Neurodegenerative and movement disorders

Question 1

Antiparkinsonias drug classifications acting on dopaminergic system

Answer 1

Dopamine precursors
Dopaminergic agonists
Selective MAO-B inhibitors
COMT inhibitors
Dopamine Facilitators

Question 2

Dopamine precurors

Answer 2

Levodopa

Question 3

Dopaminergic agonists

Answer 3

Bromocriptyne, Ropinirole, Pramipexole, Rotigotine and Apomorphine

Question 4

Selective MAO-B inhibitors

Answer 4

Selegiline, Rasagiline, Safinamide

Question 5

COMT inhibitors

Answer 5

Entacapone, Tolcapone

Question 6

dopamine facilitator

Answer 6

Amantadine

Question 7

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

Answer 7

Drugs acting on cholinergic system

Central anticholinergics

Question 8

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

Answer 8

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

Question 9

what does dopamine in the CNS activate

Answer 9

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 **

Question 10

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 _____

Answer 10

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

Question 11

LDopa is absorbed most rapidly when?

Answer 11

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

Question 12

Levodopa is always administered with?

Answer 12

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

Question 13

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?

Answer 13

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.

Question 14

Levodopa ADR

Answer 14

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

Question 15

Why is levodopa not taken with MAO inhibitors

Answer 15

can cause severe hypertensive crisis

Question 16

Whould u advise a vit supplement in parkinsonism

Answer 16

no

Question 17

Levodopa
2-5 years
5-8 years

Answer 17

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.

Question 18

Bromocriptine

Pergolide

Answer 18

Ergot derived agnoists

Question 19

Ropinirole
Pramipexole
Rotigotine

Answer 19

Nonergot agnosists

Well tolerated and safe

Question 20

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

Answer 20

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

Question 21

Dop receptor agonists used if?

Answer 21

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

Question 22

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

Answer 22

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)

Question 23

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

Answer 23

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)

Question 24

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

Answer 24

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

Question 25

Dopamine Agonists ADR

Answer 25

``` Sedation Hallucination Confusion Nausea Hypotension ```

Question 26

Apomorphine

Answer 26

Injectable dopamine agonist | Non ergot

Question 27

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

Answer 27

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

Question 28

Rasagline and Selegline

Answer 28

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

Question 29

Selegiline

Answer 29

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.

Question 30

MAO-B inhibitor ADR

Answer 30

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

Question 31

Safinamide

Answer 31

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.

Question 32

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.

Answer 32

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.

Question 33

Tolcapone and Entacapone

Answer 33

COMT inhibitors

Question 34

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)

Answer 34

``` 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. ```

Question 35

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

Answer 35

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

Question 36

COMT inhibitors ADR

Answer 36

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

Question 37

Amantadine

Answer 37

``` 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 ```

Question 38

Amantadine ADR

Answer 38

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.

Question 39

Anticholinergics

Answer 39

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

Question 40

Anticholinergics ADR

Answer 40

similar to atropine

Question 41

Treatment of huntingtons

Answer 41

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.

Question 42

Tetrabenazine (VMAT inhibitor)

Answer 42

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

Question 43

Alzheimer Rx

Answer 43

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

Question 44

Pharmacology for tics

Answer 44

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