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Neurology 1- M2 > 09 10 2014 Movement disorder drugs > Flashcards

09 10 2014 Movement disorder drugs Flashcards

1
Q

Parkinson’s Disease -what is it? -age of onset? -characteristics?

A

A progressive disorder of movement that occurs most commonly in the elderly. Age of onset = 55 years old. - Resting tremor -muscle rigidity -Bradykinesai (slowness of movement) -Impairment of postural balance leading to disturbance of gait and falling.

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2
Q

What are the neurons affected by parkinson’s disease

A

loss of dopaminergic (DA) neurons in substantial nigra pars compact (SNpc) in the basal ganglia. -up to 70-80% of DA loss occurs before disease is clinically recognizable. -decrease in dopaminergic terminals in the striatum

parkinson’s disease is diagnosed at an advanced stage of cell loss

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3
Q

What happens with the loss of DA in the corpus striatum

A

DA loss = effect of acetylcholine is relatively increased.

Loss of neurons in substancia nigra = decrease signaling to striatum.

Net effect results in decreased stimulation of the motor cortex by the basal ganglia

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4
Q

Proposed cause of PD

A
  1. Genetic
  2. Environmental
  3. Oxidative stress
  4. Energy metaoblism and aging
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5
Q

Genetic Factors?

A

Mostly genes invovled in protein degradation, mitochondrial function, and response to oxidative stress.

* alpha- synuclein –> Lewy bodies

* Parkin, DJ-1, PINK 1, LRRK2

* contribution of genetic factors is rather low

MOST PD IS IDIOPATHIC

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6
Q

Environmental Factors

A

MPTP (contaminator of synthetic heronin) is metabolized to free radical MPP+ which produces oxidative stress and cell death.

MPP+ is actively transported to neurone via a dopamine transpoert.

Things that increase risk factor for Parkinson’s disease

  1. Pesticides/Herbicides
  2. hemolytic exposure

Things that decrease chance of PD

  1. coffee drinking
  2. use of anti-inflammatory
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7
Q

Where does Oxidative Stress come from?

A

Metabolism of dopamine.

-Dopamine – MAO–> DOPAC + H2O2 —Glutathione–> 2 H2O

If system is not working properly, then it can lead to the formation of radicals.

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8
Q

Energy metabolism and aging

A

Aging decreases the capacity of neurons to undergo oxidative metabolism

  • function of complex 1 in mitochondria is reduced in patients with PD
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9
Q

What are the mechanisms of treating PD

A
  1. exogenous dopamine precursor
  2. increase relase of endogenous dopamine
  3. Direct dopamine agonist
  4. Inhibitors of dopamine metabolism
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10
Q

Levodopa

A

Synthesized from tyrosine – exogenous deopmain precursor

Decarboxylation (L-amino acid decarboxylase) converts to Dopamine.

Less than 1% penetrates CNS is administered alone.

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11
Q

Absorption rate of Levadopa

A

Depends on gastric emptying, pH of gastric juice and time of exposure to degradative enzymes.

Absorbed rapidly from small intestine by active transport system.

  • competes with aromatic amino acids
  • high protein meal will delay absorption and reduce peak plasma concentration
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12
Q

Levadoopa transport to brain?

A

Levadopa–> dopamine via decarboxylase

—COMT–> 3-O Methyldopa

COMT (Catechol-O- methyltransferse) makes compoudn that is actively transported to Brain

-substrate competes with dietray protein

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13
Q

Carbidopa

A

L-aromatic amino acid inhibitor

  • does not penetrate BBB
  • increase fraction of unmetabolized levodopa
  • increases half-life of Levodopa
  • Increases plasma concentration of Levodopa
  • Allows a reduction in levodopa dosage – decrease peripheral side effects
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14
Q

Sinemet and Sinement CR

A

Levodopa + carbidopa - fixed concentration

1:4 and 1:10 where 1 = 25mg

Sustained release formulation (Sinemet CR)

* increase among of drug going into brain

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15
Q

What are the types of adverse effects associated with Levodopa Therapy?

A
  1. GI effects
  2. Cardiovascular effects
  3. CNS effects
  4. Long term effects
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16
Q

What are the GI effects associated with Levodopa treatment?

A

when given alone 80% of patients suffer the following:

  • Anorexia, Nausea, Vomitting
  • stimulation of emetic center located in brain stem outside of blood-brain barrier
  • combination with carbidopa reduces GI effects of only 20% of patients.
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17
Q

What are the GI effects associated with Levodopa treatment?

A
  • Arrhythmias
  • Postural hypotension (activation of vascular dopamine receptors)
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18
Q

What is the danger of prescribing Levodopa with nonspecific MAO inhibitor?

A

Accentuates levodopa actions and may precipitate a lifethreatening hypertensive crisis

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19
Q

What are the CNS adverse effects of Levodopa?

A

Desired:

-decrease tremor, rigidity, and bradykinesia

Undesired:

  • Pshycological distubances
    • hallucinations, confusion, anxiety
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20
Q

What is the conventional anti-psychotic agent that are effect for psychological disease but actually make parkinson’s worse?

A

Phenothiazines

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21
Q

What is another anti-psychotic medication that can be used and does not worsen parkinson’s?

A

Clozapine

“atypical” anti-psychotic

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22
Q

What are the long term effects of Levodopa therapy?

A

1. Response fluctuations

  • Endo of dose
  • On-off phenomena

2. increase side effects

  • Dyskinesias
  • Psychiatric disturbances

3. May require adjuctive therapy.

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23
Q

What is End-of Dose Deterioration?

A

Early PD: nigrostriatal dopamine system retains some capaciy to store and relase dopamine (“ buffering effect”).

After long-term use of Levodopa: “buffering effect” is lost. Patients motor state may fluctuate drmatically with each dose of levodopa –> “wearing-off- phenomena”

-dose of levodopa may improve symptoms for 1 or 2 hours before wearing off.

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24
Q

On-Off phenomena with Levodopa therapy

A

Patients fluctuate rapidly between having no apparent effects of medication (off) and having effects of medication (on).

Off periods are marked with akinesia (state of being without movement) –> improved mobililty but often marked dyskinesia.

this is probably due to the brain adapting to variations in levodopa levels (alterations in function of dopamine receptors)

25
Q

what is drug that can be used if Levodopa has caused sever off-periods and person is not responding to other measures?

A

Apomorphine

26
Q

Drug interactions with Levodopa Therapy

A

MAO -A- inhibitors : life-threatening hypertensive crisis

Pyridoxine (vit B enhances extracerebral metabolism of levodopa)

27
Q

Contraindications with Levodopa Therapy

A

Psychotic patients

Angle-closure glaucoma

Active peptic ulcer

Use with caution if history of melanoma (Levodopa is a precursor for melanin)

28
Q

What are the two types of dopamine agonists?

A

Exictatory (D1 receptor family)

Inhibitory (D2 receptor family)

-do not require to be enzymatically metabolized– elimits production of toxic metabolites ( levodopa was made outside of the CNS and had toxic effects)

29
Q

Bromocriptine

A

Ergot derivative

D2 agonist

  • well absorbed orally
  • half life of 2-3 hours
  • used in combination with levodopa/carbidopa for advanced disease to smooth on/off response fluctuations.
30
Q

Adverse Effects of Bromocriptine?

A

-Same as Levodopa

Ergot adverse effects: (vasoconstriction)

  • Pleuropulmonary fibrosis
  • retroperitoneal fibrosis
  • erythromelalgia (blockage and inflammation of blood vessels)
  • Digital vasospasm (constriction of small arteries of the finger)
31
Q

Ropinirole

A

Non-ergot derivative.

D2 agonist

Metabolized by CYP1A2 – drugs metabolized by liver will significantly reduce clearance of drug.

32
Q

Pramipexole

A

Non-ergot derivative

D3 agonist

Excreted largely unchanged in urine.

33
Q

Ropinirole and Pramipexole benefits/usage

A
  • Effective as monotherapy in patients with mild disease
  • Effective as measn of smoothing response fluctuations in patients on levodopa therapy with more advanced disease.
34
Q

Adverse effects of ropinirole and pramipexole

A

Similar to Levodopa:

  • GI effects
  • Dyskinesia
  • Orthostatic Hypotension, arrhythmias
  • hallucinations and confusion

Ergot side effects:

-uncontrollabe tendency to fall asleep at inappropriate times; requires discontinuation of medication.

35
Q

Apomorphine

A

dopamine agonist

D4 receptors

Subcutaneous injection to treat “off” episodes in patients with advanced PD.

36
Q

Apomorphine Adverse Effects

A

-Emesis (vomitting/nausea) and requires pretreatment with ANTIEMETIC TRIMETHOBENZAMIDE 3 days before itital treatment and continued for at least two months.

37
Q

Apomorphine is contradicted with what drug?

A

Antimetics of the 5HT3 receptor class –> causes severe hypotension and loss of conciousness

38
Q

MAO-B inhibitors

A

metabolize dopamine selectively

39
Q

MAO-A inhibitors

A

metabolizes norepinephrine, serotonin, and dopamine; also found in liver and GI tract

40
Q

Selegiline

A

Irriversible MAO-B inhibitor

  • retards breakdown of dopamine in the striatum without inhibiting peripheral metabolism of catecholamines
  • modest beneficial effect when used alone.
  • also used in combination with levodopa/carbidopa to decrease response fluctuations in late PD patients.
41
Q

Adverse effects of Selegiline?

A
  • accentuate motor and cognitive effects of levodopa therapy
  • Insominia, anxiety
42
Q

Selegiline should not be taken with which drugs?

A
  1. analgesic meperidine – stupor, rigidity, agitation, and hyperthermia, tramadol, methadone, cyclobenzaprine, St. John’s wort.
  2. tricyclic antidepressants OR Serotonin-reuptake inhibitors – risk of acute serotonin syndrome!
43
Q

Rasagiline

A

more selective MAO-B inhibitor

  • does not produce amphetamine metabolites
  • may prevent progression of PD in early PD.
  • use in combination with levodopa/carbidopa to decrese respone fluctuations in late PD patients.
  • Monotherapy in mild disease.
44
Q

Adverse effects of Rasagiline

A

-Accentuate adverse motor and cognitive effects of levodopa therapy

45
Q

What are drugs that should not be taken with Rasagiline?

A
  1. Analgesic meperidine – stupor, rigidity, agitation
  2. tricyclic antidepressants or serotonin reuptake inhibitors
46
Q

Rasagiline Treatment of early PD – Neuroprotective effect

A
  1. decrese synthesis of toxic metabolites
  2. neuroprotection by reducing oxidation of dopamine
47
Q

What are the 3 drugs in the Catechol-O-methyl Transferase Inhibitors

A
  1. Tolcapone (central and peripheral effects)
  2. entacapone (peripheral effects)
  3. Stalevo – levodopa/carbidopa/entacapone
48
Q

Benefits of Tolcapone and entacapone

A
  • Inhibition of COMT prolongs plasma half-life of levodopa and increases availability of levodopa in brain.
  • adjunct to levodopa/carbidopa = reduction of levodopa dose
  • approved for patients with late PD who have developed response fluctuations.
49
Q

Adverse effects of tolcapone and entacapone

A

Levodopa related dopaminergic effects

-Diarrhea, abdominal pain, sleep disturbances

50
Q

What drugs should you be aware of when using tolcapone and entacapone?

A
  • Drug interactiosn with drugs notmally metabolzied by COMT
  • concurrent with non-specific MAO inhibitor could severely limit metabolism of levodopa.
51
Q

Tolcapone

A

More potent

Half-life 2-3 hrs

ADVERSE EFFECT:

Hepatotoxicity

  • can increase aminotransferase and transaminase activity – indicator of liver damage.
52
Q

Entacapone

A

Less potent that Tolcapone

Half life= 1-2 hrs

NO incidence of hepatotoxicity and is therefore, generally prefered.

53
Q

Anti-cholinergics drugs (5):

A
  1. trihexyphenidyl
  2. benzotropine mesylate
  3. biperiden
  4. orphenadrine
  5. procyclidine
54
Q

Anti-cholinergics benefits

A
  • May improve tremor and rigidity
  • Little effect on bradykinesia
  • If fail to respond to one drug, try others.
55
Q

Adverse effects of Anti-cholinergics

A

CNS effects: drowsiness, restlessness, inattention, confusion, delusions, hallucinations, mood changers..etc.

other adverse effects:

-Dry mouth, constipation, nausea vomiting, tachycardia, increased IOP, palpitation, blurring of vision, mydriasis…etc.

56
Q

Amatadine

A

Antiviral agent

  • mechanism is unclear: increase dopamine release, blocks dopamine uptake, stimulates dopamine receptors.
  • short lived but favorably influences bradykinesia, rigidity and tremor; it also ha antidyskinetic properties.
  • used as initial therapy of mild PD and as adjunct therapy in patients on levodopa with dose-dependent fulctuations and dyskinesias.
57
Q

Adverse effects of amatadine

A
  • restlessness, hallucinations, confusion, sleep disturbance, nausea
  • overdose may cause acute toxic psychosis
  • Livedo reticularis (swelling of small veins)
58
Q

When should you be hesitant of prescribing amatadine?

A

-patients with history of seizure or heart failure

Neurology 1- M2 (22 decks)

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