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Flashcards in Pharmacotherapy of parkinson's agents Deck (69):
1

Parkinson’s Disease

Hallmark clinical features

A. Tremor – resting; begins unilaterally and slow in frequency (4-6 oscillations/sec)
B. Rigidity (cogwheeling) - limb muscles
C. Bradykinesia - slowing of movements
D. Postural instability - not caused by visual, vestibular, cerebellar, or proprioceptive dysfunction; often leads to gait disturbances

2

Parkinsons Disease

Motor complications

Altered axial posture
Difficulty turning in bed
Slow, shuffling gait
Propulsion & festination
Micrographia (small handwriting)
Impaired fine movements
Resting Tremor
Masked Facies
Soft, hesitant or dysarthric speech – impaired ocular accommodation
Decreased eye blinking – blepharospasm
Dysphagia
Drooling

3

PD

Neuropsychiatric sx

Delirium
Dementia
Agitation
Vivid dreams/sleep fragmentation
Depression
Anxiety/panic attacks

4

PD

Sensory & Autonomic sx

Paresthesias: sensory, thermal
Akathisia (sensation of restlessness)
Orthostatic hypotension
Impaired gastrointestinal motility

5

PD

pathophysiology

 The pathogenesis of IPD is unknown
 Motor deficits of IPD occur from loss of dopaminergic nerve terminals, therefore functionally there is a depletion of dopamine in the brain.
 A positive correlation exists between the degree of dopaminergic loss and severity of clinical features.
 In the normal healthy state, a balance exists between the effects of acetylcholine and dopamine.
With loss of the latter, the balance is disturbed and cholinergic activity predominates.

6

PD

Pharmacological goal

Goal is to restore dopaminergic/cholinergic balance via dopamine agonism and/or muscarinic cholinergic antagonism.

7

PD therapy

Anticholinergic agents

Place in therapy

 Initial treatment for mild to moderate symptoms
 Adjunctive treatment with dopaminergic agents in patients with moderate to severe disease.
 Improvement in symptoms = 25%: Tremors > rigidity, no improvement in bradykinesis, posture, or gait.
 No difference in efficacy between agents, however, individual patients response may vary with different anticholinergic drugs.

8

PD therapy

Anticholinergic agents

Pharmacologic action

Site of action = muscarinic receptors in striatum

Block over-stimulated muscarinic receptors

9

PD therapy

Anticholinergic agents

list

Benztropine**
Trihexyphenidyl**
Biperiden
Cycrimine
Ethopropazine
Procyclidine
Diphenhydramine**
Orphenadrine
**Most commonly used

10

PD therapy

Anticholinergic agents

contraindications

Benign Prostatic Hypertrophy

Narrow Angle Glaucoma

G.l. Obstruction

11

PD therapy

Anticholinergic agents

SE

Central:

Confusion
Hallucinations
Choreiform movements
Memory impairment

Peripheral:

Dry mouth
Urinary retention
Blurred vision
Constipation
Tachycardia
Increased intraocular pressure

12

Amantadine

Place in therapy

Initial monotherapy for mild to moderate symptoms. (~50% response rate)

Adjunctive treatment with carbidopa/levodopa in advanced disease.

Improvement in tremor, rigidity, bradykinesia.

13

Amantadine

Pharmacologic mech

Increase central synthesis and release of dopamine.
Decrease central presynaptic dopamine reuptake.
Cholinergic antagonism? (mild)
? Neuroprotective effect (NMDA antagonist)

14

Amantadine

SE

Edema
Livedo Reticularis
CHF
Seizures
Hallucinations
Gl (nausea/vomiting, diarrhea)
Orthostatic hypotension
Depression
Confusion
Insomnia

15

Carbidopa/levodopa

Role in therapy

Most efficacious symptomatic treatment for PD

Improves quality of life

Increases survival

16

Carbidopa/levodopa

Controversies with use

? long-term use may lead to degeneration of neurons

motor fluctuations with long-term use

increased dose may increase side effects with little improvement in mobility

17

Review the pharmacology of carbidopa/levodopa

Find

18

Review comparison of standard vs controlled release sinemet

Find

19

Sinemet SE

Peripheral - nausea/vomiting, orthostatic hypotension, tachycardia/cardiac arrhythmias, PUD

Central – dyskinesias, response fluctuations (motor complications), psychiatric complications (hallucinations)

20

Sinemet

Complications of long-term use

Dramatic improvement in symptoms generally occurs upon initiation of levodopa (“honeymoon period”) but this improvement is transient. After 5 years of levodopa, 50-90% of patients will experience motor complications, which can occupy as much as 50% of the day.
When assessing levodopa response fluctuations it is important to distinguish between effects attributable to the disease progression (e.g. response fluctuations) and those that are caused by the drugs used to treat the disease (e.g. levodopa-induced dyskinesias)
In many cases, elimination of one complication will come at the expense of worsening another. The impact of “off” time for each patient will be different and unique to that patient. Most patients prefer mobility or “on” with dyskinesias rather than being “off” or immobile.

21

Possible mechanisms of response fluctuations with sinemet

Often occur with prolonged levodopa use:

Central Causes:
Reduced buffering capacity to dampen rapid increases & decreases in levodopa delivery as PD progresses
Post-synaptic changes due to oscillations in dopamine concentrations
Possibly due to direct toxicity of dopamine (?)

Peripheral Causes: Gastric stasis

22

Sinemet

Response fluctuations

On-off effect

"On-Off' effect: random and unpredictable fluctuations from mobility to parkinsonian state appearing suddenly as if a switch has been turned. Fluctuations may be brief lasting only a few minutes or they can go on for hours and increase over time in both frequency and intensity. Has no relationship to timing of dose. May be due to alteration in BBB levodopa delivery or post-synaptic alterations. May benefit from dopamine agonist, MAO-B inhibitors, COMT inhibitor, increasing the frequency of levodopa administration, or apomorphine. Initial management should include adding a dopamine agonist or apomorphine if not already part of the regimen. Switching to sustained-release levodopa has been tried in the past but recent evidence suggest this method does not reduce off-time any greater than immediate- release levodopa.

23

Sinemet

End of dose deterioration or “wearing off”

Loss of levodopa effect near the end of the dosing interval. Patient senses gradual waning of efficacy. Relates directly to levels of plasma levodopa. Effectiveness begins to diminish; ultimately, useful mobility may end within 1 hour of a single dose. Levodopa/carbidopa half-life of 1.5 hours contributes to fluctuating drug levels. More predictable than "on-off" effect. Improved by shortening dosing interval, a dopamine agonist, MAO-B inhibitor, COMT inhibitor or apomorphine. Primary options should include addition of dopamine agonists or increasing the frequency of levodopa administration.

24

sinemet

Delayed onset of response

Due to delayed gastric emptying, co-administration of levodopa with food or administration of too small a levodopa dose. Improved by taking levodopa on an empty stomach, reduction in dietary protein intake, if on CR product add an addition morning standard release carbidopa/levodopa dose, add dopamine agonist

25

Sinemet

Drug resistant “off” periods

Usually related to delayed GI emptying of increased absorption in upper GI tract. Improved by increasing dose and/or frequency, give on empty stomach, add dopamine agonists, or apomorphine.

26

Sinemet

Dopaminergic adverse effects

list

dyskinesias
Hallucinations
Hedonistic homeostatic dysregulation

27

Sinemet

Dopaminergic adverse effects

dyskinesias

Dyskinesias: develop in nearly all patients with PD as the duration of the disease progresses and levodopa therapy is used. Due to excessive dopamine and represents increasing difficulty to balance maximum response with adverse effects with long term therapy. Dyskinesias manifest as involuntary, choreiform-type movements. They may be present in large extremities, fine muscle groups such as orofacial twitching or grimacing. Careful reduction of levodopa dosage into smaller, more frequent doses is the primary strategy to treat dyskinesias. Substitution of part of the levodopa dose with a dopamine agonist may help. Initiating therapy early in the disease with a dopamine agonist has been found to have less risk for the development of dyskinesias due to its ability to provide a more continuous stimulation of dopamine receptors. The addition of amantadine or possibly a COMT inhibitor to the regimen may lessen dyskinesias.

28

sinemet

Dopaminergic adverse effects

hallucinations

Hallucinations: usually visual in nature and often revolve around animals, insects, or people. No treatment is necessary if the hallucinations are mild although it my eventually progress and become distressing to the patient. A stepwise dose reduction of dopaminergics can be attempted carefully but may aggravate immobility and cause more harm than managing the psychosis with drugs. Clozapine and quetiapine are the preferred atypical antipsychotic agents to use since the other agents have been shown to exacerbate parkinsonism.

29

Sinemet

Dopaminergic adverse effects

Hedonistic Homeostatic Dysregulation

Hedonistic Homeostatic Dysregulation: Several case series recently has raised public attention to pathological gambling induced by dopamine agonist therapy. Younger, male patients with early-onset PD characterize the core features of the syndrome. They take increasing quantities of their dopaminergic replacement therapy despite worsening dyskinesias. In the process they develop cyclical mood disorders with hypomania or manic psychosis. Other features include carrying out repetitive purposeless motor acts, hypersexuality, having the urge to walk great distances during “on” times with not purpose or destination, pathological gambling and shopping, alteration in appetite, drug hoarding, and social independence or isolation.

30

Sinemet

Drug/food interactions

drugs



Drugs that possess dopamine antagonist activity (phenothiazines, metoclopramide)
Ferrous sulfate: forms chelation complex with levodopa & carbidopa in Gl tract. Can decrease levodopa absorption by 25-50% and carbidopa 75%. Avoid concomitant administration.
Anticholinergics may alter GI absorption of levodopa by delaying gastric emptying. The drug solubilizes completely with the long gastric housing then dumps into the duodenum where very rapid absorption occurs. The result is delayed ON response with possible increase in dyskinesias once absorption occurs.

31

Sinemet

Drug/food interactions

food

Protein containing foods decrease absorption – advise patients to take Immediate release levodopa 30 minutes before or 60 minutes after meals due to competition for absorption – take controlled release levodopa with food to slow movement through GI system and improve bioavailability

32

Sinemet

contraindications

History of melanoma (dopamine is a melanin intermediate)

Concomitant non-specific MAOI (cheese effect – hypertension, vomiting, tachycardia, and headache due to build up of levodopa metabolites such as norepinephrine)

33

Direct DA agonists

advantages





Dopamine agonists do not depend on functioning presynaptic neurons for their pharmacological activity. Act directly on the dopamine receptors.
Used as initial treatment for patients age < 65; or as adjunctive therapy with carbidopa/levodopa in patients with response fluctuations (i.e., "on-off” phenomenon, "wearing off” effect). – Recent studies have found that with dopamine agonists are used as initial therapy in levodopa-naïve patients, symptoms can be successfully controlled and delay the need for levodopa therapy for as much as 4- 5 years in up to 80% of patients.
Does not generate oxidative metabolites like levodopa
Possible neuroprotective properties (free radical scavenger)
Less motor complications than seen with levodopa/carbidopa – Patients who are started initially on dopamine agonist therapy and eventually supplemented with levodopa therapy when needed were 2-3 times less likely to develop dyskinesias and motor fluctuations in the first 4-5 year of therapy than those patients receiving levodopa alone as initial therapy
Ergoline and Non-ergoline Dopamine Agonists

34

Direct DA agonists

disadvantages

Will eventually need levodopa as the disease progresses

Side effects

Does not completely prevent development of levodopa-related motor complications

Does not stop disease progression?

35

Ergot dopamine agonists

list

Bromocriptine

Pergolide – no longer on the market

36

Bromocriptine

MOA

Stimulates D2 and antagonizes D1 (partial  & serotonin agonist)

37

Bromocriptine

SE

Common/rare

common: nausea/vomiting, dyskinesias, hallucinations, confusion, headache, orthostatic
hypotension (take first dose Iying down), fatigue

rare: Raynaud’s phenomenon, refractory edema in lower limbs, pleuropulmonary and retroperitoneal fibrosis (2-5% incidence after 5 years), paresthesias, skin inflammation

38

Bromocriptine

contraindications

Hx of psychosis
Severe angina
Recent MI
PUD

39

Bromocriptine

DDI

drugs that inhibit CYP3A4 (e.g., erythromycin) increase plasma bromocriptine levels several fold

40

Ropinorole

MOA

Stimulates D-2 & D-3 receptor sites

41

Ropinirole

Vs

bromocriptine

More effective than bromocriptine at reducing motor symptoms of IPD. Efficacious as monotherapy.

Reduces “Off” time associated with “Wearing-Off phenomenon”

May reduce levodopa requirements

42

Ropinirole

SE/DDI

Side effects: dyskinesias, nausea, dizziness, sedation, somnolence (sleep attacks), headache, confusion, hallucinations

Drug interactions: ciprofloxacin and estrogen therapy (inhibitors of CYP1A2) reduce clearance while smoking (inducer of CYP1A2) increases clearance.

43

Pramipexole

MOA

Stimulates D-2 & D-3 receptor sites

44

Pramipexole

Vs

bromocriptine

More effective than bromocriptine at reducing motor symptoms of IPD. Efficacious as monotherapy.

Reduces “Off” time associated with “Wearing-Off phenomenon”

May reduce levodopa requirements

45

Pramipexole

SE/DDI

Side Effects: dyskinesias, nausea, dizziness, sedation, somnolence (sleep attacks), headache, confusion, hallucinations, and peripheral edema which poorly responds diuretics

Drug interactions: cimetidine increases pramipexole levels by 50%.

46

Rotigotine

MOA

Non-ergot dopamine agonist formulated as a transdermal patch designed for once-daily applications which may provide more continuous stimulation of dopamine receptors.

Available in 3 strengths: 2mg/24 hrs (4.5 mg rotigotine content per system), 4 mg/24 hours (9 mg rotigotine content per system) and 6mg/23 hours (13.5 mg rotigotine content per system)

47

Rotigotine

SE

Adverse effects similar to other dopamine agonists (nausea, somnolence, dizziness) along with application site reactions (mild skin irritation, erythema, and rash)

48

Apomorphine

MOA

Stimulated D1 & D2 receptor sites

49

Apomorphine

Indicated for…

Can reliably trigger an “on” response within 4-8 minutes of injection with response lasting ~ 1 Hour

Indicated for acute, intermittent treatment of hypomobility “off” episode associated with “wearing off” and “on-off” episodes, or as an adjunct/supplemental therapy to standard levodopa therapy – typically in advanced disease

50

Apomorphine

SE/contraindications

Side Effects: dyskinesias, drowsiness, dizziness, postural hypotension, hallucinations, nausea/vomiting (may need antiemetic), skin nodules at injection site

Contains a metabisulfite preservative so contraindicated in sulfite allergies

51

COMT inhibitors

MOA





Inhibits peripheral and central catechol-O-methyltransferase (COMT)- Tolcapone
Entacapone inhibits peripheral catechol-O-methyltransferase (COMT) – no central inhibition because it does not cross BBB.
Increases levodopa bioavailability and plasma half-life.
Reduces “Off” time associated with “Wearing-Off phenomenon”
Reduces levodopa requirements, levodopa dose should be decreased ~30% upon initiating COMT inhibitor

52

COMT inhibitors

list

Tolcapone

Entacapone

53

Tolcapaone

SE

non-dopaminergic: diarrhea (delayed onset of several weeks to months); urine discoloration,  liver transaminases (requires monitoring at baseline, q2 weeks x 1 year then every month x 6 months then every 8 weeks)

dopaminergic: dyskinesias, dystonia, nausea, cramps

54

Entacapone

SE

non-dopaminergic: diarrhea (delayed onset of several weeks to months); urine discoloration, currently no reports of liver transaminase abnormalities and thus does not require monitoring

dopaminergic: dyskinesias, dystonia, nausea, cramps

55

Entacapone

dosing

200mg with each levodopa dose (does not matter if CR or regular Sinemet). In some cases, may not need to give with every dose of Sinemet (max 8 tabs/day)

56

Stalevo

What is it?

Levodopa/Carbidopa/Entacapone

57

Stalevo

indications

1) To substitute (with equivalent strength of each of the three components) for immediate release carbidopa/levodopa and entacapone previously administered as individual products.

2) To replace immediate release carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose “wearing-off” (only for patients taking a total daily dose of levodopa of 600mg or less and not experiencing dyskinesias)

58

MAO-B inhibitors

Disease modifying effect?

These drugs have been studied for a possible “disease modifying effect” however their effects in this regard has yet to be proven definitively

59

MAO-B inhibitors used in PD

Selegiline

Rasagiline

60

Selegiline

MOI/problem

Prevents degradation of dopamine in the brain through MAO-B inhibition. Selegiline metabolites (hepatic metabolism) L-amphetamine and L-methamphetamine are thought to inhibit presynaptic reuptake of dopamine.

Usefulness is confounded by low bioavailability, extensive 1st pass metabolism and production of amphetamine metabolites

61

Selegiline

Indication

Adjunctive therapy with carbidopa/levodopa, effective in the treatment of "wearing off' effect.
Less effective in "on-off' phenomenon; monotherapy for early PD (neuroprotective?).

When initiating selegiline, reduce levodopa dose by 10-30%.

62

Selegiline

DDI

SSRI (particularly fluoxetine), tricyclic antidepressants, lithium, and high dose dextromethorphan should be used with caution due to possibility of serotonin syndrome (confusion, agitation, restlessness, rigidity, hyperreflexia, shivering, fever, myoclonus, diaphoresis, nausea, diarrhea, autonomic instability, flushing, coma and occasionally death). Overall risk is low and occurrence is rare.

Meperidine use is contraindicated due to possibility of serotonin syndrome. Again the risk is low.

63

Selegiline

SE

insomnia, dizziness, nausea/vomiting, orthostatic hypotension, hallucinations

64

Selegiline ODT

chars

 Formulate delivery system that allows tablets to dissolve within seconds
 Quick dissolution and absorption via the oral mucosa allows significant bypassing of 1st pass metabolism and allows for enhancement of low-dose therapeutic effect and decreased risk of side effects
 Decreases “off” time by 2 Hours
 Concentration of amphetamine metabolites are 80-90% less than selegiline
 Peak plasma concentrations are more than twice as high & less variable with this dosing formulation
 Indicated as adjunctive therapy in patients who exhibit deterioration of response to levodopa/carbidopa therapy

65

Selegiline ODT

SE

nausea, dizziness, pain, headache, insomnia, rhinitis, dyskinesias

66

Rasagiline

MOA

Selective, irreversible MAO-B inhibitor

67

Rasagiline

Clinical use

Rasagiline can be used both on its own in early Parkinson’s disease, and as an adjunct to levodopa treatment in later stages of the disorder, where it is beneficial against end-of-dose fluctuations in motor function.

68

Rasagiline vs Selegiline

Rasagiline does not have the toxic amphetamine metabolic breakdown products of the structurally similar selegiline

Greater potency in MAO_B inhibition than selegiline

69

Rasagiline

SE

Weight loss, vomiting, anorexia, balance difficulties, orthostatic hypotension, depression, dizziness, hallucinations, sleep disorders, dyskinesias, peripheral edema