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Flashcards in 09 10 2014 Movement disorder drugs Deck (58):
1

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

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.

2

What are the neurons affected by parkinson's disease

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

3

What happens with the loss of DA in the corpus striatum

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

Proposed cause of PD

1. Genetic

2. Environmental

3. Oxidative stress

4. Energy metaoblism and aging

5

Genetic Factors?

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

6

Environmental Factors

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

Where does Oxidative Stress come from?

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

Energy metabolism and aging

Aging decreases the capacity of neurons to undergo oxidative metabolism

- function of complex 1 in mitochondria is reduced in patients with PD

9

What are the mechanisms of treating PD

1. exogenous dopamine precursor

2. increase relase of endogenous dopamine

3. Direct dopamine agonist

4. Inhibitors of dopamine metabolism

10

Levodopa

Synthesized from tyrosine -- exogenous deopmain precursor

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

Less than 1% penetrates CNS is administered alone.

11

Absorption rate of Levadopa

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

12

Levadoopa transport to brain?

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

13

Carbidopa

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

14

Sinemet and Sinement CR

Levodopa + carbidopa     - fixed concentration

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

 

Sustained release formulation (Sinemet CR)

 

* increase among of drug going into brain

15

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

1. GI effects

2. Cardiovascular effects

3. CNS effects

4. Long term effects

16

What are the GI effects associated with Levodopa treatment?

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.

17

What are the GI effects associated with Levodopa treatment?

-Arrhythmias

-Postural hypotension (activation of vascular dopamine receptors)

18

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

Accentuates levodopa actions and may precipitate a lifethreatening hypertensive crisis

19

What are the CNS adverse effects of Levodopa?

Desired:

-decrease tremor, rigidity, and bradykinesia

 

Undesired:

-Pshycological distubances

    -hallucinations, confusion, anxiety

20

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

Phenothiazines

21

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

Clozapine

"atypical" anti-psychotic

22

What are the long term effects of Levodopa therapy?

1. Response fluctuations

-Endo of dose

-On-off phenomena

2. increase side effects

-Dyskinesias

-Psychiatric disturbances

3. May require adjuctive therapy.

23

What is End-of Dose Deterioration?

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.

24

On-Off phenomena with Levodopa therapy

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

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

Apomorphine

26

Drug interactions with Levodopa Therapy

MAO -A- inhibitors : life-threatening hypertensive crisis

Pyridoxine (vit B enhances extracerebral metabolism of levodopa)

27

Contraindications with Levodopa Therapy

Psychotic patients

 

Angle-closure glaucoma

 

Active peptic ulcer

 

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

28

What are the two types of dopamine agonists?

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

Bromocriptine

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

Adverse Effects of Bromocriptine?

-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

Ropinirole

 

Non-ergot derivative. 

D2 agonist

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

32

Pramipexole

Non-ergot derivative

D3 agonist

Excreted largely unchanged in urine.

33

Ropinirole and Pramipexole benefits/usage

-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

Adverse effects of ropinirole and pramipexole

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

Apomorphine

dopamine agonist

D4 receptors

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

36

Apomorphine Adverse Effects

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

37

Apomorphine is contradicted with what drug?

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

38

MAO-B inhibitors

metabolize dopamine selectively

39

MAO-A inhibitors

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

40

Selegiline

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

Adverse effects of Selegiline?

-accentuate motor and cognitive effects of levodopa therapy

-Insominia, anxiety

 

42

Selegiline should not be taken with which drugs?

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

Rasagiline

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

Adverse effects of Rasagiline

-Accentuate adverse motor and cognitive effects of levodopa therapy

45

What are drugs that should not be taken with Rasagiline?

1. Analgesic meperidine -- stupor, rigidity, agitation

 

2. tricyclic antidepressants or serotonin reuptake inhibitors

46

Rasagiline Treatment of early PD -- Neuroprotective effect

1. decrese synthesis of toxic metabolites

2. neuroprotection by reducing oxidation of dopamine

47

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

1. Tolcapone (central and peripheral effects)

2. entacapone (peripheral effects)

5. Stalevo -- levodopa/carbidopa/entacapone

48

Benefits of Tolcapone and entacapone

-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

Adverse effects of tolcapone and entacapone

Levodopa related dopaminergic effects

-Diarrhea, abdominal pain, sleep disturbances

 

50

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

-Drug interactiosn with drugs notmally metabolzied by COMT

 

-concurrent with non-specific MAO inhibitor could severely limit metabolism of levodopa.

51

Tolcapone

More potent

Half-life 2-3 hrs

 

ADVERSE EFFECT:

Hepatotoxicity

- can increase aminotransferase and transaminase activity -- indicator of liver damage.

52

Entacapone

Less potent that Tolcapone

Half life= 1-2 hrs

 

NO incidence of hepatotoxicity and is therefore, generally prefered.

53

Anti-cholinergics drugs (5):

1. trihexyphenidyl

2. benzotropine mesylate

3. biperiden

4. orphenadrine

5. procyclidine

54

Anti-cholinergics benefits

-May improve tremor and rigidity

-Little effect on bradykinesia

-If fail to respond to one drug, try others. 

55

Adverse effects of Anti-cholinergics

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

Amatadine

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

Adverse effects of amatadine

-restlessness, hallucinations, confusion, sleep disturbance, nausea

-overdose may cause acute toxic psychosis

- Livedo reticularis (swelling of small veins)

58

When should you be hesitant of prescribing amatadine?

-patients with history of seizure or heart failure