parkinsons

Question 1

parkinsons epidemiology

Answer 1

-Approx 1.5 million cases of Parkinson’s in US (MC in elderly)
-Neurodegenerative disease
-Motor impairment due to loss of nigrostriatal dopamine neurons

Question 2

causes of PD

Answer 2

-Majority – unknown/idiopathic
-Small % of pts have familial parkinsonism with an autosomal dominant pattern of inheritance
-Some forms of parkinsonism may be due to viral inflammation, brain trauma, stroke, poisoning from manganese, CO, pesticide or MPTP
-Drug induced – antipsychotics

Question 3

patho of PD

Answer 3

-Dopamine deficiency in specific area of the brain called substantia nigra. Also have loss of dopamine in neostriatum in presence of intracellular Lewy bodies
-Imbalance between dopamine and acetylcholine (decrease dopamine, increase ACH)
-imbalance of two neurotransmitters leads to tremor, rigidity, and bradykinesia

-NO CURE

Question 4

Question 5

increase dopaminergic activity

Answer 5

-Increase dopamine levels (levodopa)
-Dopamine receptor agonists
-MAO inhibitors
-COMT inhibitors
-Amantadine (Symmetrel)- also for influenza

Question 6

decrease acetylcholine activity

Answer 6

-anticholinergics

Question 7

Answer 7

Question 8

Question 9

levodopa

Answer 9

-pts > 65yo
-MOA - It is the biochemical precursor to dopamine
-Levadopa alone -> 70% in gut, 30% in periphery, 1% in the brain -> take with -> carbidopa increases this amount to 20% in the brain
-Take drug more often throughout the day for better effect (rather than fewer times a day in a larger dose)

-Transported into brain by amino acid transport systems, gets converted to dopamine and can exert it therapeutic benefit

-If given alone, metabolized peripherally by dopa-decarboxylase enzyme to dopamine. To avoid this – levodopa given in combo with carbidopa (peripheral decarboxylase inhibitor)

Question 10

carbidopa/levodopa

Answer 10

-Indications: Can be used for all types of parkinsonism except if associated with antipsychotic drug therapy (can be used 1st line for older patients >65)
-Reduces amount of dopamine getting broken down in the periphery
-Take it early so you can function in day

-As disease progresses pt may get:
-Wearing off effect: duration of benefit from each dose decreases
-On-off effect: sudden, unpredictable fluctuations between mobility and immobility

-Precautions – narrow angle glaucoma, CVD, asthma, PUD

-MOA – increases dopamine levels in CNS via mechanisms previously discussed

-Available PO as immediate release or sustained release. Dose provided as mg of Carbidopa/mg of Levodopa. (ex – Sinemet 10/100 is 10mg of Carbidopa and 100mg of Levodopa)
-also available as orally disintegrating tablet

Question 11

carbidopa/levodopa ADRs and DDI

Answer 11

-CVS: Orthostatic hypotension (these pts don’t really get up quick any ways), arrhythmias
-CNS: vivid dreams, hallucinations, confusion, sleep disturbances
-GI: N,V,D, anorexia

-Motor function:
-Dyskinesia** (abnl movements of limbs, hands, trunks and tongue). Can occur in 40-90% of pts.
-dystonias

DDI
-Nonselective MAO-I – contraindicated
-Pyridoxine (Vit B6) – cofactor for dopa-decarboxylase, so may enhance the peripheral metabolism of levodopa
-Antipsychotics, BDZ, phenytoin may inhibit antiparkinsonism effects
-Food-drug interaction
-High protein meals* may compete with amino acid transport of levodopa across BBB -> Mediterranean

Question 12

dopamine agonists

Answer 12

-May be preferred to levodopa b/c have longer DOA in younger patients (<65) –
-Pts with bradykinesia and/or rigidity, postural instability/gait impairment

-Less likely to cause dyskinesia, wearing off and fluctuations
-Less effective than levodopa as monotherapy
-can add to levodopa to reduce off time, improve symptoms or manage dyskinesias
-May impair impulse control problems (gambling, hypersexuality, binge eating, overspending, excessive computer use)

-bromocriptine
-pramipexole
-ropinrole

Question 13

bromocriptine

Answer 13

-MOA – dopamine receptor agonist at D2 receptor and partial D1 antagonist and ERGOT alkaloid (not the safest, it’s a fungus)
-Uses – PD, amenorrhea, infertility, hypogonadism, prolactin-secreting adenomas and acromegaly
-Contraindications – uncontrolled HTN, IHD, PVD
-Warnings – renal & hepatic dysfunction, psychosis, CVD

-ADRs:
-CNS: h/a, dizziness, sedation, somnolence (take at bed), hallucinations
-GI – nausea, constipation
-CVS – orthostatic hypotension
-Hallucinations- LSD, vasospasms -> gangrene, spontaneous abortion

-DDI – CYP3A4 substrate and inhibitor

Question 14

pramipexole

Answer 14

-MOA – selective D2 receptor agonist. NOT ergot derivative
-Uses – PD and Primary Restless Legs Syndrome
-Warnings – Renal insufficiency
-ADRs – similar to bromcriptine, but less severe and frequent. May also cause dyskinesias. Excessive sedation.
-DDI – CNS depressants

Question 15

ropinrole

Answer 15

-MOA – selective D2 & D3 receptor agonist. NOT ergot derivative.
-D2 > D3
-Uses – PD and Restless Legs Syndrome
-Warnings – same as Mirapex
-ADRs – same as Mirapex
-DDIs – CNS depressants, CYP450 substrate and inhibitor

Question 16

MAO inhibitors

Answer 16

-selegiline
-rasagiline

Question 17

Selegiline

Answer 17

MAO inhibitors

-MOA – irreversible inhibitor of MAO-B, an enzyme which metabolizes dopamine. Little effect on MAO-A

-Uses – PD, moderate benefit in early disease. Good to use in combo w/ levodopa and other agents b/c decreases the dose needed and therefore the ADRs (esp motor fluctuations, dyskinesias, sedation and OH)
-comination with Levo – may reduce off time
-Can be used first line

-Contraindications – Use with meperidine (opiod), TCAs and SSRIs due to increased risk of serotonin syndrome

-ADRs
-CVS: Orthostatic hypotension
-CNS: hallucinations, dizziness, sedation
-GI: n,v, constipation, dry mouth
-GU: sexual dysfunction
-IN HIGH DOESES -> MAO-A interaction - tyramine containing foods -> cheese, wines, meats -> ADRs

-DDI – CYP450 substrate and inhibit

Question 18

rasagiline

Answer 18

-MAO- B inhibitor similar to selegiline (Eldepryl)
-FDA-approved as adjunct agent, but also indicated as monotherapy, while this is an off-label use for selegiline.
-5x more potent than selegiline – use lower dose

Question 19

COMT inhibitors

Answer 19

-MOA – inhibit the COMT enzyme in PNS and CNS -> increase levodopa available to cross BBB and increase levodopa and dopamine concentration in CNS

-Uses – adjunct with carbidopa/levodopa for PD, not for monotherapy, prolongs doa of levodopa
-ADRs – similar to other PD drugs, especially GI
-DDI – CYP450 inhibitor, CNS depressants, cardiac drugs metabolized by COMT

-tolcapone
-entacapone- first line

Question 20

tolacapone

Answer 20

-Warning: can cause severe hepatic toxicity. Last line agent!!!. Informed consent to patient.
-Requires LFT monitoring

-COMT inhibitor

Question 21

entacapone

Answer 21

COMT inhibitors
-first line
-Iron chelator – separate dosing
-Causes brown-orange urine discoloration
-New combo product “Stalevo® contains carbidopa, levodopa and entacapone – decreases pill burden

Question 22

adenosine antagonist

Answer 22

-MOA – selective antagonist at the adenosine A2A receptor (A2AR), but the precise mechanism by which it exerts its therapeutic effect in Parkinson’s disease is unknown
-Uses – adjunct to levodopa/carbidopa for treatment of “off”episodes
-ADR – dyskinesia, constipation, dizziness, nausea, insomonia

-Example –
-istradefylline (Nourianz)- Not recommended in pregnancy

Question 23

amantadine

Answer 23

-MOA – Exact MOA for PD is unknown. It may affect dopamine release and uptake
-Also used for influenza A
-Uses – in early stage PD in combo with Sinemet. Also an antiviral agent.
-Can be used as monotherapy, to target tremor, or added to levodopa in later disease for dyskinesias
-Warnings: renal & liver disease, seizure disorders
-ADRs – Orthostatic hypotension, CNS effects - confusion, n,v, constipation, Livedo reticularis!!
-DDI –anticholinergics may potentiate CNS side effects

Question 24

anticholinergics

Answer 24

-MOA – blocks muscarinic receptors in striatum, reducing cholinergic activity and improving dopamine/ACH balance
-Use – moderate antiparkinsonian activity. Initial or Monotherapy. Esp if tremor is main symptom and patient is younger (<65). Used in early stages of disease or as adjunct to levodopa/carbidopa therapy. Also used to treat drug-induced parkinsonism from anti-psychotic therapy
-ADRs – anticholinergic side effects. Sedation, blurred vision, dry mouth, constipation, urinary retention. Confusion, delirium and hallucinations with higher doses

-Examples in this category include
-Trihexyphenidyl (Artane) (C)
-Benztropine mesylate (Cogentin) (B)
-Procyclidine (Kemadrin) (C)
-Diphenydramine (Benadryl) (B)

Question 25

apomorphine

Answer 25

-injectable drug – if pt is having an off -> need someone else to inject them, also good for pts that awake immobile -> inject in morning
-MOA - dopamine agonist. Chemically related to morphine, but does not relieve pain and is not addictive
-Uses: treat acute episodes of hypomobility
-NO pain relief
-Precaution: sulfite sensitivity/allergy – but it is not a sulfonamide structure
-Contraindications: Do not use w/ 5ht3 receptor antagonists due to significant hypotension

-ADRs: severe n/v, must be taken in combo with an antiemetic (NOT 5HT3 antagonists b/c of DDI), hypotension, hallucinations, cardiac/cerebral ischemia, injection site reactions, sedation, flushing, dyskinesias, priapism (< 1%)
-Can use sublingually for ED

Question 26

MJ, a 56 year-old female with PD currently treated with carbidopa-levodopa comes to your office c/o of going from being fairly mobile to complete ly immobile within a few minutes.

Answer 26

1 What is your initial assessment based on this patients complaint?
Tolerance- on and off is coming sooner
Lower the dose and make it more frequent

2 How could you manage this patient at this point?

3 Write a prescription and provide patient education?

Pt says they are better but now they are having tremors- amantadine, bromo, anticholinergic