Movement Disorder Drugs

Question 1

Pathology of Parkinson’s

Answer 1

Parkinson’s Disease is a progressive neurodegenerative disorder of unknown cause that culminates in loss of voluntary movement.

The fundamental disease process is an on-going degeneration of the dopaminergic neurons of the substantia nigra.

The essential neurochemical characteristic is a “Dopamine deficiency disease”.

Question 2

Why is it difficult to directly replace Dopamine

Answer 2

dopamine itself does not cross the blood-brain barrier.

Question 3

What two enzymes deactivate dopamine

Answer 3

monoamine oxidase (MAO).

catecholamine O-methyltransferase (COMT)

Question 4

Drug used to Increase Dopamine Synthesis

Answer 4

Levodopa

Question 5

MOA of Levodopa

Answer 5

Dopamine synthesis occurs via hydroxylation of tyrosine to dihydroyphenylalanine (L-DOPA / levodopa) and subsequent decarboxylation of L-DOPA to dopamine (Fig. 1).

L-aromatic amino acid transporters function in transporting L-DOPA across the blood brain barrier.

Question 6

Pharmacokinetics of levodopa

Answer 6

Levodopa is rapidly absorbed from small intestine with peak plasma levels within 2 h.

L-DOPA is taken up from the GI tract via aromatic amino acid transporters.

Thus, aromatic amino acids may compete with L-DOPA for transport and food can delay absorption; particularly a high protein meal.

Majority (2/3) of oral dose of L-DOPA is excreted in urine within 8 hours as:

dihydroxyphenylacetic acid (DOPAC) [via conversion of L-DOPA to DOPAC by monoamine oxidase]

and homovanillic acid (HVA) [via conversion of DOPAC to HVA by catechol O-methyltransferases (COMT)].

Question 7

Obstacle for delivery of L-dopa to the brain

Answer 7

When administered alone, less than 3% of levodopa gets to the brain as much of peripheral DOPA is decarboxylated to dopamine, which does NOT cross the blood brain barrier.

Conversion of L-DOPA to dopamine in the periphery therefore competes with the amount of L-DOPA available for conversion to dopamine in the CNS.

Conversion of L-DOPA to dopamine in the periphery also leads to increased catecholamine synthesis in the periphery and associated toxicities.

Question 8

Levodopa toxicities

Answer 8

Peripheral Toxicity of Levodopa includes GI symptoms (e.g. nausea, vomiting, anorexia) and cardiovascular symptoms (e.g. postural hypotension)

CNS Toxicity of Levodopa includes neurological symptoms (e.g. dyskinesias) and behavioral symptoms (e.g. insomnia, anxiety, 15% suffer confusion, psychosis)

Question 9

Fluctuations in therapeutic response to levodopa

Answer 9

“wearing off” (“end of dose”) phenomenon - with time, the effects of levodopa in providing symptomatic relief may begin to wear off between doses.

“on-off” phenomenon is related to the wearing off phenomenon and relates to feeling better “on” after a dose of levodopa and worse “off” before another dose is scheduled.

With time, the duration of “on” time may get shorter and “off” time longer.

The timing of “on-off” fluctuations can be unpredictable in some patients making it difficult to manage by shortening the interval between levodopa doses.

For some patients the “on-off” fluctuations can be modulated by including dopamine agonists as part of the treatment plan.

Question 10

Levodopa drug interactions

Answer 10

Sympathomimetic drugs (ß agonists) cause cardiac stimulation.

Pyridoxine (vitamin B6) decreases efficacy of levodopa by increasing extracerebral metabolism of dopa (pyridoxine is converted to a coenzyme for aromatic L-amino acid decarboxylase).

Antipsychotic drugs also decrease efficacy of levodopa by decreasing dopa levels.

Monoamine oxidase A inhibitors can cause hypertensive crisis by elevating peripheral norepinephrine levels.

Question 11

Carbidopa MOA

Answer 11

Carbidopa functions as an inhibitor of peripheral aromatic L-amino acid (AKA: DOPA) decarboxylase.

It is a structural analog of L-dopa and functions as a competitive inhibitor of DOPA decarboxylase

Carbidopa does NOT cross the blood brain barrier and therefore only inhibits the peripheral decarboxylase enzyme, thus increasing the amount of L-DOPA reaching the brain.

Helps reduce catecholamine synthesis

Question 12

Carbidopa administration

Answer 12

Carbidopa is usually administered combined with levodopa as Sinemet = carbidopa + levodopa: 1:4 or 1:10; (25/100, 25/250).

Most patients eventually require Sinemet 25/250 3 times daily.

Dopamine agonists can be added to reduce response fluctuations.

Question 13

Carbidopa effect on levidopa dosing

Answer 13

Carbidopa decreases conversion of levodopa to dopamine in gut and blood.

Consequently, a lower total dose of levodopa can be given to get similar amounts of levodopa delivered to the brain when compared with levodopa alone.

Question 14

Benefits and disadvantages of carbidopa

Answer 14

Advantages of combining carbidopa with levodopa

Increased amount of levodopa reaching the brain; decreased peripheral side effects.

Disadvantage of combining carbidopa with levodopa

Increased risk for CNS side effects if the dose of levodopa is NOT decreased when used in conjunction with carbidopa.

Question 15

What are ergot alkaloids

Answer 15

Ergot Alkaloids are dopamine receptor agonists that are natural products originally isolated from the grain fungus, ergot.

Question 16

Bromocriptine, Pergolide MOA

Answer 16

Ergot alkaloids

Bromocryptine is a D2 agonist.

Pergolide is a D1 & D2 agonist that increases “on-time” among response fluctuators & reduces levodopa dose.

Pergolide is associated with valvular heart disease and is no longer available.

Question 17

Ergot alkaloids admin and side effects

Answer 17

Administration

Ergot alkaloids have additive therapeutic effects with levodopa

Toxicity

Toxicities associated with Ergot alkaloids include hypotension, nausea, hallucinations (lysergic acid diethylamide, LSD, is an ergot derivative)

Question 18

Pramipexole, Ropinirole MOA

Answer 18

Newer ergot alkaloids

Pramipexole is a D3 agonist.

Ropinirole a D2 agonist.

Question 19

Pramipexole, ropinirole Admin

Answer 19

Potent agonists can be used alone for mild Parkinson’s disease.

In advanced disease they are used in association with levodopa to smoothen response to levodopa.

Effects are similar to older agonists.

Pramipexole and Ropinirole have vague structural similarity to dopamine.

Both drugs have also been prescribed for restless leg syndrome.

Question 20

Pramipexole, Ropinirole pharmacokinetics

Answer 20

Pramipexole is excreted unchanged in the urine.

Ropinirole is metabolized by CYP1A2

Other drugs metabolized by this liver enzyme may affect clearance

Caffeine is CYP1A2 substrate

Question 21

Pramipexole, Ropinirole toxicities

Answer 21

Pramipexole and ropinirole have been associated with compulsive gambling in a small number of patients.

Pramipexole and ropinirole are structurally distinct from ergot alkaloids and so lack many of their side effects

Question 22

Apomorphine MOA

Answer 22

Apomorphine is a morphine decomposition product, but does not bind to morphine receptors and instead functions as a non-selective dopamine receptor agonist.

Question 23

Apomorphine admin

Answer 23

Apomorphine hydrochloride (Apokyn) is sometimes used for temporary relief or “rescue” from off-periods of akinesia. Injected subcutaneously with rapid uptake

clinical benefit can be achieved within 10 minutes and persists up to 2 h.

Pretreatment with antiemetic trimethobenzamide recommended for prevention of nausea.

Question 24

Apomorphine toxicity

Answer 24

Adverse effects include: restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations and confusion.

Overdose can cause acute toxic psychosis.

Livedo reticularis and other dermatologic reactions have been described.

Question 25

Dopamine and catecholamine metabolism

Answer 25

Dopamine is metabolized to homovanillic acid by the concerted activities of catecholamine O-methyltransferases (COMT) and monoamine oxidase (MOA).These enzymes are also involved in catecholamine and L-DOPA metabolism.

MOA-A functions predominantly in the periphery whereas MAO-B is found in the CNS.

Question 26

Details of metabolsim of L-Dopa in periphery

Answer 26

COMT enzymes are capable of metabolizing catecholamines, dopamine, and L-DOPA.

COMT converts L-DOPA to 3-O-methyldopa, which competes with L-DOPA for transport across gut and blood brain barrier.

Metabolism of L-DOPA by COMT therefore not only reduces the amount of L-DOPA but also interferes with it crossing the blood brain barrier thus having a dual effect on the amount of L-DOPA reaching the brain.

Question 27

Entacapone, Tolcapone MOA

Answer 27

Both entacapone and tolcapone are inhibitors of COMT.

Both entacapone and tolcapone inhibit peripheral metabolism of levodopa to 3-O-methyldopa.

This inhibition will increase DOPA available for transport into the CNS.

This adjunct treatment is useful for smoothing of response to L-DOPA.

Tolcapone, but not entacapone, also inhibits COMT in the CNS and blocks the conversion of dopamine to 3-methoxytryptamine

Question 28

Entacapone, Tolcapone admin and pharmacokinetics

Answer 28

Administration

Either drug is given with levodopa and is frequently paired with inhibitors of DOPA decarboxylase.

Pharmacokinetics

Both entacapone and tolcapone are rapidly absorbed, bound to plasma proteins, and metabolized prior to excretion.

They have a short half-life of about 2 h.

Question 29

Entacapone, Tolcapone toxicity

Answer 29

Entacapone is preferred although tolcapone more potent.

However, tolcapone has potential hepatotoxicity. If used, patient liver enzymes must be carefully monitored for signs of liver toxicity.

Question 30

Selegiline MOA

Answer 30

In the CNS, the major pathway of dopamine metabolism is by MAO-B in glia.

Selegiline is an inhibitor of MAO-B and does not act on MAO-A in the periphery.

Inhibition of MAO-B blocks metabolism of dopamine to dihydroxyphenylacetic acid (DOPAC) and results in a build up of dopamine in CNS.

conversion of dopamine to DOPAC is accompanied by the production of hydrogen peroxide.

Treatment with selegiline therefore reduces reactive oxygen species and has been reported to block progressive neurodegeneration.

Question 31

Selegiline admin

Answer 31

Selegiline is often given together with levodopa.

Similar to carbidopa, selegiline can increase adverse effects associated with levodopa.

Consequently doses of levodopa should be decreased when both drugs are used in combination.

Selegiline prolongs usefulness of levodopa.

It decreased incidence of dyskinesias, “on-off” fluctuations that occur with prolonged use of levodopa.

Question 32

Selegiline drug interactions

Answer 32

It is important that selegiline NOT be given to patients taking meperidine, tricyclic agents or serotonin uptake inhibitors.

There is a risk of acute toxic interactions.

Question 33

What is Rasagiline

Answer 33

Similar drug to selegiline - newer MAO-B inhibitor with similar properties.

Question 34

What are the Drugs that Inhibit Cholinergic Signaling

Answer 34

Trihexyphenidyl, Benztropine, Biperiden, Orphenadrine, Procylcidine

Question 35

Trihexyphenidyl, Benztropine, Biperiden, Orphenadrine, Procylcidine MOA

Answer 35

The drugs is this category are antagonists for muscarinic receptors.

The exact mechanism by which muscarinic antagonists work to relieve Parkinson’s symptoms is unknown but it was originally thought that they corrected an imbalance between dopamine and cholinergic signaling caused by the degeneration of dopaminergic neurons

Question 36

Admin of cholinergic inhibitors

Answer 36

Benztropine, trihexyphenidylare have used adjunctively with other anti-Parkinson agents to treat all types of Parkinson syndromes including anti-psychotic-induced extrapyramidal symptoms.

In general, anticholinergic agents can help control tremors but are less effective for treating bradykinesia or rigidity.

They can also block dopamine reuptake, thus prolonging dopamine’s effects.

Less efficacy that levodopa in treating Parkinson’s syndrome.

Most physicians no longer use anticholinergics because of the associated toxicities.

Question 37

Cholinergic inhibitors toxicities

Answer 37

Side effects include:

dry mouth

blurry vision

urinary retention

nausea & vomiting

constipation

cardia arrhythmia

tachycardia

CNS toxicity

delirium

confusion

Toxicities may be exacerbated by other antimuscarinic drugs:

tricyclic antidepressants

antihistamines.

Question 38

Cholinergic inhibitors and dementia

Answer 38

the use of anticholinergic drugs has been positively associated with increased risk for cognitive decline and dementia, therefore exacerbating risks beyond those linked to Parkinson’s disease alone

Question 39

Amantadine MOA

Answer 39

Amatadine is an anti-viral agent that was found to have anti-Parkinson’s activity by accident.

Amantadine is thought to function by increasing the synaptic concentration of dopamine by stimulating dopamine release and/or inhibiting its reuptake into neurons

Question 40

Amantadine admin

Answer 40

Less efficacious than levodopa, can be tried alone in mild Parkinson’s, but often used to enhance levodopa efficacy

Question 41

Amantadine toxicities

Answer 41

Adverse effects nevertheless include: restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations and confusion.

Overdose can cause acute toxic psychosis.

Livedo reticularis and other dermatologic reactions have been described.

Livedo reticularis refers to a condition in which dilation of capillary blood vessels and stagnation of blood within these vessels causes mottled discoloration of the skin.

It is described as being reticular (net-like) cyanotic (reddish blue discoloration) cutaneous discoloration surrounding pale central areas.

It occurs mostly on the legs, arms and trunk and is more pronounced in cold weather.