Ch.22: Drugs for Parkinson's Disease

Question 1

Cardinal Symptoms of PD

Answer 1

• dyskinesia: tremor at rest, rigidity, postural instability, bradykinesia
• autonomic disturbances
• depression
• psychosis and dementia

Question 2

Initial Treatment

Answer 2

• mild symptoms: MAO-B inhibitor (Selegiline)
• more severe: Levadopa or a dopamine agonist
• levadopa is more effective than dopamine agonists but long-term use carries a higher risk for disabling dyskineslas
• management of motor flucutations: “off” times can be reduced with dopamine agonists, COMT inhibitors and MAO-B inhibitors; drug induced dyskinesias
• neuroprotection: no proven drug yet

Question 3

Levodopa

Answer 3

• only given in combo with carbidopa (promost BBB entry)
• highly effective but benefits diminish over time
• oral administered; rapidly absorbed from small intestine
• food delays absorption, amino acids compete for intestinal absorption and transport across BBB, high protein food reduce therapeutic effects
• adverse: dyskinesias
• symptoms be controlled for first 2 years- return at end of 5 years
• acute loss of effect: gradual loss develops near end of dosing interval and indicates that drug levels have declined to subtherapeutic value
• can be minimized by: shortening dosing interval, giving a drug that prolongs plasma half-life (entacapone), giving a direct-acting dopamine agonist

Question 4

Levodopa: Mechanism

Answer 4

• increasing dopamine synthesis in straitum
• enters brain via active transport system carried across BBB
• converted to dopamine
• helps restore a proper balance between dopamine and ACh
• activity of decarboxylases is enhanced by Vit B6 and can prevent levodopa from working

Question 5

Levodopa: Adverse Effects

Answer 5

N/V:
- low initial doses and admin with food can reduce therapeutic effects by decreasing absorption
- giving additional carbidopa without levodopa can help reduce N/V
CV:
- alpha-adrenergic agonist
- postural hypotension
- increase intake of salt and water
psychosis:
- visual hallucinations
- vivid dreams or nightmares
- paranoid ideation
CNS:
- anxiety and agitation
- memory/cognitive impairment
- insomnia
- behavioural changes (gambling, binge eating, alcohol abuse)
dyskinesias: 
- activates malignant melanoma (perform careful skin assessment)

Question 6

Levodopa: Interactions

Answer 6

• first-gen antipsychotic drugs block receptors for dopamine and decrease therapeutic effects
• MAO inhibitors: levodopa can cause a hypertensive crisis if administered to an individual taking a nonselective MAO inhibitor
• anticholinergic drugs: excessive stimulation of cholinergic receptors contributes to the dyskinesias of PD- by blocking these receptors, anticholinergic agents can enhance responses to leodopa
• Pryidoxine (vit B6): decrease amount og levodopa available to reach CNS; reduce effect; carbidopa suppresses decarboxylase

Question 7

Levodopa: Food Interactions

Answer 7

• high protein content can reduce therapeutic responses to levodopa
• neutral amino acids compete for absorption and transport across BBB
• spread their protein consumption evenly throughout the day

Question 8

Carbidopa/Levopdopa

Answer 8

• allows dosage of levodopa to be reduced by 75%
• reduces CV responses to levodopa as well as N/V
• inhibits decarboxylase- eliminates concerns about decreasing the effects of levodopa by taking a vitamin preparation that contains pyridoxine
  disadvantage:
• no adverse effect of its own
• abnormal movements can occur sooner and be more intense than with levodopa alone

Question 9

Dopamine Agonists

Answer 9

• first-line of drugs for PD
• direct activation of dopamine receptors in the straitum
• comparision with levodopa: less effective, not dependent on enxymatic conversion to be active, does not compete with dietary proteins, lower inceidence of response failure, less likely to cause dyskinesias
• two types: derivates of ergot and nonergot derivatives

Question 10

Pramipexole

Answer 10

• nonergot dopamine agonist
• used alone in early PD and with levadopa later on
• max benefits take several weeks to develop
• adverse: monotherapy: Nausea, dixxy, saytime somnolence, insomnia, constipation, weakness, hallicuinations
• combined: orthostatic hypotension, dyskinesias, and increase hallucinations
• rare: pathological gambling

Question 11

Bromocriptine

Answer 11

• ergot derivative
• approved for PD
• poorly tolerated
• direct-acting dopamine agonist
• activate dopamine receptors
• used alone for early PD and in combo with levodopa for advanced PD
• advantage: prolong therapeutic responses when combines and reduce motor fluctuations; reduced dosage of levodopa
• adverse: Nausea; psychological reactions; retrroperitoneal fibrosis, pulmonary infiltrates

Question 12

COMT Inhibitors

Answer 12

• inhibit metoblism of levodopa in periphery
• no direct therapeutic response on its ow
• entacpone (safer and more effective) then Tolcapone

Question 13

Entacapone (Comtan)

Answer 13

• selective and reversible inhibitor of COMT
• inhibits metabolism of levodopa in intestine and peripheral tissues
• prolongs time levodopa is available to brain
• adverse: dyskinesias, orthostatic hypotension, nausea, hallicuinations, sleep disturb, impluse control disorders, vomiting, yellow-orange discoloration of urine

Question 14

Selegiline (Eldpryl)

Answer 14

• modest improvement in motor function
• causes selective and irreversible inibition of MAO-B
• suppress destruction of dopamine and prolong effects of levodopa
• dramatically decline within 12-24 months

Question 15

Benztropine

Answer 15

• anticholinergic drug
• reduce tremor and ridigity
• no reduction of bradykinesia
• better tolerated but less effective
• second line defense
• younger patients with mild symptoms
• avoid in elderly who are intolerant to CNS side effects