Treatment of Parkinson's disease

Signs of Parkinsonism

Tremor at rest

Rigidity

Akinesia or bradykinesia

Postural instability/disturbances

What does the Nigrostriatal pathway do?

Connects substantia nigra to dorsal striatum of basal ganglia

Associated with movement control:

• Excites the direct pathway via stimulation of D1 receptors

• Inhibits the indirect pathway via stimulation of D2 receptors

Explain dopamine synthesis

L-tyrosine (first precursor) is converted to L-DOPA via tyrosine hydroxylase

L-DOPA crosses the blood brain barrier (BBB)

L-DOPA is then converted to dopamine via DOPA decarboxylase

Dopamine is packaged and stored in synaptic vesicles by vesicular monoamine transporter (VMAT) and when released binds to post-synaptic dopamine receptors

Dopamine is broken down into inactive metabolites by:

• Monoamine oxidase (MAO) →MAO-A and MAO-B

• Catechol-O-methyl transferase (COMT) (also involved in peripheral degradation of L-DOPA)

• Aldehyde dehydrogenase (ALDH)

** enzymes

What type of neurotransmitter is dopamine?

Catecholamines

** same as adrenaline and noradrenaline

How do D1-like and D2-like receptors work?

D1-like receptors:

• Comprising D1 and D5 subtypes

• Increase intracellular levels of cAMP by activating adenylate cyclase

D2-like receptors:

• Comprising D2, D3, and D4 subtypes

• Decrease intracellular levels of cAMP by inhibiting adenylate cyclase

General Pharmacological Management Advice for anti-Parkinsonian medication

Anti-Parkinsonian medications are ‘critical medications’ and are time- sensitive

Patients who miss doses or receive late doses could experience akinesia (freezing)

Suddenly stopping PD medications may also precipitate neuroleptic malignant syndrome, which can be life-threatening

First-line management of Parkinsonian motor symptoms

• Levodopa (if motor symptoms affect quality of life)

• Dopamine (receptor) agonists (if motor symptoms DON’T affect quality of life)

• MAO-B inhibitors (if motor symptoms DON’T affect quality of life)

Adjuvant treatments of motor symptoms:

• COMT inhibitors

• Amantadine

How does levodopa work?

Similar to the precursor L-DOPA → increase L-DOPA

Levodopa can cross the BBB, allowing for central conversion to dopamine in the CNS

Absorption: well absorbed in small intestine, specifically duodenum

** effectivness dcreaeses with time

What else do you need to prescribe with Levodopa and why?

only 1% of administered levodopa will cross the BBB → so will also have peripheral conversion → causes side effects (i.e. nausea, hypotension)

To counteract this it is given with a dopa decarboxylase inhibitor: Carbidopa / Benserazide

→ Allows for more availability of levodopa in CNS and so lower doses can be used

→ Also reduces peripheral side effects

Adverse effects of levodopa

‘On-Off Phenomenon’ (Rapid Fluctuations in Clinical State):

May have sudden worsening of bradykinesia and rigidity → can last from few minutes to a few hours, then improve again

** Likely related to fluctuating plasma concentration of levodopa

May get hyperkinetic movements: chorea, dystonia, and athetosis (when levodopa levels are high)

Psychiatric Disturbances: Manifests as schizophrenia-like syndrome with delusions and hallucinations + may also have confusion, disorientation, insomnia or nightmares

Peripheral Side Effects: nausea, vomiting and orthostatic hypotension

How do Dopamine Agonists work?

Stimulates postsynaptic D2 dopamine receptors in the corpus striatum, allowing for normal control of movement via the basal ganglia

Bypasses the need for dopamine

Absorption: absorbed in GI tract, metabolised by liver

** Less motor complications but also less effective than levodopa

What are the 2 Types of Dopamine Agonist and which ones are preferred and why?

Preferred: Non-ergoline Derivatives eg. Bromocriptine, Pergolide, Lisuride, Cabergoline

→ Higher affinity and selectivity for D2-like receptors, little/no interaction with other neurotransmitter receptors

NOT preferred: Ergoline Derivatives eg. Pramipexole, Ropinirole, Rotigotine, Apomorphine

→ less selective

→ more adverse effects: Nausea and vomiting, hallucinations, somnolence + serious risk of developing cardiovalvular, pleuropulmonary, and retroperitoneal fibrosis

Adverse effects of Non-ergoline Derivatives of Dopamine Agonists

• Somnolence

• Hallucinations

• Compulsive behaviours/impulse control disorders: compulsive gambling, compulsive shopping, hypersexuality, and binge eating

→ associated with both dosage and duration of treatment with dopamine agonists

How do MAO-B Inhibitors work?

Inhibits the activity of MAO-B → allows for longer/ more availability of dopamine within the CNS

Absorption: metabolised by liver

** less effective than levodopa

Name some MAO-B Inhibitors

Irreversible MAO-B inhibitors:

• Selegiline

• Rasagiline

Reversible MAO-B inhibitors:

• Safinamide

Adverse effects of MAO-B Inhibitors

Tyramine effect:

An interaction with tyramine, amino acid found in certain foods, can cause rapid and severe increase in blood pressure known as a hypertensive crisis

→ now they are more selective so not as prevelant but longer use increases the chance

Tyramine-rich foods:

• Aged cheeses

• Cured or smoked meats

• Pickled foods

• Some fermented products like sauerkraut and soy sauce

Other symptoms:

• Nausea

• Light headedness

• Confusion or hallucinations

How do COMT Inhibitors work?

** Adjuvant treatment for those who have developed dyskinesia or motor fluctuations despite optimal levodopa therapy → used in combination with levodopa

It reversibly inhibits COMT enzyme with the aim of slowing the peripheral breakdown of levodopa → increases the amount available for conversion to dopamine in the brain and reducing the fluctuations in plasma level

Name the 2 types of COMT Inhibitors and what they do

Peripherally Selective COMT Inhibitors:

• Do not cross BBB so do not inhibit COMT in the brain

• Entacapone or Opicapone

Partially Peripherally Selective COMT Inhibitors:

• Cross BBB but exact clinical relevance of inhibiting central COMT in PD is uncertain → most effect is from peripheral inhibition of COMT

• Tolcapone

Adverse effects of COMT Inhibitors

• May exaggerate some levodopa-related side effects, especially dyskinesia

• Confusion

• Hallucinations

• Discoloration of urine

• Diarrhoea

How does Amantadine work?

Adjuvant treatment if dyskinesia remains poorly controlled by other therapies → used in combination with levodopa

Mechanism: poorly understood

Adverse effects of Amantadine

• Drowsiness

• Light headedness / dizziness

• Confusion

• Dry mouth

• Constipation

• Hallucinations (rare)

Explain some drug interactions with Levodopa and MAO-B inhibitors

** can also interact with eachother: MAO-B inhibitors which can worsen dyskinesias caused by levodopa