Levodopa Treatment Insights

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Questions and Answers

What are the acute common side effects of levodopa?

Delusions and sleep disturbances

Confusion and agitation

Nausea and dizziness (correct)

Insomnia and hallucinations

Which psychological effects are more common in older patients taking levodopa?

Nausea and hallucinations

Agitation and confusion (correct)

Sleepiness and dizziness

Delusions and insomnia

What percentage of patients may never respond to levodopa treatment?

25%

30%

15% (correct)

50%

What is a long-term effect associated with levodopa treatment?

Dyskinesias in many patients Signup and view all the answers

What change in effectiveness of levodopa treatment is observed after 5 years?

1/3 still respond, while 2/3 show decreased response Signup and view all the answers

What are dyskinesias primarily characterized by?

Rapid jerking or slow muscle spasms Signup and view all the answers

What is a consequence of long-term levodopa therapy in relation to dopamine receptors?

Downregulation of D1 and D3 receptors Signup and view all the answers

What does dopamine dysregulation syndrome (DDS) involve?

Addictive patterns of dopamine therapy use Signup and view all the answers

Which regions of the body are affected by dyskinesias?

Limbs, trunk, tongue, and orofacial regions Signup and view all the answers

Which statement regarding dopamine transmission after long-term levodopa treatment is true?

Dopamine transmission is further decreased Signup and view all the answers

What is the primary benefit of using MAO-B inhibitors in the treatment of Parkinson's disease?

They prevent the breakdown of dopamine secreted by dopaminergic neurons. Signup and view all the answers

Which of the following adverse effects is associated with the use of MAO-B inhibitors?

Nausea and dyskinesia Signup and view all the answers

What is an important dietary consideration when taking MAO-B inhibitors?

Avoid tyramine containing foods. Signup and view all the answers

What is the most common age of onset for Parkinson's disease?

57 years Signup and view all the answers

Which of the following statements is true regarding the demographics of Parkinson's disease?

It is 1.5 times more common in men. Signup and view all the answers

What characterizes the neurodegenerative disorder Parkinson's disease?

It is a chronic progressive neurological disorder. Signup and view all the answers

What type of drugs are used as COMT inhibitors in Parkinson's treatment?

Drugs that inhibit the action of catechol-O-methyltransferase. Signup and view all the answers

Which of the following describes a potential risk associated with Stalevo® treatment?

Cardiovascular risk. Signup and view all the answers

What is a key advantage of dopamine agonists in late progression of Parkinson's Disease (PD)?

They can be used without needing intact dopamine terminals. Signup and view all the answers

What does Apomorphine primarily help with in patients experiencing off episodes?

It improves symptoms during an existing off episode. Signup and view all the answers

Which of the following describes a common adverse effect associated with dopamine agonists?

Impulse control disorders. Signup and view all the answers

Why might younger patients prefer dopamine agonists over L-dopa?

Dopamine agonists have a longer half-life and fewer motor complications. Signup and view all the answers

What is one of the main reasons patients may discontinue dopamine agonists?

They experience more adverse effects compared to L-dopa. Signup and view all the answers

What is the significance of dopamine agonist withdrawal syndrome?

It necessitates a tapered dose reduction and monitoring for depression. Signup and view all the answers

How do centrally acting antimuscarinic preparations differ?

They vary in their potency and efficacy among different patients. Signup and view all the answers

In the context of L-DOPA's effectiveness, what is necessary for L-DOPA to be synthesized into dopamine?

Nerve terminals. Signup and view all the answers

What is the primary mechanism of NMDA receptor antagonists like Memantine?

Block NMDA receptors to prevent calcium influx Signup and view all the answers

Which condition is primarily treated with the drug Riluzole?

Amyotrophic Lateral Sclerosis (ALS) Signup and view all the answers

What is a common adverse effect associated with the drug Memantine?

Dizziness Signup and view all the answers

Which drug is likely used off-label for neurodegenerative diseases?

Perampanel Signup and view all the answers

How does Riluzole enhance glutamate reuptake?

By activating EAAT-1 Signup and view all the answers

What is one likely adverse effect of using Riluzole?

Nausea Signup and view all the answers

Which of the following drugs primarily targets excitatory neurotransmission?

Perampanel Signup and view all the answers

What is the approval status of Riluzole in the UK?

Approved Signup and view all the answers

What is the primary effect of COMT inhibitors such as entacapone and tolcapone?

They extend the action of Levodopa. Signup and view all the answers

What type of therapy is Amantadine primarily associated with?

Reducing dyskinesia associated with Levodopa. Signup and view all the answers

What is the intended use of anticholinergics in Parkinson's disease?

To inhibit acetylcholine activity. Signup and view all the answers

Which of the following is a criterion to consider deep brain stimulation in Parkinson's disease?

Presence of motor off fluctuations. Signup and view all the answers

Which first-line medication is commonly used for Parkinson's disease symptom control?

Levodopa plus Dopa Decarboxylase Inhibitor. Signup and view all the answers

What effect does deep brain stimulation have over time?

It becomes less effective as neuronal degeneration occurs. Signup and view all the answers

What is a characteristic side effect associated with Levodopa treatment?

Dyskinesia. Signup and view all the answers

Which factor does NOT influence the choice of medication for Parkinson's disease?

Historical family preferences. Signup and view all the answers

What is a key characteristic of MAO-B inhibitors in Parkinson's disease treatment?

They have limited efficacy with fewer side effects. Signup and view all the answers

What is the overall efficacy of anticholinergics in treating Parkinson’s disease?

Minor effect on symptoms. Signup and view all the answers

Neural transplantation aims to address which problem in Parkinson's disease?

Increasing neurotransmitter synthesis. Signup and view all the answers

Why are dopamine agonists considered a preferable choice in some cases for Parkinson's disease therapy?

They pose a lower risk of motor side effects compared to Levodopa. Signup and view all the answers

Which statement about gene therapy in Parkinson's disease is true?

It aims to increase neurotransmitter synthesis. Signup and view all the answers

What is a common side effect of levodopa that is often minimized by starting with a low dose?

Dizziness Signup and view all the answers

What neurological effect can occur in patients due to long-term use of levodopa?

Hallucinations Signup and view all the answers

Which of the following statements is true regarding the response to levodopa treatment over time?

15% of patients may never respond to levodopa treatment. Signup and view all the answers

What percentage of patients may experience a decrease in response to levodopa after five years?

67% Signup and view all the answers

Which of the following adverse effects is less common in patients older than 65 taking levodopa?

Agitation Signup and view all the answers

What long-term change occurs to dopamine receptors in patients receiving levodopa treatment?

Sequestration of receptors Signup and view all the answers

What is the primary characteristic of dopamine dysregulation syndrome (DDS) in patients undergoing treatment?

Addictive pattern of dopamine replacement therapy use Signup and view all the answers

Which abnormal movements are primarily associated with dyskinesias?

Rapid jerking or slow muscle spasms Signup and view all the answers

What effect does downregulation of dopamine receptors in the nigrostriatal system have?

Decreased dopamine transmission Signup and view all the answers

What type of muscle movements are affected by dyskinesias?

Movements in limbs, trunk, and orofacial areas Signup and view all the answers

What primary function does carbidopa serve when used alongside levodopa?

Inhibits DOPA decarboxylase in the periphery Signup and view all the answers

Which characteristic describes the mechanism of action of MAO-B inhibitors?

Inhibits the breakdown of dopamine Signup and view all the answers

In which context can dopamine agonists be considered particularly beneficial?

In early stages or as adjunct therapy with levodopa Signup and view all the answers

What is a noted limitation of using levodopa as a long-term treatment?

Efficacy may decrease over time with long-term use Signup and view all the answers

Which of the following accurately describes levodopa's mechanism of action?

Crosses the blood-brain barrier and converts to dopamine Signup and view all the answers

What type of effects does deep brain stimulation primarily target in Parkinson's disease treatment?

Altered activity in brain regions associated with motion control Signup and view all the answers

Which drug class does NOT have the primary function to reduce peripheral side effects of levodopa?

Anticholinergics Signup and view all the answers

What is a common therapeutic approach when using dopamine agonists?

Combine with other therapies for advanced stages Signup and view all the answers

Which of the following describes the common mechanism of action of MAO-B inhibitors in treating Parkinson's disease?

Prevent breakdown of dopamine Signup and view all the answers

What is a significant concern associated with the use of tolcapone as a COMT inhibitor in Parkinson's disease treatment?

Potential for severe hepatic toxicity Signup and view all the answers

Which of the following is a recognized adverse effect of MAO-B inhibitors?

Orthostatic hypotension Signup and view all the answers

In Parkinson's disease, why are tyramine-containing foods a concern for patients taking MAO-B inhibitors?

They risk inducing serotonin syndrome Signup and view all the answers

What characterizes Parkinson's disease in terms of its prevalence?

Second most common neurodegenerative disorder Signup and view all the answers

Which demographic factor significantly influences the prevalence of Parkinson's disease?

Gender, with higher rates in men Signup and view all the answers

What is a potential risk associated with the combined therapy using Stalevo®?

Higher incidence of cardiovascular events Signup and view all the answers

Which of the following statements is true regarding the adverse effects of MAO-B inhibitors?

Dyskinesia is a potential side effect Signup and view all the answers

What is the mechanism of action of NMDA receptor antagonists such as Memantine?

Block NMDA receptors to reduce calcium influx Signup and view all the answers

Which drug specifically inhibits the presynaptic release of glutamate?

Riluzole Signup and view all the answers

What is a common adverse effect associated with the use of Riluzole?

Elevated liver enzymes Signup and view all the answers

In what condition is the drug Perampanel likely used off-label?

Parkinson's Disease Signup and view all the answers

What specific mechanism does Riluzole employ to enhance glutamate reuptake?

Activation of EAAT-1 Signup and view all the answers

Which of the following drugs is approved in the UK for the treatment of Amyotrophic Lateral Sclerosis (ALS)?

Riluzole Signup and view all the answers

What side effect is likely encountered with the use of AMPA receptor antagonists like Perampanel?

Drowsiness Signup and view all the answers

Which of the following conditions is primarily indicated for treatment with Memantine?

Dementia with Lewy bodies Signup and view all the answers

What is the primary action of COMT inhibitors like entacapone and tolcapone in Parkinson's disease management?

They prolong the action of Levodopa. Signup and view all the answers

Which of the following is a characteristic of deep brain stimulation (DBS) in Parkinson's disease treatment?

DBS may become less effective over time due to neuron degeneration. Signup and view all the answers

In what scenario is deep brain stimulation considered for a Parkinson’s disease patient?

Presence of tremor unresponsive to medication. Signup and view all the answers

What is the main indication for using amantadine in Parkinson's disease treatment?

To reduce dyskinesia associated with Levodopa use. Signup and view all the answers

Which type of medication is usually not a first-line treatment option for Parkinson’s disease?

Anticholinergics. Signup and view all the answers

What is one key downside of using deep brain stimulation over time?

Effectiveness diminishes due to neuronal degeneration. Signup and view all the answers

Which of the following is a crucial consideration when planning the initial treatment strategy for Parkinson's disease?

Personalizing treatment based on patient-specific factors. Signup and view all the answers

What is the expected degree of symptom control when using Levodopa in early Parkinson's disease treatment?

Good degree of symptom control. Signup and view all the answers

What is a primary aim of gene therapy in Parkinson's disease management?

To increase neurotransmitter synthesis and growth factors. Signup and view all the answers

What role does GABA play in the pathophysiology related to Parkinson's disease?

GABA inhibits both motor and cognitive functions. Signup and view all the answers

Which first-line medication strategy is NOT typically employed for controlling Parkinson's symptoms?

Multi-drug regimen from the onset. Signup and view all the answers

Which of the following accurately describes the effectiveness of anticholinergics in treating Parkinson's disease?

Limited and often associated with anticholinergic effects. Signup and view all the answers

Study Notes

Course Information

Class: Year 2
Course Code: CNS
Title: MCT - Pharmacology of Anti-Parkinsonian and Antidementia Drugs
Lecturer: Colin Greengrass, Ph.D.
Date: December 2023
Institution: RCSI

Learning Objectives

Describe the mechanism of action and adverse effects of drugs targeting cholinergic neurotransmission in neurodegenerative disease.
Describe the mechanism of action and adverse effects of drugs targeting dopaminergic neurotransmission in neurodegenerative disease.
Describe the mechanism of action and adverse effects of drugs targeting protein aggregation in neurodegenerative disease.
Describe the mechanism of action and adverse effects of drugs targeting excitotoxicity in neurodegenerative diseases.

Parkinson's Disease

Chronic progressive neurological disorder.
Second most common neurodegenerative disorder after Alzheimer's disease.
1.5 times more common in men.
Mean age of onset is 57 years.
Often idiopathic (cause unknown).
Possible causes: neurotoxins, familial, early onset (<50 years) often inherited.

Parkinson's Disease - Motor Symptoms

Unilateral in early stages, bilateral as disease progresses.
Bradykinesia (slowness of movement).
Hypokinesia (poverty of movement).
Stiffness or rigidity.
4-6Hz tremor when at rest.

Non-Motor Symptoms of Parkinson's Disease

Depression.
Anxiety.
Fatigue.
Reduced sense of smell.
Cognitive impairment.
Sleep disturbance.
Constipation.

Parkinson's Disease - Pathophysiology

Loss of 60-80% of neurons can occur before the disease is clinically apparent.
Dopamine neurons in the substantia nigra are pigmented black due to neuromelanin.
During PD progression, dopamine production and storage are gradually lost.
This leads to mild symptoms that develop into significant incapacity.

Parkinson's Disease - Dopamine Deficiency

Deficient transmission in the nigrostriatal pathway.
Dopamine is the major neurotransmitter in the pathway.
Dopamine content of the substantia nigra and corpus striatum is less than 10% of normal in post-mortem brains.
Disorder affects other brain structures, including brainstem, hippocampus, and cerebral cortex (non-motor symptoms).

Normal Function in Nigrostriatal Circuitry

The cortex has glutamatergic input.
Muscarinic receptors (M1 and M2) and cholinergic are involved.
Dopaminergic receptors (D1 and D2) are also present.
GABAergic neurons inhibit motor and cognitive function.

Levodopa (L-DOPA)

Mainstay of Parkinson's treatment.
Inactive precursor of dopamine.
Dopamine cannot cross the blood-brain barrier (BBB).
Levodopa can cross the BBB.
Levodopa crosses into the neuron, increasing precursor concentration for dopamine synthesis inside the neuron.
Levodopa is metabolized centrally and peripherally.
Peripheral metabolism needs to be inhibited to increase brain concentration.

Treatment Strategies for Parkinson's

Dopamine agonists increase dopamine transmission.
Muscarinic cholinergic antagonists are also used.
Using dopamine agonists or to increase the dopamine transmission or by using muscarinic cholinergic antagonists.
Inhibiting the breakdown of dopamine by MAO-B or COMT inhibitors.
DDC inhibitors (e.g., carbidopa/benserazide) - block the breakdown of levodopa outside the brain to increase levodopa in the brain thus decreasing peripheral bioavailability.
COMT inhibitors (e.g., entacapone/tolcapone) inhibit dopamine breakdown in the brain.

First Endpoint in Parkinson's Treatment

Eventually, the degeneration of the nigrostriatal pathway can be so extensive that increasing dopamine no longer works.
Dopamine agonists are used at D1 and D2 receptors to compensate.

Second Endpoint in Parkinson's Treatment

Dopamine receptor downregulation can occur and dopamine agonists become ineffective.
A drug holiday may be attempted.

Dopamine Synthesis

Dopamine synthesis only occurs within dopaminergic neurons.
Tyrosine is converted to L-DOPA and then to dopamine.

Dopamine Neurotransmission

Dopamine is synthesised in the cytoplasm.
Transported to secretory vesicles using VMAT.
Dopamine stimulation of post-synaptic receptors and pre-synaptic autocrine receptors occurs during release.
Dopamine is removed from the synaptic cleft by the dopamine transporter (DAT).
Dopamine in the terminal is degraded by COMT (catechol-O-methyltransferase) or MAO (monoamine oxidase).
Dopamine is transported back into secretory vesicles by VMAT.

Action of Dopamine Inhibition

Lack of dopamine precursors.
Reuptake of dopamine through DA transporters (DAT).
Breakdown of dopamine by MAO and COMT (outside brain).

Drug Targets for Increasing Dopamine Neurotransmission

Increasing the DA precursor.
Blocking the reuptake of dopamine through DA transporters.
Blocking the breakdown of dopamine by MAO or COMT.
Using dopamine receptor agonists.

Other Treatment Options in PD

Amantadine: Originally anti-viral, it increases dopamine release, blocks NMDA receptors, and reduces levodopa-induced dyskinesia in advanced disease.

Deep Brain Stimulation

Chronic deep brain stimulation using an implanted electrode.
The electrode is implanted into the STN or GPi.
Connected to a pulse generator to deliver controlled electrical pulses.

Question 1

Last PD therapy with efficacy: Dopamine Agonists.

Question 2

Possible therapeutic target for Deep Brain Stimulation: Dopamine Agonists.

Pathogenesis of Alzheimer's Disease

Associated with brain shrinkage and loss of neurons, especially in the hippocampus and basal forebrain.
Loss of cholinergic neurons in hippocampus and frontal cortex is a feature of the disease.
Believed to contribute to short-term memory loss.
Two microscopic features are characteristic of the disease: extracellular amyloid plaques, and intraneuronal neurofibrillary tangles.
These are protein aggregates from misfolding of native proteins.
Tau dissociates from microtubules and is deposited intracellularly, aggregating as neurofibrillary tangles.
Amyloid plaques are thought to be a result of overproduced fragments of APP (Amyloid Precursor Protein).

Alzheimer's Disease - Prevalence

Rises sharply with age, up to 20% in patients aged 85-89.
Common symptoms: difficulty remembering names/recent events, loss of executive function, apathy, and depression.

Current Pharmacological Therapy for Alzheimer's Disease

Loss of cholinergic neurons and decreased nicotinic receptor density in the cortex is characteristic.
Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine) are used to address loss of cholinergic neurotransmission.
Modest cognitive improvement.
Cholinergic side effects (e.g., nausea, anorexia, vomiting, diarrhea).

NMDA Antagonists (Memantine)

Mechanism: Non-competitive antagonist at NMDA receptors.
Prevents excessive calcium influx from abnormal glutamate activity.
Protects neurons from excitotoxicity, potentially slowing neurodegeneration and preserving cognitive functions.
Adverse Effects: Dizziness, headache, constipation, confusion.
Clinical use: moderate to severe Alzheimer's Disease.

Aducanumab and Lecanemab -Anti-Amyloid Monoclonal Antibodies

Therapy aims to reduce amyloid burden and slow disease progression.
Aducanumab (2021): Targets both soluble and insoluble fibrillar forms of amyloid beta(Aβ); shown to reduce plaque.
Lecanemab (2023): Primarily targets soluble Aβ oligomers; shown to have a significant slowing effect on the clinical rating scale in early AD.
Likely not effective in later stage due to extensive amyloid plaque buildup.

Excitotoxicity and Neurodegeneration

Excitotoxicity is caused by the over-activation of receptors for the excitatory neurotransmitter glutamate.
Leads to excessive calcium influx into neurons, resulting in neuronal damage or death.
Several diseases are linked to excitotoxicity (e.g., Alzheimer's, ALS, Huntington's, Parkinson's, multiple sclerosis, prion diseases).

Bibliography

A list of relevant books is presented.

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Description

Test your knowledge on the effects of levodopa, commonly prescribed for Parkinson's disease. This quiz covers acute side effects, psychological impacts in older patients, and response rates to treatment. Dive into the long-term effects and changes in effectiveness after prolonged use.