Neuro 2 Parkinson Disease & Therapeutics

Front 1

Catacholamines include (3)

Precursor?

Rate limiting step?

Back 1

Norepineprine
Epinephrine
Dopamine

Tyrosine

oxidation of tyrosine to L-DDPA

Front 2

What do catecholamines do?

Back 2

Affect mood, attentiveness and emotion by effecting the function of point to point neurotransmission.

Front 3

Review figure 12-1

Back 3

Golan Page 186

Front 4

What is required to get DA into synaptic vesicles? (2)

Back 4

Proton ATPase to concentrate protons in the vesicle
Electropositive vesicle interior
(VMAT)

Front 5

DAT

Back 5

The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that binds the neurotransmitter dopamine; DAT provides the primary mechanism through which dopamine is cleared from synapses, transporting dopamine from the synapse into a neuron. DAT is present in the peri-synaptic area of dopaminergic neurons in areas of the brain where dopamine signaling is common.

Front 6

Once dopamine is released into the postsynaptic cleft, what may occur (2)?

Back 6

Dopamine may be reabsorbed by the presynaptic neuron or it is broken down by MAO or COMT

Front 7

Where does MAO work, CNS or PNS?

Back 7

Both CNS (MAO-B) & PNS (MAO-A)

* MAO-B is often used in the CNS, however, MAO-A retards the breakdown of ALL central and peripheral catecholamines which can be life-threatening.

Front 8

The sequential action of the COMT and MAO degrades DA to the stable metabolite __________ ____ (HVA) which is excrreted in the _______

Back 8

Homovanillic acid
urine

Front 9

_________ is expressed in the brain, liver, kidney and heart, and it inactivates catecholamines by adding a methyl group to the hydroxyl group at the 3 position of a benzene ring.

Back 9

COMT

Front 10

D1 Class receptors
vs
D2 Class receptors
(Golan page 189)

Back 10

D1 lead to increased cAMP (2 receptors 1,5)

D2 class receptors inhibits cAMP generation (3 receptors 2,3,4)

Front 11

Dopamine receptors in striatum, playing a role in motor control by basal ganglia and nucleus accumbens and olfactors tubercle.

Back 11

D1 and D2

Front 12

Dopamine receptors in anterior pituitary gland lactotrophs, regulate prolactin.

Back 12

D2

Front 13

What is required for synaptic vesicle trafficking to and fusion with the presynaptic membrane.

Back 13

Ca++

Front 14

Drugs that block dopamine ___ receptors are used to treat nausea and vomiting.

Back 14

D2

Front 15

BASAL GANGLIA
Primary input

Primary output

Back 15

Striatum (caudate and putamen)

Globus pallidus pars interna and substantia nigra pars reticula

Front 16

Cortical inputs to basal gangial are _________ and use ___________ as a transmitter.

Back 16

excitatory
glutamate

(medium spiny neurons)

Front 17

The medium spiney neurons release the inhibitory transmitter GABA and send their projections to tow downstream targets.
Direct pathway-
Indirect pathway-

Back 17

Direct pathway-(D1) stimulates movement
Indirect pathway-(D2) - inhibits the thalamus therefore inhibiting movement.

Front 18

Increased levels of dopamine in the striatum tend to activate D1 expressing neurons of the direct pathway while inhibiting the D2 expressing movement. So,

Back 18

both of these effects promote movement.

**It is the opposite in Parkinson's (it is thought that the indirect pathway is overactive- surgery to subthalamic nucleus)

Front 19

In parkinson's disease there is a selective loss of dopaminergic neurons in the

Back 19

substantia nigra pars compatcta
(70% of neurons lost by time of onset of symptoms, 95% loss on autopsy)

Front 20

Typical presentation of parkinson's diesease:

May be due to exposure to:

Back 20

Bradykinesis (slow movement)
Rigidity
Impaired postural balance
Tremor when limbs are at rest

Certain pesticides, mutations, mostly unknown multifactorial

Front 21

Treatment of Parkinson's Disease:

Current goal is:

Back 21

Mainly symptomatic control, safe, but disease will take its course especially cognitively (dimentia)

Neuroprotective and neurorestorative

Front 22

3 categories of Parkinson's Disease therapeutic treatment:

Back 22

1 DA precursors
2 DA receptor agonists
3 Inhibitors of DA degradation

Front 23

Most effective treatment for PD is:
How come DA cannot be used?

Back 23

Levodopa
DA cannot cross the BBB, but L-DOPA can is is converted to DA by AADC once in the CNS.

Front 24

Why must Levodopa be co-administered with carbidopa?

Back 24

Carbidopa will inhibit AADC so Levodopa has a chance to cross the BBB before it is made into DA, but still only 10%. However, this decreases adverse effects of peripheral DA (nausea)

Front 25

Problems with Levodopa

Back 25

Effects at early stage
Patients develop tolerance thus requiring larger doses
*Cause dyskinesias of head and trunk @ max levodopa concentrations
Chronic therapy causes adaptations in post syn neurons in striatum (pg 194 golan)

Front 26

Explain on and off periods due to Levodopa

Back 26

ON: normal to dyskinetic, shortly after administration, can be overcome by lowering dose
OFF: Periods of freezing and increased rigidity, occur as plasma levels of levodopa decrease.
Symptoms get worse over time

Front 27

Dopamine precursor: transported across BBB by neutral AA transporter and then made into DA by AADC via decarboxylation.

Back 27

Levodopa

Front 28

DA receptor agonist advantages:

Disadvantages are excessive sedation, vivid dreams, and hallucinations.

Back 28

Delay onset of "off" periods
Nonpeptide, so do not compete with Levodopa to cross BBB
Do not require AADC so remain effective late in disease process
Longer 1/2 life than Levodopa (less frequent dosing and more uniform response to drug)

Front 29

Dopamine Receptor Agonists (4):
Ergot derivatives bind to and activate postsyn dopamine receptors directly.

Back 29

Bromocriptine (ergot derivative:*n/v, edema, HTN)
Pergolide (ergot derivative:*n/v, edema, HTN)
Pramipexole (used more often than ergot derivatives)
Ropinirole (used more often than ergot derivatives)

Front 30

Clinical applications of Pramipexole &
Ropinirole, and adverse effects.

Back 30

PD
Restless Leg Syndrome
(Extrapyramidal movements, somolence, dizziness, hallucinations, dream disorder, asthenia, amnesia)
*don't use with other sedating meds

Front 31

Adverse effects and contraindications of Levodopa

Back 31

AE: Dyskinesia, heart disease, orthostatic hypotension, psychotic disorder, loss of appetite, n/v
contrain: Hx of melenoma, narrow angle glaucoma, simultaneous use of MAO inhibitors.

Front 32

Inhibitors of Levodopa or Dopamine metabolism (4): Inhibits breakdown of DA in CNS by inhibiting MAO-B or COMT, or inhibits breakdown by COMT in periphery

Back 32

Rasagiline (CNS)
Selegiline (CNS)
Tolcapone (periphery)
Entacapone (periphery)

Front 33

Misc Anti-PD medications (3):

Back 33

Amantadine
Trihexyphenidyl
Benztropine

Front 34

Amantidine is used for PD and _________.
This drug is contraindicated if there is a:

Back 34

Influenza A

Hypersensitivity to Amantidine

Front 35

Adverse effects of amantidine:

Back 35

Neuroleptic malignat syndrome, exacerbations of mental disorder, insomnia, dizziness, hallucinations, agitation, orthostatic hypotension, pertipheral edema, dyspepsia, livedo reticularis (vascular prob characterized by purplish mottling of skin)

Front 36

What are the treatments for parkinsons's disease?
(1)
(1&2)
(1,2&3)

Back 36

L-dopa
Carbidopa
Bromocriptine

bromocriptine is also marketed for amenorrhea

Front 37

Amantidine is more effective than anticholinergics and less effective than L-dopa. It is also used to treat:

Back 37

A2 influenza prophylactically