Movement Disorders and Parkinson’s Disease

What are some causes of Parkinson’s disease?

• Aging

• Genetic factors

• Free radicals- loss of anti-oxidant defiance mechanism

• Environmental factors

• Pesticides (rotenone and Paraguat)

What are the genetic influences of Parkinson’s disease?

1. Alpha-synuclein: mutation or over expression

2. Levy bodies: abnormal build of proteins

3. PARK2 gene mutation: loss of function of Parkin proteins- neuronal cell death

What is the pathological hallmark of Parkinson’s disease?

Loss of dopaminergic neurons of the substantial nigra pars compacta

What are the major pathways of dopaminergic neurons?

1. Nigrostriatal system (substantia nigra to striatum)

2. Ventral regimental area (VTA)

3. Tubero-infundibular pathway (hypothalamus to median eminence)

4. Area postrema

Describe the nigrostriatal system

• Contains about 80% of brains dopamine

• Degeneration results in abnormalities of movement

Describe Ventral regimental area (VTA)

• Neurons that project from the ventral regimental area to the limbic system and prefrontal cortex

• Inner ate forebrain areas, cerebral cortex, nucleus accumbens and other limbic structure- motivation, goal, directed thinking, positive reinforcement

• Degeneration of this pathway- schizophrenia

Describe Tubero-infundibular pathway

• Neurons that originate in the hypothalamus, and project axons to the median eminence with the anterior pituitary gland

• Inhibits release of prolactin by pituitary lactotrophs

Describe Area postrema

• High contents of class D2 receptors

• These dopamine receptors activate the vomiting centers of the brain and is one of the causes of emesis

• (D2) Dopamine receptors are used to treat nausea and vomiting

Describe Striatum

• Information processing center of basal ganglia

• Cortical input to striatum are excitatory and use glutamate as a transmitter

• The striatum is also the target of the dopaminergic nigrostriatal pathway

Compare the direct and indirect pathway

Dopamine inhibits indirect pathway and stimulates the direct pathway

• Direct pathway: enables movement

• Indirect pathway: inhibits movement

• D1- direct pathway (Ca2+ mobilization)

• D2- indirect pathway (K+ currents)

Effect of Parkinson’s disease on dopaminergic pathways that regulate movement

Direct pathway vs. Indirect pathway

Direct pathway - D1 receptors expressing neurons (turn up motor activity)

Indirect pathway - D2 receptor expressing neurons (turn down motor activity)

Normal proper movement

• Normal level of dopamine in the striatum

• Activate the D1 expressing neurons in the direct pathway and inhibiting the D2 expressing neurons in the indirect pathway

Parkinson’s disease

• Reduced movement → dopamine deficiency

• Direct pathway is inactive and indirect pathway is overactive

Catecholamine synthesis

Pic

Tyrosine: - mainly from diet - small proportion is synthesized in liver from phenylalanine

Explain dopaminergic neurotransmission

• Catecholamine reuptake pump

• Monoamine Oxidase

Catecholamine reuptake pump

• DAT couples with Na+ /K+ -ATPase pump

Monoamine oxidase (MAO) or catechol-O-methyl transferase ( COMT) – Enzymes responsible to degrade dopamine

• MAO-A in brain and periphery

• MAO-B responsible for catabolizing CNS dopamine

What are the pharmacologic classes for the treatment of Parkinson’s?

1. Dopamine precursors

2. Dopamine receptor agonists

3. Inhibitors of dopamine degradation

What do the current treatments of Parkinson’s do?

1. Treat symptoms but not alter the underlying degenerative process

2. Not respond to nonmotor symptoms (cognitive impairment and dementia)

What is the MOA of Levodopa?

1. Replenish dopamine

2. L-DOPA is readily transported across BBB by neural amino acid transporter

3. Oral administration: Levodopa is readily converted into dopamine by AADC in the gastrointestinal tract

Amino acid decarboxylase inhibitor

• Diminishes the amount of L-DOPA that can reach BBB for transport into CNS 2.

• Increases the peripheral adverse effects that result from the generation of dopamine in the circulation

• Levodopa -1-3% reaches CNS

Carbidopa

AADC inhibitor (periphery)- administered in combination with L-DOPA

• prevents the conversion of levodopa to dopamine in the periphery

• availability of L-DOPA to CNS - 10

Why is Levodopa- Carbidopa an effective combination therapy?

1. Decreases levodopa dosage requirements by 70–80%

2. Reduces the incidence of peripheral adverse effects (nausea and vomiting)

3. Relief from akinesia, rigidity, and tremor •

Continued therapy - tolerance and sensitization - requires more drug (narrowing of the therapeutic window)

Carbidopa/levodopa ratio

1:4 or 1:10

Sinemet

10/100 -10 mg Carbidopa and 100 mg Levodopa 25/100 -25 mg Carbidopa and 100 mg Levodopa 25/250 -25 mg Carbidopa and 250 mg Levodopa

Duopa

• Intestinal suspension

• a gel suspension of levodopa/carbidopa

• for the management of patients in advanced stage

Crexont

Combination extended- and immediate-release treatment

Levodopa- adverse effect

1. Off” periods and “On” Periods

2. Dyskinesias

Off” periods and “On” Periods

Fluctuation in motor function - periods of freezing and increased rigidity (“off” periods) alternating with periods of normal or even dyskinetic movement (“on” periods)

1. “Off” periods- plasma levels of Levodopa decline- compensated by higher drug dosage

2. “On” periods- large amount of dopamine is delivered to the striatum overcome by smaller drug dose

Dyskinesias

High dose - uncontrollable rhythmic movement of the head, trunk, and limbs

Levodopa long term treatment- declines in therapeutic response

Dopamine receptor agonists derivatives

Ergot derivatives

Nonergot agonis

Dopamine receptor agonists MOA

Activates dopaminergic neurotransmission

Dopamine receptor agonists Clinical Use

1) Initial stage of the disease

2) Younger individuals - initial treatment (monotherapy)

Dopamine Receptor agonist ADE

nausea, hypotension, cardiac conduction abnormalities, hallucinations, confusions

Dopamine dysregulation syndrome

Pathological gambling - compulsive eating and hyper sexuality (require discontinuation of medication)

Contraindicated in patients with psychiatric illness

Ergot derivatives

Bromocriptine (D2 agonist)

Nonergot agonists

Rotigotine (D2) (Neupro)

Pramipexole (D3>D2) (Mirapex)

Ropinirole (D3>D2) (Requip)

Apomorphine (D1 and D2 agonist)

Inhibitors of Dopamine Metabolism

Inhibitors of MAO-B and COMT (catechol-O-methyl transferase)

MAO-B inhibitors Drugs

Selegiline (Carbex,Eldepryl)

Rasagiline (Azilect)

Safinamide (Xadago)

MAO-B inhibitors Use

• Monotherapy or in combination with other medications (Levodopa and Carbidopa)

• Improve motor function for patients experiencing dyskinesia and “off” periods

MAO-B inhibitors disadvantages

effective for monotherapy - not as effective as Levodopa - does not interfere with MAO-A

Safinamide: (Xadago)

Selective monoamine oxidase B inhibitor

Inhibits glutamate release

Blockade of voltage-dependent Na+ and Ca2+ channels

Adverse Effects of MAO-B inhibitors

• Involuntary movement

• CNS depression

• Serotonin syndrome

Selegiline vs. Rasagiline

Selegiline: potentially toxic metaboliteamphetamine (cause sleeplessness and confusion)

Rasagiline: more potent, no toxic metabolite

Formulations

• Eldepryl

• Zelapar

• Emsam

• Azilect

COMT inhibitors

• Tolcapone

• Entacapone

• Opicapone

• Stalevo

COMT inhibitors MOA

• inhibits catechol-O-methyl transferase

• inhibits the degradation of levodopa as well as dopamine Opicapone: (Ongentys)

• inhibits only peripheral COMT enzymes

• Reduce ‘off’ periods that are associated with decreasing plasma levodopa levels

Tolcapone: (Tasmar)

• cross the BBB

• inhibits central as well as peripheral COMT

• associated with hepatic toxicity

Entacapone (Comtan

inhibits peripheral COMT

most widely used COMT inhibitor

Opicapone: (Ongentys)

inhibits only peripheral COMT enzymes

Stalevo

combined with Carbidopa, Entacapone, and Levodopa

Which inhibitors should not be given together?

COMT inhibitors should not be given with non-selective MAO inhibitors

Peripheral and central metabolism of levodopa

Nondopaminergic Pharmacology

Amantadine

Trihexyphenidyl

Benztropine

Amantadine

• MOA

• Therapeutic Action

1. MOA: Block of excitatory NMDA (N-methyl D-aspartate) receptors

2. Therapeutic Action: Prescribed in combination with levodopa-carbidopa - used to treat levodopa induced dys

Symmetrel vs. Osmolex

Symmetrel : Immediate-release amantadine Osmolex ER: Extended release formulation

Anticholinergic drugs

Trihexyphenidyl

Benztropine

For Anticholinergic drugs:

1. What is the Therapeutic Action?

2. ADE

3. Contraindication?

1. Muscarinic receptor antagonist - adjuvant therapy with levodopa- carbidopa

   1. Regulate interactions of direct and indirect pathway neurons - effective for treating tremor in young patients

2. dry mouth, urinary problem, impairment of memory and cognition

3. Patients with glaucoma, GI obstruction