-methyldopa (3-OMD)
- Hence, Levodopa must be administered with Carbidopa, which inhibits dopamine decarboxylase and thus reduces metabolism of Levodopa in the periphery.
- Used in combination with Levodopa and Carbidopa is Entacapone, which inhibits peripheral COMT and prolongs the time that Levodopa is available to the brain.
Levodopa is carried across blood-brain barrier by amino acid transporter.
- Once inside the brain, Levodopa is efficiently converted to dopamine
- thus supplementing depleted dopamine levels in the midbrain.
- However, dopamine is also susceptible to breakdown by
- COMT: convert to 3-methoxytyramine (3-MT)
- Drug: Tolcapone: inhibits COMT
- MAO-B: convert to 3,4dihydroxyphenylacetic acid (DOPAC)
- Drug: Selegiline & Rasagiline: selectively inhibit MAO-B
Note: In comparison to Entacapone, Tolcapone can better penetrate the blood–brain barrier, and thus can act both in the central nervous system and in the periphery.
By decreasing the metabolism of dopamine, these drugs help to increase dopamine levels in the brain.
Why use the precursor of Dopamine (Levodopa) instead of Dopamine?
Blood-brain barrier is a tightly packed layer of endothelial cells that restricts free access of molecules between the blood and the brain.
Dopamine cannot freely pass through this barrier, but Levodopa can.
b. Drug that mimic dopamine
- Parkinson’s is a progressive disease.
- With time, the number of dopamine producing neurons decreases, and fewer cells are capable of making dopamine.
- Some drugs have been developed to mimic dopamine and directly stimulate dopamine receptors in the brain.
- Drug:
- Bromocriptine
- Ropinirole
- Pramipexole
- Rotigotine
- Apomorphine
c. Antimuscarinic agents
- Dopamine depletion leads to increased acetylcholine release
- then activates muscarinic receptors located on the neurons responsible for smooth motor control
- The overstimulation of these neurons by acetylcholine then causes tremors and rigidity.
- Drug:
- Benztropine
- Biperiden
- Procyclidine
- Trihexyphenidyl
- blocking the muscarinic acetylcholine receptors and cholinergic nerve activity
- restore the balance between acetylcholine and dopamine
- may improve the symptoms of Parkinson's disease.
d. Amantadine
- Mechanism of action is poorly understood
- Speculated:
- prevents dopamine reuptake
- facilitates presynaptic dopamine release
- blocks glutamate NMDA receptors
4. Side effects
Levodopa & Carbidopa
- nausea,
- loss of appetite
- hypotension
- mental disturbances
- discoloration of urine, sweat or saliva
Selegiline and Rasagiline
- nausea
- insomnia
- dyskinesia
- visual hallucinations
Entacapone and Tolcapone
- discoloration of urine, sweat or saliva
- diarrhea
- get severe particularly with the use of Tolcapone
Tolcapone
- liver toxicity
All dopamine agonists
- nausea
- orthostatic hypotension
- mental disturbances
- daytime sleepiness
Bromocriptine
- pulmonary and cardiac fibrosis
Drugs that block muscarinic receptors
- anticholinergic side effects such as
- constipation
- urinary retention
- dry mouth
- blurred vision.
5. Reference
https://youtu.be/Z84iypHdftQ
Related link:
【Neuro】Pesticides-induced Parkinson’s Disease
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