CNS I Pharm - PD Drugs Flashcards

1
Q

3 major symptoms of PD

A

Akinesia – problems with or slowness in initiating movements

Resting “pill rolling” tremor – early hallmark

Rigidity/Postural Instability – most debilitating part of the disease; gets progressively worse, patients can also fall and hurt themselves

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2
Q

Pathophysiology of PD (quick)

A

DA producing neuronal cells in the SNPc die and their terminals in the striatum (C + P) also degenerate

When we lost ~75% of our DA in the striatum and 50-60% in the substantia nigra, we see symptoms

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3
Q

Compensatory Mechanisms to increase DA when 25-30% is lost

A

25-30% lost –> Passive mechanisms: 1) Tyr hydroxylase is activated to a higher extent (rate limiting step in DA synthesis, so the rate of DA synthesis increases) and 2) Uptake of DA via transporter – as neurons die, transporters are lost; so the uptake compensates by DECREASING, so that we have more DA at the synapse

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4
Q

Compensatory mechanism of replacing DA (50% lost)

A

Increased Firing Rate –> SNPc sends axons to the striatum, which then send inhibitory inputs back to the SNPc –> if there is not enough striatum activity, it fires LESS so there are fewer inhibitory inputs on the SNpc (so more DA firing! Fewer neurons but fire FASTER since there is no neg feedback)

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5
Q

Compensatory mechanism of replacing DA (> 50% lost)

A

DA receptor UPREGULATION; last ditch attempt; post-synaptic receptors in striatum upregulate to catch as much DA as possible; when we lave receptors in PD patients (radiolabel) we see an increased signal in one hemisphere)

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6
Q

DA Pathway Review

A

Cortex sends stimulatory signals to the Striatum

DA neurons from the SNpc project to striatum, activating it

Striatum, when active, sends GABA inhibitory signals to the SNpr and GPi

SNpr/GPi usually INHIBIT the THALAMUS/reticular formation/superior colliculus to prevent movement

When the active striatum sends INHIBITORY signals to the GPi/SNpr it INHIBITS the INHIBITOR and thus the thalamus is NOT inhibited and movement can occur!

There is also an indirect pathway which does the opposite, and DA from the SNpc can INHIBIT that pathway (still initiating movement)

ALSO, too much DA –> Striatum inhibits the SNpc DA neurons

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7
Q

Pathway in PD

A

The DA neurons in the SNpc are LOST and so are their inputs in the striatum

Striatum no longer active – continual inhibition of the thalamus from the GPi/SNpr –> unopposed inhibition = no movement

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8
Q

DOPAMINE AGONISTS

A

First drugs administered to NEWLY DIAGNOSED PD patients

They are given as monotherapy at first, but are NOT AS GOOD AS L-DOPA

However, they DELAY THE NEED for L-DOPA by a year or more, and they have less side effects!

As the dose is slowly increased, the patient may show symptoms of increased DA in the brain (dyskinesias - too much movement, and vomiting are most common)

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9
Q

LEVODOPA

A

Crosses the BBB unlike regular DA

Very effective at treating PD! Actively transported across BBB and gut-blood barrier

Once inside body, it is converted to DA by L-Aromatic Amino Acid Decarboxyalse

Half-life = 90 minutes

Only 1-2% of LDOPA SURVIVES FIRST PASS and GETS INTO BRAIN!!!!

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10
Q

LEVODOPA in the periphery

A

Converted to DA by LAAD and methyldopa by COMT

Too much DA in periphery TRIGGERS AREA POSTREMA (VOMIT CENTER)
Most common side effect is EMESIS

Increased DA in periphery can also act on kidneys and cause orthostatic hypotension

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11
Q

LEVODOPA in the brain

A

Converted to DA, broken down by MAO and COMT

Side effects of too much DA = DYSKINESIA (mimics huntingtons)

Too much L-DOPA in frontal lobes = PSYCHOSIS!
but DONT treat with haloperidol like we would normally for psychosis –> blocks DA in the brain in a PD patient —> won’t be able to move!

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12
Q

CARBIDOPA

A

Blocks LAAD JUST in the periphery, so more L-DOPA can get to the brain

Decarboxylase inhibitor that DOES NOT cross BBB - so only LDOPA goes to brain

No DA in the GI tract = no EMESIS!

CARBIDOPA + L-DOPA IS A VERY COMMON TREATMENT FOR PD!!!!! 8-10% more DA survives first pass

Dose has to be about 4x LESS than LDOPA alone to compensate for all the extra DA

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13
Q

High protein diet and PD?

A

Protein can compete with L-DOPA at the amino acid BBB transporter –> so less L-Dopa will get into the brain –> at least be careful when eating lots of protein!

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14
Q

Wearing off Syndrome

A

After a patient uses L-Dopa for a while, DA receptors will DOWN REGULATE

Thus, a dose of L-Dopa will not last as long or be as effective as it once was

How do we deal with this? Increase L-Dopa, Increase frequency of dosing, Switch to slow release formulas, slow degradation via COMT/MAO inhibitors (preserve L-Dopa in brain and in periphery)

EVENTUALLY all these drugs won’t help and wearing off will cause L-Dopa to be ineffective :(

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15
Q

On-Off Syndrome

A

Big problem in treating PD with L-Dopa

Usually occurs 5-7 years after initiating therapy – Drug works sometimes (on) and sometimes just doesn’t (off)

Don’t know when it happens, no rhyme or reason; increasing dose will not help

It is NOT a pharmacokinetic problem or down-regulation issue – no reason

DEEP BRAIN STIMULATION + L-Dopa may work!

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16
Q

COMT Inhibitors

A

Work to block COMT in the periphery and in the brain –> Less L-Dopa is wasted in periphery, so the bioavailability of L-Dopa is increased and more can go to the brain (normally COMT turns L-Dopa into methyldopa)

These are newer drugs (TOLCAPONE and ENTACAPONE)

Reduce the amount of L-Dopa a patient needs and therefore can be used early in PD and in fluctuating PD (on/off)

Tolcapone – hepatic necrosis risk

Enticapone - better drug, often combined with Levo + Carbidopa

17
Q

MAO Inhibitor

A

Irreversibly inhibit the breakdown of DA in the neuron

May also be neuroprotective (could potentially prevent PD in future?)

Side effects include insomnia, hallucinations, nausea; DONT give with TCAs or SSRIs –> serotonin syndrome!

Rasagiline can be added to Levo + Carbi + Enticapone

18
Q

AMANTIDINE

A

Antiviral; when it was being tested in trials, patients with PD had FEWER SYMPTOMS and MS patients had LESS FATIGUE

Drug helps increase the release of DA from nerve terminals and inhibits its reuptake!

Helps with tremor and bradykinesia

Too much = Dyskinesia

19
Q

Anticholinergics in PD

A

In the basal ganglia, DA and ACh activity compete against but balance each other out

In PD, DA is DEPLETED, so cholinergic activity increases (producing TREMOR)

Giving anticholinergic can reduce tremors and rigidity

Side effects what we would expect – dry mouth, constipation, urinary retention, sedation, dry eyes, confusion, hallucinations

20
Q

Deep Brain Stimulation

A

Should be called DBI because it INHIBITS!

Electrode is implanted into the VIM thalamus, GPi or STN

Inhibit the GPi and STN makes sense –> increases movements!!

DBS in the VIM thalamus helps CONTROL TREMORS (not so much rigidity)