5.1 Dopaminergic Pathways & Anti Parkinson Drugs

Question 1

What are the 3 main dopaminergic pathways in the brain?

1. Nigrostriatal [Substantia nigra zona compacta (SNc) → striatum]: Control of ______________
2. Mesolimbic [Ventral tegmental area → : _______, __________, _______, ________]: Emotion/ environment sensing
3. Tubero-infundibular [Short neurones running from the __________ to median eminence and pituitary gland]: Regulate hormone secretion

Answer 1

movement ;

nucleus accumbens, frontal cortex, limbic cortex, olfactory tubercle;

arcuate nucleus of hypothalamus

Question 2

Dopamine has diverse functions in the brain with great potential for clinical benefit and side effects for drugs which manipulate any of these pathways:
• Synthesised from L-tyrosine, which is converted by _______________ into L-DOPA (rate-limiting step of biosynthetic pathway)
• L-DOPA is rapidly converted into dopamine by _______________
• Packaged into storage vesicles via the _____________ (safe from enzymatic breakdown within vesicles)
• Release of dopamine into the synapse occurs when a nerve impulse arrives at the presynaptic terminal → interacts with various postsynaptic dopaminergic receptors

Answer 2

tyrosine hydroxylase;

DOPA decarboxylase;

VMAT 2 uptake protein

Question 3

Dopamine has diverse functions in the brain with great potential for clinical benefit and side effects for drugs which manipulate any of these pathways:
• Synthesised from L-tyrosine, which is converted by _______________ into L-DOPA (rate-limiting step of biosynthetic pathway)
• L-DOPA is rapidly converted into dopamine by _______________
• Packaged into storage vesicles via the _____________ (safe from enzymatic breakdown within vesicles)
• Release of dopamine into the synapse occurs when a nerve impulse arrives at the presynaptic terminal → interacts with various postsynaptic dopaminergic receptors

After dopamine serves its functions, it is deactivated by reuptake systems into the nerve endings (via VMAT 1) and into adjacent astrocytes for breakdown.

Answer 3

tyrosine hydroxylase;

DOPA decarboxylase;

VMAT 2 uptake protein

Question 4

What are the receptors of the D2 family and what are the mechanisms?

Answer 4

Coupled to Gi (inhibits adenylyl cyclase → decreases [Ca2+])

Question 5

What are the 4 cardinal signs of Parkinson’s disease

Answer 5

• Rest tremor: Shaking of the limb when relaxed (tremor disappears when limb is in motion)
• Rigidity: Stiffness, heavy/weak feeling of limbs
• Bradykinesia: Slowness of movement
• Postural abnormality: Occurs later in the disease (e.g. forward tilt of trunk, reduced arm swinging, shuffling gait)

Question 6

Patients with Parkinson’s disease often present with the following motor symptoms:
• Pill-rolling rest tremor
• Poverty of blinking
• Impassive face (mask-like)
• Lack of arm swing
• Disorders of posture (flexion of ______________)
• Short steps, shuffling gait
• Monotony of speech and loss of volume of voice
• Difficulty with fine movements (___________ – small handwriting)
• Loss of balance (lack of righting reflex, retropulsion – difficulty terminating movement)

The onset of symptoms is often unilateral (on one side) then spreads to both sides with symptoms worsening over time (some patients become severely disabled terminally):
• Bilateral onset: often due to more severe Parkinson-like disorders (e.g. progressive supranuclear palsy, multiple system atrophy) → affects many areas of basal ganglia

Answer 6

neck and trunk;

micrographia

Question 7

Patients often also present with more general non-motor symptoms in Parkinson’s disease:
- Depression: Occurs in up to 50% of patients
- Pain: Occurs in ____________ (particularly in those with tremor) due to waste product build-up
- Taste/smell deficits: Complete/partial loss of smell very early on in the disease
- Cognitive deficits: Ranges from very slight cognitive decline to full-blown dementia early on in the disease
- Autonomic dysfunction
• Increased urinary frequency (urgency)
• Impotence (inability to reproduce)
• __________ (occurs well before motor symptoms)
• Increased sweating (__________)
• Postural (________________) hypotension

Answer 7

joints and limbs;

Constipation;

hyperhidrosis;

orthostatic

Question 8

The main pathology which produces loss of motor functions is the loss of dopaminergic neurones (normally projects to the ________________) in the substantia nigra:
• Aetiology of Parkinson’s disease is still not known
• Dopaminergic neurones contain ______________ which is an oxidative product of dopamine metabolism
• Marked depigmentation in the substantia nigra occurs due to the loss of dopaminergic fibres in patients with Parkinson’s disease
• Associated with Lewy bodies (darkly centred structure with a white halo around it) packed with altered proteins (_____________) → thought to be involved in vesicular trafficking/maintenance:
o May act as a defensive mechanism (sink/dustbin for altered proteins which are toxic to the body)
o Eventually, the altered bodies accumulate in the cell and trigger apoptosis

Answer 8

putamen and caudate nucleus;

neuromelanin (pigment);

α-synuclein;

Question 9

The main pathology which produces loss of motor functions is the loss of dopaminergic neurones (normally projects to the ________________) in the substantia nigra:
• Aetiology of Parkinson’s disease is still not known
• Dopaminergic neurones contain ______________ which is an oxidative product of dopamine metabolism
• Marked depigmentation in the substantia nigra occurs due to the loss of dopaminergic fibres in patients with Parkinson’s disease
• Associated with Lewy bodies (darkly centred structure with a white halo around it) packed with altered proteins (_____________) → thought to be involved in vesicular trafficking/maintenance:
o May act as a defensive mechanism (sink/dustbin for altered proteins which are toxic to the body)
o Eventually, the altered bodies accumulate in the cell and trigger apoptosis

Answer 9

putamen and caudate nucleus;

neuromelanin (pigment);

α-synuclein;

Question 10

The substantia nigra is part of the basal ganglia (important in transposing thoughts to action → e.g. thinking about moving a cup to actually moving the cup):
• Important role in dopamine release (controls activity of the basal ganglia loop) → allows for _____________________

Answer 10

fine tuning and termination of movement

Question 11

Other brain areas are also affected in Parkinson’s disease:

• _______________: Source of ascending noradrenergic neurones
• Cholinergic pathways: ________________ and ____________-

Answer 11

Locus cerules;

Dorsal vagal nucleus and nucleus basalis of Meynert

Question 12

Basal ganglia direct pathway: Runs directly from the _______________:
• Regulated by D1 receptors (stimulates direct pathway) → loss of dopaminergic input causes ____________ via D1 in Parkinson’s disease

Answer 12

putamen to the internal globus pallidus (GPi);

loss of stimulatory activity

Question 13

Basal ganglia indirect pathway: Passes through various nuclei (_________________) before reaching innervation centres (e.g. GPi):
• Regulated by D2 receptors (inhibits indirect pathway) → loss of dopaminergic input causes loss of inhibitory activity via D2 in Parkinson’s
• Results in hyperactivity (especially in the ________________)

Answer 13

external globus pallidus/GPe → subthalamic nucleus/STN;

glutamate pathways running from the STN to GPi

Question 14

Normally, there is a balance between the indirect and direct pathways, so that interpretation of cortical signals to move is possible, and these signals flow back through the motor cortex down the spinal cord to allow muscular movement:
• Parkinson’s disease: imbalance between the indirect and direct pathways → greater ___________ in inhibitory pathways → inhibits ________________
• Dopamine does not cause Parkinson’s disease → instead due to the imbalance induced by dopamine (due to lack of dopamine in other basal ganglia pathways)

Answer 14

release of glutamate;

initiation and control of movement via motor cortex and spinal cord

Question 15

There is a spread of α-synuclein within the brain in Parkinson’s disease beginning from the lower parts of the brainstem in 6 stages:

Pre-symptomatic phase (no motor symptoms)

• 1 & 2: Largely in the ______________
• 3: Major degeneration in the substantia nigra → worsening of this results in appearance of motor symptoms

Symptomatic phase (motor symptoms present)

• 4: Pathology spreads to ____________________
• 5 & 6: Spreads to _____________ → cognitive decline (may be very rapid)

Answer 15

lower parts of the brainstem (dorsal motor nucleus of vagus, raphe nucleus, locus cerules);

amygdala, nucleus of Meynert and hippocampus;

cortical areas of the brain

Question 16

Dopamine cannot be given as a treatment for Parkinson’s disease as it does not cross the blood-brain barrier:
• Can only cross at the ________________ (possesses a leaky blood-brain barrier) which acts as an early warning system in the brain for ingested toxins
• Giving dopamine induces nausea/vomiting → stimulates CTZ dopamine receptors

There are other drugs which may be given to treat Parkinson’s disease including:
• Dopamine replacement therapy (dopamine precursors)
• Dopamine agonists
• MAO-B inhibitors
• COMT inhibitors
• Amantadine
• Anticholinergic therapy

Answer 16

chemotactic trigger zone

Question 17

Dopamine precursors (e.g. L-DOPA) are given to increase production of dopamine:
• L-DOPA is given instead of tyrosine as DOPA decarboxylase works more quickly than tyrosine hydroxylase (rate-limiting)
• However, DOPA decarboxylase is also present in the peripheral tissues → if L-DOPA is administered alone, 95% is metabolised in the peripheral tissues:
o Activation of dopamine receptors of the CTZ → nausea & vomiting
• Often given together with _______________ that cannot cross the blood-brain barrier (only inhibits peripherally)

Answer 17

selective DOPA decarboxylase inhibitors (e.g. benserazide, carbidopa)

Question 18

What are the components of Sinamet?

Answer 18

Carbidopa + L-DOPA

Question 19

What are the components of Madopar?

Answer 19

Benserazide + L-DOPA

Question 20

L-DOPA is the gold standard drug for the treatment of Parkinson’s disease, and is useful in treating _________________ in newly diagnosed patients:
• Initiated at low doses before being increased until the maximum benefit is achieved without side effects
• Effectiveness of L-DOPA declines over time due to the loss of neurones with disease progression (intact neurones required for conversion of L-DOPA to dopamine)

Answer 20

hypokinesia, rigidity, and tremor

Question 21

Acute side effects of L- DOPA
1. Nausea (prevented by ___________ – peripherally acting dopamine antagonist acting in the CTZ)
2. Hypotension
3. Psychological effects (increased ________________ in other parts of the brain e.g. mesolimbic system → also uses dopamine)
• Schizophrenia-like syndrome (with delusions/hallucinations)
• Confusion/disorientation
• Nightmares

Answer 21

domperidone;

dopamine receptor activation

Question 22

Side effects of L-DOPA after 6 years
1. Dyskinesia (abnormal movements of the limbs and face in 54% of patients; may occur within 2 years of treatment)
• Resolved using _______________ → risk of reappearance of Parkinson’s disease symptoms
2. ________________ (rapid fluctuations in clinical state in 64%)
• On – drug is effective (symptoms suppressed)
• Off – symptoms resurface for minutes to hours

Answer 22

reduced L-DOPA doses;

On-off oscillations

Question 23

Dopamine agonists are ______________ (inducing inhibitory effects on the indirect pathway):
• 1st generation drugs (bromocriptine, pergolide) and 2nd generation drugs (__________)
• Longer duration of action than L-DOPA (due to longer half-life) → can be taken only once a day compared to 4 – 5 times daily for L-DOPA
o Smoother therapeutic profile with more sustained response
o Lower incidence of dyskinesia due to longer duration of action
• Actions are independent of dopaminergic neurones as they act directly on the dopaminergic receptors
• May be used as a __________________

Answer 23

D2-specific;

ropinerol;

monotherapy or given in conjunction with L-DOPA

Question 24

What are common side effects of dopamine agonists?

Answer 24

Confusion, dizziness, nausea/vomiting (CTZ), hallucinations (mesolimbic)

Question 25

What are side effects of dopamine agonist with an ergot structure?

Answer 25

Found in early phase dopamine agonists (e.g. bromocriptine):

• Problems with heart valves

Question 26

What are side effects of dopamine agonist with a non ergot structure?

Answer 26

Found in newer generation drugs (e.g. ropinerol):

• Addictive behaviours (e.g. gambling, compulsive tidying/washing of hands)

Question 27

Which of the following is an irreversible selective inhibitor of MAO- B and 5 times more potent than the other? Deprenyl (Seligiline)/ Rasagiline

Answer 27

Rasagiline

Question 28

What is Deprenyl (Selegiline) metabolised into?

Answer 28

methamphetamine and amphetamine

Question 29

What is Rasagiline metabolised by?

Answer 29

hepatic CYP1A2 (contraindicated in hepatic insufficiency)

Question 30

What are the side effects of Deprenyl?

Answer 30

• Severe hypertension (at high doses due to loss of selectivity)
• Insomnia (if administered after late-afternoon; due to metabolism into methamphetamine and amphetamine)

Question 31

What are the side effects of Rasagiline?

Answer 31

Flu-like symptoms, joint pain, depression, stomach upset, headaches, dizziness
*Risk of hypertensive crisis if used with other MAO inhibitors (non-selective MAO inhibition)

Question 32

COMT inhibitors (-capones) act in a similar way to MAO-B inhibitors, by inhibiting the enzymes responsible for metabolism of dopamine to increase dopamine levels:
• In the CNS, inhibition of COMT prevents dopamine breakdown in the brain, but most clinical benefit results from ___________________
• Peripheral COMT converts L-DOPA to ________________, which competes with L-DOPA for the same transport system across the blood-brain barrier:
o COMT inhibitors stop 3-OMD formation, increasing the penetration of L-DOPA across the blood-brain barrier, increasing brain concentrations
o Allows _________________ (especially useful in patients who exhibit motor fluctuations/on-off fluctuations)
• Side effects: _________________

Answer 32

peripheral inhibition of COMT ;

3-O-methyl-DOPA (3-OMD);

reduction of L-DOPA dosage ;

cardiovascular complications (contraindicated in patients with underlying cardiovascular problems → may cause death)

Question 33

What is the mechanism by which Amantadine helps with Parkinson?

Answer 33

• Increases the amount of dopamine released per nerve impulse
• Prevents dopamine reuptake
• Glutamate antagonist (helps to block the effects of increased glutamate from STN during imbalance of direct and indirect pathways in the basal ganglia)

Question 34

What are the uses of Amantadine?

Answer 34

• Treatment of influenza
• Parkinson’s disease (bradykinesia, rigidity, tremor to lesser extent)
• Elevation of mood (antidepressant)

Question 35

What are the limitations of Amantadine?

Answer 35

Tolerance to amantadine can develop → only given for limited amounts of time (as an alternative where other drug treatments are failing in a Parkinson’s patients)

Question 36

____________________ are the 2 main anticholinergic agents used to treat tremors in Parkinson’s disease (less efficacious; used as adjunct):
• Dopamine acts as an inhibitory transmitter on cholinergic neurones in the striatum → loss of dopaminergic input into the striatum and loss of dopamine in Parkinson’s leads to increased cholinergic neuronal activity
• Partially linked to the generation of tremor in Parkinson’s patients → effective in some patients at controlling tremors
• Side effects: worsening cognitive decline (due to cholinergic deficits in the cortex) → contraindicated in patients with _____________________ etc.

Answer 36

Procyclidine and trihexyphenidyl;

cognitive decline, mood changes, xerostomia

Question 37

In a parkinson patient with psychological features, what are the guidelines?

Answer 37

Avoid dopamine agonists (will worsen features)

Question 38

In a parkinson patient with mild symptoms, what is the guideline?

Answer 38

MAO-B inhibitor (Rasagiline) monotherapy

Question 39

In a young parkinson patient with mild symptoms and wishe to continue working, what is the guideline?

Answer 39

L-DOPA (start at low doses then increase slowly until maximum benefit without side effects) → best for maximal restoration of motor function
• As disease progresses, L-DOPA response decreases
• Increase L-DOPA dosage or add MAO-B inhibitor (preserves dopamine synthesised from L-DOPA)
• Severe side effects to L-DOPA (e.g. dyskinesia): reduce L-DOPA dosage AND add dopamine agonist or COMT inhibitor (streamlines delivery of L-DOPA into brain)
• Severe side effects to dopamine agonist and COMT inhibitors/level of disability too great: give infusible drugs (e.g. apomorphine – powerful dopamine agonist)

Question 40

Deep brain stimulation is a non-drug treatment which is gaining popularity, involving surgery for implantation of electrodes and post-surgical activation:
• Only one-third of patients are suitable for surgery (only worth considering where drug therapy is starting to fail as surgery poses its own set of risks as well)

The loss of dopamine from the substantia nigra releasing into the putamen causes an imbalance between the direct (diminished) and indirect (overactive) pathways:
• Overactivity of glutamate pathways from the ____________ and projecting to the _________ leads to increased ______________ transmission → inhibits movement flowing out of the motor cortex
• Subthalamic nucleus is targeted in deep brain stimulation → helps to dampen down glutamate activity and alleviate Parkinsonian symptoms at certain frequencies

Answer 40

subthalamic nucleus;

GPi and SNr;

GABAergic