Pharm/Drugs for movement and neurodegenerative disorders

Question 1

What is the goal of treatmtent in AD regarding ACh?

What mechanism do we manipulate to accomplish this goal?

Answer 1

the goal of treatment of AD is to maintain appropriate level of cholinergic signaling in the brain

We can reversibly inhibit cholinesterase so the ACh stays in the synapse longer.

**the cholinesterase inhibitors readily cross the BBB, they are orally active, and they may also increase the release of ACh.

Question 2

What is the goal of treatment of AD in regards to glutamte?

what do we manipulate to accomplish this goal?

Answer 2

The goal iof treating AD is to reduce the excitotoxic effects of glutamate

We can use an NMDA Receptor Antagonist (memantine)

this is neuroprotective. It blocks glutamate signaling and reduces excitotoxicity

Question 3

What drugs do we use to reduce excitotoxic effects?

What are the side effects of these drugs?

Answer 3

We use NMDA receptor Antagonists to decrease excitotoxic effects.

1. Memantine- blocks glutamate signalling
   
   1. AE: dizziness, cause increased agitations and delusions
2. Combination of memantine and donepezil
   
   1. Better outcomes in combination than when used alone.
   2. **when used in combination patients have enhanced cognition, activities of daily living and behavior

Question 4

What causes excitotoxicity?

Answer 4

Excitotoxity is a result of increased intercellular Ca++ in the cell secondary to an increase in the frequency of depolarization of a cell.

The post synaptic cell responds to glutamate. Receptors sensitive to glutamate open and calcium rushes into the cell. The increased calcium in the post synaptic cell leads to an increase in free radicals which leads to cell death.

Receptors involved are: AMPAR, KAR, VSCC

Question 5

Characteristics of PD

what causes these characteristics?

Answer 5

Parkinson’s disease is characterized by a resting tremor, rigidity, bradykinesia, and postura instability resulting from a degeneration of dopaminergic neurons in the basal ganglia

Question 6

What are the treatment stratigies for PD?

Answer 6

Treatment strategies for PD include:

1. Maintain dopamine levels in the brain
   
   1. increase synthesis
   2. inhibit breakdown
   3. increase release
2. simulate dopamine
3. other treatments
4. surgical proceedures

Question 7

How do we increase synthesis of dopamine?

1. what do we give orally?
2. what do we combine it with?
   
   1. what does the additional drug do?

Answer 7

We can increase the synthesis by giving its precursor, Levodopa. We combine levodopa with carbidopa (Sinemet) to prevent the converion of L-dopa to dopamine in the peripheral tissues. Carbidopa remains in the peripheral tissues (it can not cross the BBB) and is a dop decarboxylase inhibitor.

Question 8

L-Dopa + carbidopa

1. Clinical uses
2. When do we see the best results with use of the drug?
3. How do we dose?

Answer 8

L-Dopa + carbidopa is used to relieve the clinical features of PD especially the bradykinesia, but does NOT STOP THE PROGRESSION OF PD.

We see the best results within the first few years of obtaining the medication.

Doeses start small (x3/day) it can be increased but that can enhance the side effects. The daily dose needs to be reduced over time to avoid side effects not initially present. Patients become less responsive to treatment over time.

Question 9

L-Dopa (+ carbidopa) adverse effects- most common

how do we minimize the effects?

what triggers vomiting? Do we give an anti-emetic?

Answer 9

L-Dopa (+ carbidopa) adverse effects

1. GI- Anorexia/Nausea/Vomiting
2. Minimized by taking medication with food or by dividing doses
3. Vomiting is due to stimulation of the chemoreceptor trigger zone in the brainstem and tolerance can develop to L-Dopa
   
   1. You DO NOT give an antiemetic because they exacerbate the parkinsonism

Question 10

What are the adverse behavioral effects of L-Dopa (+ carpidopa)

what can we give to prevent these effects?

Answer 10

L-Dopa can cause depression, anxiety, agitation, delusions, hallucinations, and somnolence, These effects are more common when L-Dopa and carbidopa are given together. Pshycosis can be treated with primavanserin (an atypical antipsychotic with unknown mechanisms).

Other atypical antipsychotics can be given to counteract the adverse behavioral effects, these include olanzapine, quetiapine, and risperidone.

Question 11

L-Dopa (+carbidopa) adverse effects:

Cardiovascular:

Answer 11

L-Dopa may produce cardiac arrhythmias due to an incresed catecholamine formation in the periphery. The incidence of cardiac arrhythmias.

A more often occuring side effect is postural hypotension. postural hypotension is a common but asymptomatic side effect that usually diminishes with time.

Hypertension can sometimes occur in the presence of nonselective MAOI sympathomimetics or large doses of L-Dopa.

Question 12

L-Dopa adverse effects:

Fluctuations in response

what is on-off phenomenon

what can we use to treat an “off” period?

Answer 12

Fluctuations in response to treatment with L-Dopa will become more frequent with prolonged use. They can relate to timing of dose intake causing an End-of-dose akinesia or unrelate to the time of dose.

The “on-off” phenomenon is marked by “off periods” marked by akinesia which alternate with “on” periods of improved mobility but marked dyskinesia.

Off periods can be treated with SC amomorphine

Question 13

L-Dopa drug interactions:

1.

2.

Contra indications for L-Dopa:

Answer 13

L-Dopa drug interactions:

1. pyridoxine enhances peripheral breakdown of L-Dopa (w/o carbidopa)
2. Monoamine Oxidase A inhibitors (MAOI A): can cause a hypertensive chrisis- elevated BP, vascular damage to kidneys, headache, and mental confusion.

Contra indications for L-Dopa:

1. psychotic patients because it will exacerbate mental disturbance
2. Angle-closure glaucome (increased IOP)
3. history of melanoma/undiagnosed skin lesions because l-Dopa is also a precursor to skin melanin which can lead to malignant melanoma.

Question 14

How can we inhibit the breakdown of Dopamine?

Answer 14

We can increase the amount of dopamine in a synapse by inhibiting the enzymes that break down dopamine:

Monoamine Oxidase B Inhibitors

MAO B metabolizes dopamine and can be inhibited by the drugs selegiline and rasagiline

Catechol-O-Methyltransferase Inhibitors

COMT metabolizes L-Dopa in periphery and brane. It is more active when dopa decarboxylase is inhibited.

tolcapone and entacapone

Question 15

Selegiline

1. MOA
2. Use:
3. side effects:

Answer 15

Selegiline

1. MOA: selective irreersible inhibitor of MAO-B
2. Use: adjunctive therapy to prolong the antiparkinsonism effect of L-Dopa (allows for lower doses of L-Dopa) and may reduce mild or on-off or wearing off phenomena
3. side effects: may potentiate the adverse effects of L-dopa and may cause insomnia so it is taken at breakfast and lunch

Question 16

Rasagiline

MOA:

Use:

Contra indications:

Answer 16

Rasagiline

MOA: MOA-B inhibitor

Use: more potent than selegiline to prevent MPTP-induced parkinsonism. it can be a monotherapy in early disease or as adjunctive therapy in advanced disease

Contra indications for all MAOI: do not give to patients taking meperidine, anti-depressants (tricyclic, SSRIs) and Tyramine because they may cause excessive stimulation of the CNS and CV system (aka Serotonin Syndrome)

Question 17

Pt. presents with:

1. myoclonus, hyperreflexia, and tremor.
2. tachycardia, diaphoresis, hyperthermia, flushing
3. confusion, irritability, agitation

What does this patient have?

Answer 17

This patient has Serotonin Syndrome.

(SS SAC somatic, autonomic, cognitive)

The myoclonus, hyperreflexia, and tremor are somatic symptoms

the tachycardia, diaphoresis, hyperthermia, and flushing are signs of autonomic instability

and the confusion, irritability, and agitation are all cognitive.

Question 18

What can we give to

Inhibit Breakdown of dopamine?

Answer 18

The “capones” inhibit the breakdown of dopamine by selectively inhibiting COMT. This prolongs L-dopa activity and produces a more prolonged “on-time”

entacapone- decreases metabolism of L-Dopa in the periphery (doesn’t cross BBB)

tolcapone- decreases metabolism in BOTH periphery and CNS

Question 19

What are the adverse effects of the “capones”?

Answer 19

Adverse effects of the capones are due to an increased exposure L-dopa (the increased exposure to L-dopa means that you should lower the dose of L-Dopa in the first 48 hours when adding this medication)

dyskinesias, nausea, confusion

dark urine

TOLCAPONE INCREASES LIVER HEPATOTOXICITY

(tolcapone is not as potent as entacapone so the dosage is increased which leads to the hepatotoxicity)

Question 20

Stalveo

Answer 20

Stalveo is a combination of

L-dopa + carbidopa + entacapone

**this simplifies the drug regimine if the patient is stable on an appropriate dose**

Question 21

Drugs to treat PD

1. Drugs to increase the release of Dopamine?
2. MOA:
3. Uses:
4. Adverse Effects

Answer 21

Drugs to treat PD

1. Drugs to increase the release of Dopamine? Amantadine
2. MOA: unknown
3. Uses: benefits are short-lived and lasts only a few weeks.
   
   1. Used to reduce bradykinesia, rigidity, and tremor
4. Adverse Effects:
   
   1. CNS: restlessness, depression, insomnia, hallucinations
   2. Dermatological: livedo reticularis (clearly visible vasculature through the skin)