Drugs for Parkinsons

Question 1

What enzyme converts tyrosine to L-DOPA?

Answer 1

tyrosine hydroxylase

Question 2

What enzyme converts L-DOPA to Dopamine (DA)?

Answer 2

aromatic amino acid decarboxylase (AADC)

Question 3

What are the major dopamine (DA) pathways in the brain?

Answer 3

nigrostriatal pathway and mesocortical/mesolimbic pathways

Question 4

What makes up the clinical syndrome of Parkinson’s Disease?

Answer 4

-rest tremor (2/3 patients have this and is often the earliest sign)
-bradykinesia/akinesia
-rigidity
-postural instability

Question 5

What are other symptoms of Parkinson’s Disease?

Answer 5

-mask-like face, shuffling gait
-autonomic (sweating, constipation, hypersalivation, urinary retention)
-weight loss, anorexia
-depression

Question 6

What are the proposed causes of Parkinson’s Disease?

Answer 6

-protein aggregation (alpha-synuclein, PARK1)
-impaired protein degradation (parkin, PARK2)
-mitochondrial dysfunction
-oxidative stress

Question 7

Describe the NORMAL balance of cholinergic and dopaminergic input on GABAergic outflow:

Answer 7

in the striatum, ACh from the cholinergic interneuron is excitatory and increases GABA output and dopamine (DA) from the nigrostriatal neuron is inhibitory and decreases GABA output. Ach and DA work in balance for GABA output.

Question 8

Describe how the balance of cholinergic and dopaminergic input on GABAergic outflow changes in Parkinson’s Disease:

Answer 8

nigrostriatal neurons die so dopamine (DA) is not released and cannot exert it’s inhibitory function on GABA. there is an increase in GABA activity because ACh can still exert it stimulatory activity.

Question 9

What are the possible pharmacotherapy options for Parkinson’s Disease?

Answer 9

-DA replacement (L-DOPA)
-enzyme inhibitors to enhance CNS delivery
-MAO-B inhibition to prolong CNS effects
-enhance DA release, block reuptake
-directly stimulate DA receptors
-anticholinergics (antimuscarinics)

Question 10

MOA: L-DOPA

Answer 10

some L-DOPA can reach the brain (< 5% of administered dose) via aromatic amino acid transporter which can then be converted to dopamine via L-DOPA decarboxylase

Question 11

What are the peripheral toxicities of L-DOPA?

Answer 11

SE are caused by conversion to DOPAMINE
-nausea (stimulates chemoreceptor trigger zone in brainstem)
-cardiac palpitations and arrythmias (beta agonism)
-postural hypotension (vascular DA receptors)

Question 12

What CNS side effects/toxicities may occur with L-DOPA therapy?

Answer 12

-too much DA in the striatum= dyskinesias (abnormal involuntary movement), occurs in about 50% of pt
-DA at the wrong location (limbic system, nucleus accumbens)= psychosis
-ON-OFF phenomenon= “on” is when Parkinson’s symptoms are controlled (but dyskinesias, “off” is when symptoms are not well controlled. this is caused by variable CNS metabolism of DA.

Question 13

What are the contraindications for L-DOPA therapy?

Answer 13

-psychosis
-melanoma (L-DOPA is the precursor for melanin in skin)
-closed angle glaucoma (due to alpha1 agonist activity at high concentrations of dopamine)

Question 14

Drug Interactions: L-DOPA

Answer 14

-NON-SELECTIVE MAO INHIBITORS (antidepressants) can prevent the metabolism of dopamine which increases the risk of hypertensive crisis (alpha1 agonism activity)
-PYRIDOXINE (vitamin B6) enhances the peripheral metabolism of L-DOPA leading to more peripheral side effects
-ANTIPSYCHOTICS block DA receptors so no effect

Question 15

MOA: Carbidopa

Answer 15

DOPA decarboxylase inhibitor that inhibits the conversion of L-DOPA to dopamine in the periphery so more L-DOPA can reach the CNS

Question 16

What drugs are COMT inhibitors restricted to the periphery?

Answer 16

-entacapone
-tolcapone
-opicapone

Question 17

What is the MOA of MAO-B inhibitors?

Answer 17

MAO-B is predominantly found in the striatum while MAO-A is found in the periphery, so selective MAO-B inhibitor blocks metabolism of dopamine (increased dopamine levels in the CNS) while avoiding hypertensive crisis

Question 18

What are the therapeutic uses of D2 agonists?

Answer 18

-allows L-DOPA dose to be reduced
-alleviates on-off phenomenon
-pt who are refractory to L-DOPA
-younger patients even prior to L-DOPA

Question 19

What drugs are D2 agonists?

Answer 19

-ropinirole
-pramipexole
-rotigotine
-bromocriptine
-apomorphine

Question 20

What are the adverse effects of D2 agonists?

Answer 20

SE very similar to L-DOPA
-peripheral effects such as nausea and hypotension (can be alleviated by adding a PERIPHERAL dopamine antagonist)
-CNS effects such as dyskinesias (lower incidence than L-DOPA) and psychosis (higher incidence than L-DOPA)

Question 21

What are the contraindications of D2 Agonists?

Answer 21

-psychosis
-peripheral vascular disease
-peptic ulcers

Question 22

MOA: Amantadine

Answer 22

enhance DA release and inhibit the reuptake of DA presumably by blocking NMDA glutamate receptors

Question 23

What is the indication of Amantadine?

Answer 23

may be used as an adjunct for L-DOPA/carbidopa fluctuations and dyskinesias, but sometimes useful as initial therapy for Parkinson’s- reduces bradykinesia, rigidity and tremor in early stages but benefits are short lived

Question 24

What drugs are muscarinic antagonist for the treatment of Parkinson’s?

Answer 24

benztropine and trihexyphenidyl

Question 25

What are the therapeutic applications of muscarinic antagonists?

Answer 25

-combo with L-DOPA
-can be used in very mild Parkinson’s if tremors are the only symptom- does not work so well on bradykinesia