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PHarm > Neurodegenerative and movement disorders > Flashcards

Neurodegenerative and movement disorders Flashcards

1
Q

Antiparkinsonias drug classifications acting on dopaminergic system

A 
Dopamine precursors
Dopaminergic agonists
Selective MAO-B inhibitors
COMT inhibitors
Dopamine Facilitators
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2
Q

Dopamine precurors

A

Levodopa

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3
Q

Dopaminergic agonists

A

Bromocriptyne, Ropinirole, Pramipexole, Rotigotine and Apomorphine

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4
Q

Selective MAO-B inhibitors

A

Selegiline, Rasagiline, Safinamide

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5
Q

COMT inhibitors

A

Entacapone, Tolcapone

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6
Q

dopamine facilitator

A

Amantadine

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7
Q

Benztropine, Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden, orphenadrine, procyclidine,
Antihistaminics – Orphenadrine, Promethazine

A

Drugs acting on cholinergic system

Central anticholinergics

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8
Q

Leodopa is a?
It crosses the?
Converted to ? by ?

A

a levorotatory isomer of dopa and a prodrug

crosses BBB and is taken up by dopaminergic neurons

then converted to dopamine (DA) by aromatic amino acid decarboxylase (AAAD) or dopa decarboxylase to restore DA activity in the corpus striatum

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9
Q

what does dopamine in the CNS activate

A

Dopamine in the CNS interacts with postjunctional dopamine D2 and D3 receptors and activate inhibitory G proteins (Gi), inhibits adenylyl cyclase, decrease cAMP, and open **potassium channel **

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10
Q

L-Dopa
Orally absorbed and metabolized in the intestine by ______ and ____
Metabolized in the periphery (blood) by ____ and ______
Get transport back by ______ uptake or metabolized by ____ and _____

A

Orally absorbed and metabolized in the intestine by MAO and decarboxylation (~90%)

Metabolized in the periphery (blood) by COMT and decarboxylation

Get transport back by presynaptic uptake or metabolized by MAO and COMT

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11
Q

LDopa is absorbed most rapidly when?

A

absorbed rapidly from the small intestine in empty stomach

high protein food interferes with the absorption and also transport of levodopa into the CNS

should be taken in empty stomach (usually 45 minutes before a meal)

has an extremely short half-life (1-2 hours), hence causes fluctuations in plasma concentration, leading to “On-off” phenomenon

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12
Q

Levodopa is always administered with?

A

Levodopa is always administered with peripheral decarboxylase inhibitor

Ex: Carbidopa and Benserazide.
These do not cross BBB.
Carbidopa inhibits the peripheral metabolism of levodopa and increases the CNS bioavailability of the drug

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13
Q

Carbidopa and L-dopa are used in ratio of ?

Reduces the daily requirements of levodopa by approximately __?

Combining Carbidopa with Levodopa helps in decreasing peripheral side effects?

A

Carbidopa and L-dopa are used in ratio of 1:4 or 1:10
Carbidopa : L-dopa :: 25:100 mg

Reduces the daily requirements of levodopa by approximately 75%

peripheral side effects: incidence of nausea, vomiting, orthostatic hypotension and cardiac arrhythmia.

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14
Q

Levodopa ADR

A

Dyskinesias and Response Fluctuations

Therapy for more than 10 years.
- characterized by a variety of repetitive involuntary
abnormal movements (dystonia, tics, ballismus,
tremor, myoclonus, etc) affecting the face, trunk
and limb
- may be relieved by decreasing the dose of
levodopa

Psychosis: hallucinations, vivid dreams and distorted thinking (with chronic use)

Postural Hypotension (due to activation of vascular dopamine D1 receptors)

Nausea and vomiting
- attenuated if levodopa given along with carbidopa, with non-protein food, in divided doses, or with nonphenothiazine antiemetics
due to the direct effects of dopamine on the CTZ in the CNS and also on the GIT

Cardiac arrhythmia (due to dopaminergic action on the heart)

Pathologic gambling (which is more common with dopamine agonists), compulsive shopping, binge eating, hypersexual behavior, or compulsive repetitive behaviors such as endless writing, singing or talking have also been associated with levodopa therapy.

Drug holiday in the treatment helps in alleviating neurological and behavioral adverse effects

Drug holiday varies from 3 – 21 days - not recommended

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15
Q

Why is levodopa not taken with MAO inhibitors

A

can cause severe hypertensive crisis

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16
Q

Whould u advise a vit supplement in parkinsonism

A

no

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17
Q

Levodopa
2-5 years
5-8 years

A

For the first 2-5 years of treatment, a sustained response,

As disease progresses, effect from each dose become shorter (the “wearing-off” effect)

Later, more unpredictable fluctuations between mobility and immobility (the “on-off” effect).

After about 5-8 years, more dose-related clinical fluctuations and dose-related dyskinesias (chorea, dystonia).

More levodopa related -resistant motor problems & non-motor symptoms like autonomic, cognitive and psychiatric.

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18
Q

Bromocriptine

Pergolide

A

Ergot derived agnoists

19
Q

Ropinirole
Pramipexole
Rotigotine

A

Nonergot agnosists

Well tolerated and safe

20
Q

Why are dopamine receptors agonsists used as first line or as adjunct to Ldopa+carbidopa

A 
Don't require enzymatic conversion
No potential toxic metabolites
Do not compete for other substances for transport
Limited adverse effects
Lower incidence of response fluctuations
Can allow a reductiong in Ldopa dosage

BUT less effective than levodopa for motor symptoms of PD, but less dyskinesias or motor fluctuations

21
Q

Dop receptor agonists used if?

A

More On-Off phenomenon or “wearing off” or “end-of-dose” akinesia:
Disease refractory to levodopa

22
Q 
Bromocriptine and Pergolide are \_\_\_ agonists
which is more potent?
known to cause?
Bromocriptine is mainly used in?
Why was pergolide withdrawn
A

Are ergot alkaloids - D2 agonist.

Pergolide is more potent
These ergot compounds are known to cause pulmonary and retroperitoneal fibrosis.

Bromocriptine is mainly used in Hyperprolactinemia (for suppression of lactation) and Acromegaly.

Bromocriptine is still marketed in the US;
Pergolide was withdrawn associated with heart-valve fibrosis and regurgitation
More GIT symptoms (vomiting)

23
Q 
Pramipexole, Ropinirole and Rotigotine 
have a \_\_\_ and\_\_\_\_\_\_ agonist action
Delay the need for?
\_\_\_\_\_\_les frequent comparted to levodopa
\_\_\_\_\_\_\_\_\_\_\_\_\_ common ADR
A

Non-ergot derivative, have D2 and D3 agonist action

Delay the need for levodopa when used in early stages of PD, and may decrease the dose of levodopa in advanced disease

Less nausea and GI side effects; do not cause fibrosis
Dyskinesias less frequent than with levodopa

Sleep disturbance is seen as adverse effect with these drugs (sudden attacks of uncontrollable sleep)

24
Q

Pramipexole, Ropinirole & Rotigotine
Can cause nausea, lower-extremity edema and _______?

_______ disorder, manifested by pathologic gambling, excessive shopping, binge eating or hypersexuality

Are effective as monotherapy in mild to moderate ____ and also as adjunct to ______ in patients with motor fluctuations or reduce the frequency of off-periods

A

Can cause nausea, lower-extremity edema and postural hypotension, (most significantly) hallucinations - adverse effects
Impulse-control disorder, manifested by pathologic gambling, excessive shopping, binge eating or hypersexuality
Are effective as monotherapy in mild to moderate PD, and also
As adjunct to L-dopa therapy in patients with motor fluctuations or reduce the frequency of off-periods
May allow reductions in L-dopa dosage

25
Q

Dopamine Agonists ADR

A 
Sedation
Hallucination
Confusion
Nausea
Hypotension
26
Q

Apomorphine

A

Injectable dopamine agonist

Non ergot

27
Q

Apomorphine in patients with?
action within?
Prior to injection should be premedicated with?
Contraindicated with?

A

in patients with advanced PD with intermittent “off” episodes despite optimized therapy

onset of action within 10 min

prior to injection, patients should be premedicated with the anti-emetic Trimethobenzamide or Domeperidone

contraindicated with 5-HT3 receptor blockers (e.g ondansetron) →severe hypotension

28
Q

Rasagline and Selegline

A

MAO-B inhibitors

MAO–B is predominantly seen in the CNS

Selective irreversible inhibitor of monoamine oxidase B at normal doses

MAO-B enzyme responsible for degradation of dopamine and phenylethylamine.

Decrease dopamine metabolism in the CNS and prolong its action

29
Q

Selegiline

A

Used as monotherapy in early disease, it can delay initiation of levodopa treatment.
Adjunct to levodopa in advanced disease.
Selegiline can be used to treat early Parkinson’s disease, as well as, help in managing symptoms of depression.

30
Q

MAO-B inhibitor ADR

A

Dyskinesia and psychosis; mild amphetamine-like stimulating action (selegiline is metabolized to amphetamine); nausea and orthostatic hypotension

Precaution: in patients taking SSRIs, TCAs meperidine, propoxyphene, St. John’s wort & dextromethorphan. (risk of “serotonin syndrome”)

Concurrent levodopa and an inhibitor of both forms of monoamine oxidase (ie, a nonselective inhibitor) must be avoided: hypertensive crises

31
Q

Safinamide

A

Approved by the FDA
Used as add on drug to reduce response fluctuations in patients taking carbidopa levodopa
It is not effective as monotherapy for Parkinson’s disease.

32
Q

Catechol-O-methyltransferase (COMT)

Inhibition of ________ is associated with compensatory activation of other pathways of levodopa metabolism, COMT

COMT allow the conversion of L-dopa to __________ in the gut, liver and brain

3-OMD competes with levodopa for an active transport across intestinal mucosa and blood-brain barrier.

↑ed 3-OMD (3-OMD has partial agonist at dopamine receptor) have been associated with a poor therapeutic response to levodopa.

A

Catechol-O-methyltransferase (COMT) & Parkinsonism
Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, COMT
COMT allow the conversion of L-dopa to 3-O-methyldopa (3-O-MD) in the gut, liver and brain
3-OMD competes with levodopa for an active transport across intestinal mucosa and blood-brain barrier.
↑ed 3-OMD (3-OMD has partial agonist at dopamine receptor) have been associated with a poor therapeutic response to levodopa.

33
Q

Tolcapone and Entacapone

A

COMT inhibitors

34
Q

Tolcapone & Entacapone prolong the action of _______ by diminishing_______

Levodopa clearance is ________, half life of levodopa is increased.

Prevents the degradation of dopamine into 3-O-methyldopa (3-OMD)

A 
COMT inhibitors (Tolcapone & Entacapone)
Also prolong the action of levodopa by diminishing its peripheral metabolism 
Levodopa clearance is decreased, half life of levodopa is increased.
Prevents the degradation of dopamine into 3-O-methyldopa (3-OMD)
Block the conversion of L-dopa to  3-O-methyldopa (3-O-MD) in the gut, liver and brain
Reduce formation of 3-O-MD which competes with levodopa for transport into brain tissue.
35
Q

COMT inhibitors used as adjunt with?
Reduces ?
Peripherl/Central?

A

These are used as adjunct drug with levodopa who have developed response fluctuation.

Reduce the “wearing off”/“on-off” effects with Levodopa

Tolcapone is slightly more potent and has a longer duration of action.

Entacapone has only peripheral effect.

Tolcapone has both central and peripheral effects

36
Q

COMT inhibitors ADR

A

Dyskinesia, Nausea, Diarrhea (more often with Tolcapone)

Tolcapone:
Fatal Hepatotoxicity can occur; increase in liver enzyme levels
use only in patients not responding to other treatments
Monitor liver function

Entacapone:
Short acting; preferred over Tolcapone as
No risk of hepatotoxicity

37
Q

Amantadine

A 
Antiviral
increases dop function by enhancing release from presynaptic fiber and blocking uptake
inhibits NMDA receptors
Muscarinic blocker activity
Short term
Less efficacious than ldopa
38
Q

Amantadine ADR

A

Behavioral effects include restlessness, agitation, insomnia, confusion, hallucinations, and acute toxic psychosis.

Also causes livedo reticularis (reddish-blue mottling of the skin with edema around ankle) and other atropine-like adverse effects

Peripheral edema

Should be used with caution with a history of seizures or heart failure.

39
Q

Anticholinergics

A

Benztropine, Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden, orphenadrine, procyclidine

Interacts and blocks at central muscarinic receptors.

Blockade of cholinergic transmission produces effects similar to augmentation of dopaminergic transmission,

Lead to correct the imbalance in the dopamine/acetylcholine activity

40
Q

Anticholinergics ADR

A

similar to atropine

41
Q

Treatment of huntingtons

A

No causal therapy is available!
Treatment of Huntington’s disease includes
Medical therapy for hyperkinetic/choreatic movements
Monoamine‑depleting drugs (tetrabenazine, deutetrabenazine)
NMDA-receptor antagonists (e.g., amantadine)
GABA facilitatory drugs like Benzodiazepines help in reducing excessive movements.
Treatment with antipsychotics can be used to control behavioral changes. (Clozapine, Haloperidol, fluphenazine & olanzapine)
SSRIs may reduce depression, aggression, and agitation.

42
Q

Tetrabenazine (VMAT inhibitor)

A

It acts mainly as a reversible inhibitor of monoamine uptake into granular vesicles of presynaptic neurons
Weak D2 postsynaptic receptor blocker in high doses.
Tetrabenazine depletes all three monoamines, but particularly dopamine

43
Q

Alzheimer Rx

A

Symptomatic therapy can be attempted with
cholinesterase inhibitors(ChEIs)
N-methyl-D-aspartate(NMDA) antagonists (e.g.,memantine).

44
Q

Pharmacology for tics

A

Alpha agonists: Clonidine, Guanfacine
Antipsychotics: Haloperidol, Fluphenazine, Pimozide, Risperidone
Dopamine depletory agent: Tetrabenazine
Clonidine and clonazepam are sometimes useful.
Topiramate

PHarm (7 decks)

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