Haf Pharm Dopamine 2008

Front 1

does dopamine cross the BBB?

Back 1

no!

Front 2

where is dopamine synthesized?

Back 2

striatum and nucleus accumbens

Front 3

describe the nigrostriatal pathway.

Back 3

substantia nigra --> striatum

Front 4

describe the mesocorticolimbic pathway.

Back 4

ventral tegmental area --> nucleus accumbens and frontal cortex

Front 5

what caused Parkinson's disease? what percentage of neurons remains and where?

Back 5

death of the nigrostriatal projection..10% of DA neurons remain in the striata

Front 6

describe the normal mechanism of the DA neuron.

Back 6

the nigrostriatal DA neuron normally has a negative input on the D2 receptor, while the cholinergic interneuron acting on a muscarinic receptor has a positive input -- both are acting on the GABA efferent in the striatum --> inhibitory action

Front 7

describe the mechanism of the diseased Parkinsons neuron.

Back 7

with Parkinson's, the DA negative input is lost --> the amount of GABA inhibition increases --> patients have less activity due to the over active GABA efferent.

Front 8

what is the Parkisonian Triad of Symtpoms?

Back 8

R - rigidity (cog wheel, increased muscle tone)
A - akinesia (bradycardia)
T- tremor (cog wheel, pill rolling) - 2/3 of patients, earlier sign of parkinsons

Front 9

What are other symptoms of Parkinsons?

Back 9

alterations in posture
mask face
shuffling gait
loss of association
hypersalivation

Front 10

What is the significance of MPTP?

Back 10

drug used in the 1970s that induced parkisonian like symptoms
- MPTP --> via MAO-B --> MPP+
- MPP+ is selective for nigrostriatal neurons --> induces parkinsonian symptoms and kills nigrostriatal neurons

Front 11

what drug inhibits MAO-B in animal models?

Back 11

selegiline

Front 12

How can the imbalance of neuronal activity in PD be corrected?

Back 12

Increase the amount of DA precursor L-DOPA

Front 13

describe L-DOPA metabolism.

Back 13

L-DOPA crosses the BBB via the LAT and is metabolized to DA via L-AAD (in the CNS)

Front 14

where is the majority of L-DOPA decarboxylated? how much is metabolized? are there side effects?

Back 14

95% of L-DOPA is metabolized in the periphery via the L-AAD enzyme reaction (the COMT reaction results in 3-O-MD production)...side effects result!

Front 15

where are the L-DOPA side effects seen and why?

Back 15

peripheral- production of DA before L-DOPA can get to the CNS
central - due to increased synthesis of DA within the CNS

Front 16

what are the peripheral toxicities and side effects caused by L-DOPA?

Back 16

nausea (CTZ trigger zone in prostrema of medulla)
orthostatic hypotension (stimulation of peripheral DA receptors - kidney)
arrythmia (stimulation of B1 receptors in the heart...low risk)

Front 17

what are the central toxicities and side effects caused by L-DOPA?

Back 17

psychotic symptoms- D2 receptors in the limbic system are overractive with increased DA (nucleus accumbens)
dyskinesia - abnormal involuntary movements in 50% of patients (tics, bobbing, rocking of trunk and extremities - titrate drug)
on off phenomenon

Front 18

describe the on-off phenomenon. where does this side effect originate?

Back 18

on phase = PD symptoms are controlled (pt may have dyskenesia)
off phase = symptoms are not controlled (pt may have dystonias)

the on-off effect is a central side effect!

Front 19

what region of the brain does increased DA result in therapeutic effects, not toxicities?

Back 19

striatum

Front 20

describe variable metabolism of DA and the on-off phenomenon.

Back 20

when enzymes such as COMT and MAO-B are inhibited, the on-off phenomenon is inhibited. when metabolic levels are maintainted and even, symptoms improve...if unequal...the on-off phenomenon persists.

Front 21

what are the main contraindications for L-DOPA?

Back 21

psychosis - already have too much DA activity
melanoma - L-DOPA is the precursor for melanin in skin
narrow angle glaucoma - due to alpha agonist at high concentrations of DA - high stimulation of alpha1 causes inability of vitreous humor to drain

Front 22

Does DA have interactions with any other drugs? If so, what drug does it interact with?

Back 22

yes = pyridoxine.
- vit B6 => enhances the extracerebral metabolism of L-DOPA as a co-factor for L-AAD
- in the periphery = B6 enhances L-AAD activity --> inc. DA levels --> nausea, cardiac arrythmias, orth.hypo.
(recall = DA doesnt cross BBB!!! so..its builds up in the periphery)

Front 23

how do nonselective MAO inhibitors (antidepressants)interact with L-DOPA?

Back 23

nonselective MAO inhibitors prevent metabolism of DA --> risk of hypertensive crisis

Front 24

can DA be administered with typical antipsychotic drugs? why?

Back 24

no! D2 blockers will antagonize therapeutic efficacy of L-DOPA

Front 25

describe the tolerance pattern of L-DOPA.

Back 25

L-DOPA = effective for 3-4 yrs.
at first- well tolerated
in time- increased intolerance to side effects-> decrease the dose
also - as neurons die off --> decreased effectiveness of L-DOPA results

Front 26

describe the range of L-DOPA effectiveness in patients.

Back 26

1/3 = good
1/3 = somewhat effective
1/3 = ineffective
(good against most features - mainly, bradykinesia and akinesia)

Front 27

what are the known mechanisms to prevent Parkinson's disease?

Back 27

1) provide more L-DOPA
2) increase the delivery of precursor DA to the CNS and inhibit metabolism of CNS DA (Carbidopa and tolcapone)
3)inhibit metabolism of central DA by MAO-B (selegiline)
4)stimulate CNS D2 receptors directly with agonist (bromocriptine, ropinirole)
5)enhance DA release from remanining terminals and inhibit reuptake (amantidine)
6)rebalance using muscarinic agonists (benzotropine)

Front 28

describe the effect of carbidopa.

Back 28

- blocks L-AAD action in the periphery, increasing the amount of L-DOPA that enters the CNS (decreasing the amount of DA in the periphery)
-prevents peripheral conversion
- L-DOPA crosses to CNS!

Front 29

what does carbidopa use result in aside from blocking L-AAD activity?

Back 29

in the periphery, COMT activity increases --> increased levels of COMT and 3-O-MD (compensatory increase)

Front 30

which drug inhibits central and peripheral L-DOPA metabolism by COMT? does it cross the BBB?

Back 30

tolcapone - crosses the BBB!! (inhibits the DA shunt pathway!)

Front 31

what are the effects of carbidopa and tolcapone?

Back 31

- reduction in >75% amount of administered L-DOPA
- peripheral side effects due to L-DOPA conversion to DA are diminished
(* dont forget - tell patients to avoid B6 use - which enhances peripheral metabolism of L-DOPA to DA)

Front 32

what are the negative effects of carbidopa and tolcapone?

Back 32

-CNS effects could be worsened because more DA is made available centrally
---> dyskinesias and psychotomimesis, on-off phenomenon
(inhibition of COMT can worsen central side effects)

Front 33

what effect does tolcapone have on the on-off phenomenon?

Back 33

- on-off metabolism is related to the variable metabolism of DA centrally
- block this metabolism = more DA is available to alleviate symptoms --> reduces doses of carbidopa and L-DOPA

Front 34

side effects of tolcapone?

Back 34

alone = diarrhea
otherwise = not much, will worsen L-DOPA side effects therefore, may need to reduce the L-DOPA dose with tolcapone

Front 35

does tolcapone effect the dosage amount of L-DOPA?

Back 35

yes. because tolcapone worsens the side effects of L-DOPA, the dose of L-DOPA may need to be reduced

Front 36

discuss the available preparations of L-DOPA.

Back 36

1) marketed as Dopar and Larodopa
2) carbidopa = marketed as Lodosyn
3) both = available in fixed ration of 1:10 and 1:4 (Sinemet)
4) cardidopa, L-DOPA, and entacapne = available as three doses of entacapone (Stalevo)
5) entacapone = popular = LOW LIVER TOXICITY!!
(combos are available)

Front 37

discuss the Parkinsonian mechanism related to the inhibition of MAO-B metabolism.

Back 37

in the CNS - drugs such as selegiline --> inhibit MAO-B metabolism ...increasing levels of DA in the CNS (MAO-A is left intact to metabolize catecholamines in the periphery and avoid HTN crisis)

Front 38

how does the inhibition of MAO-B metabolism relate to idiopathic parkinsonism?

Back 38

- may prevent conversion of some endog/exogenous substances to neurotoxic metabolites
- smokers = 40% lower risk of parkinsonism --> due to MAO-B inhibition by some component of tobacco smoke

Front 39

what are the therapeutic uses of MAO-B inhibitors?

Back 39

1) reduction in L-DOPA dose
2) reduces on-off phenomenon
3) selegiline aka Eldepryl
4) Rasagiline aka Azilect = used alone for early symptomatic tx.

Front 40

side effects/CIs of selegiline?

Back 40

- central side effects of L-DOPA are WORSENED by selegiline
- DO NOT GIVE it with non-selective MAO inhibitor --> may ppt HTN crisis!

Front 41

describe the mechanism of:
bromocriptine
ropinirole
pramipexole

Back 41

stimulate CNS D2 receptors DIRECTLY with agonist

Front 42

therapeutic uses of D2 agonists?

Back 42

allows L-DOPA dose to be reduced
alleviates on-off phenomenon
can be used in patients becoming refractory to L-DOPA

Front 43

what are the side effects and toxicities of the D2 agonists?

Back 43

peripheral effects
- nausea via action at CTZ
- hypotension
- relieve by adding a dopamine antagonist that does not cross the BBB (peripheral DA antagonist)

Front 44

how are the drugs ropinirole and pramipexole classified?

Back 44

non-ergots

Front 45

what are the advantages of non-ergots?

Back 45

can be titrated up to full dose more quickly
few GI problems
better tolerated in general
preferred for younger pts by some docs -- while L-DOPA is used for older patients with increased cognitive problems

Front 46

what are the contraindications of D2 agonists?

Back 46

psychosis
recent MI
peripheral vascular disease
peptic ulcers

Front 47

significance of dyskinesias and psychosis regarding DA2 agonists?

Back 47

central side effects!

Front 48

describe how release enhancer drugs work.

Back 48

release enhancers = enhance the DA release from the remaining, active DA terminals
- they also inhibit reuptake!

Front 49

what kind of drug is amantidine?

Back 49

release enhancer and inhibitor of DA reuptake (antiviral agent)

Front 50

what are the therapeutic uses for release enhancing drugs?

Back 50

- initial therapy
- reduce = bradykinesia, rigidity, tremor in early stages
- short lived benefits!

Front 51

side effects of DA release enhancers?

Back 51

mild =
restlessness
depression
irritability
insomnia
agitation
excitement
hallucinations
confusion
overdose =
ACUTE TOXIC PSYCHOSIS

Front 52

describe the role of muscarinic antagonisits in Parkinsonian disease. give an example of a drug of this category.

Back 52

anticholinergics = cholinergic interneuron is blocked --> rebalance --> striatal GABAergic efferent activity

Front 53

therapeutic effects of anticholingergics?

Back 53

useful combo w/L-DOPA
treat = mild Parkinsonism
(esp if tremor only)
better = tremor and rigidity (rather than bradykinesia)

Front 54

what are the central side effects and toxicities of anticholinergics?

Back 54

drowsiness
mental slowness/confusion
inattention
restlessness

Front 55

what are the peripheral side effects of anticholinergics?

Back 55

dry mouth
blurred vision
mydriasis
urinary retention
nausea
vomiting

Front 56

what are the contraindications of anticholinergics?

Back 56

prostatic hypertrophy (already has urinary ret.)
obstructive GI disease
narrow angle glaucoma

Front 57

what are the surgical therapies used to tx Parkinsonism?

Back 57

pallidotomies
thalamotomies
- predate pharm tx
- revived in 80s for pts who become refractory to drug tx.

Front 58

what kind of transplants can be done to tx Parkinsonism?

Back 58

non-neural tissue
neural tissue
stem cells (hope!)